Enhancing autophagy or increasing longevity by administration of urolithins or precursors thereof

Abstract

To provide methods, compounds, and compositions useful for increasing autophagy and promoting the longevity.SOLUTION: The methods, compounds, and compositions relate to urolithins and urolithin precursors and use thereof. Certain urolithins are represented by Formula I, while certain urolithin precursors are represented by Formula IV. The urolithin may be urolithin A, urolithin B, urolithin C, or urolithin D. The urolithin precursor may be ellagic acid or an ellagitannin. The methods include in vivo, ex vivo, and in vitro uses of the compounds and compositions.SELECTED DRAWING: None

Description

Description of Related Applications

[0001] This application claims the benefit of priority to U.S. Provisional Patent Application No. 61 / 791,137, filed March 15, 2013; U.S. Provisional Patent Application No. 61 / 712,886, filed October 12, 2012; and U.S. Provisional Patent Application No. 61 / 665,137, filed June 27, 2012. [Technical Field]

[0002] The present invention relates to enhancing autophagy or extending lifespan by administering urolithins or their precursors. [Background technology]

[0003] Autophagy is a lysosomal degradation pathway in both animals and plants that is essential for development, differentiation, homeostasis, and survival. In animals, autophagy primarily functions as an adaptive mechanism to protect organisms from diverse pathologies, including infection, cancer, neurodegeneration, cardiac disease, and aging. The repertoire of routine housekeeping functions performed by autophagy includes the removal of defective proteins and organelles, the prevention of the accumulation of abnormal protein aggregates, and the clearance of intracellular pathogens. The autophagy pathway is uniquely capable of degrading entire organelles, such as mitochondria, peroxisomes, and the endoplasmic reticulum.

[0004] Several reports have shown that proteins required for autophagy induction, such as sirtuin 1, are downregulated in aging tissues; autophagy levels decrease with aging. Decreased autophagy levels are also associated with obesity, diabetes, cancer, neurodegenerative diseases, cardiovascular disease, osteoarthritis, and age-related macular degeneration.

[0005] Several compounds have been identified that stimulate autophagy, including rapamycin, resveratrol, metformin, spermidine, and glucosamine.

[0006] Urolithins are metabolites derived from ellagitannins and ellagic acid produced, for example, by mammalian colonic microflora (e.g., human colonic microflora). Urolithins are known to exhibit antioxidant activity. Summary of the Invention [Means for solving the problem]

[0007] One aspect of the invention is a method of increasing autophagy in an animal, comprising the step of administering to an animal in need thereof an effective amount of a urolithin or a precursor thereof, thereby increasing autophagy in the animal.

[0008] One aspect of the invention is a method of increasing longevity in an animal, comprising the step of administering to an animal in need thereof an effective amount of a urolithin or a precursor thereof, thereby increasing longevity in the animal.

[0009] One aspect of the invention is a method of increasing autophagy in a cell, comprising contacting the cell with an effective amount of a urolithin or a precursor thereof, thereby increasing autophagy in the cell.

[0010] One aspect of the invention is a method of increasing the longevity of a cell, comprising contacting the cell with an effective amount of a urolithin or a precursor thereof, thereby extending the longevity of the cell.

[0011] One aspect of the invention is a method of increasing autophagy in eukaryotic cells in vitro, comprising the step of contacting eukaryotic cells in vitro with an effective amount of a urolithin or a precursor thereof, thereby increasing autophagy in the eukaryotic cells in vitro.

[0012] One aspect of the invention is a method of increasing the lifespan of a eukaryotic cell in vitro, comprising the step of contacting the eukaryotic cell in vitro with an effective amount of a urolithin or a precursor thereof, thereby increasing the lifespan of the eukaryotic cell in vitro.

[0013] One aspect of the invention is a composition comprising a urolithin or a precursor thereof; and a compound selected from the group consisting of rapamycin, resveratrol, metformin, and spermidine.

[0014] One aspect of the invention is a compound of formula II: [ka] During the ceremony, X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , and X 8 is independently selected from the group consisting of H and OH; However, the compound is X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , and X 8 is H; X 1 is OH and X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , and X 8 is H; X 2 is OH and X 1 , X 3 , X 4 , X 5 , X 6 , X 7 , and X 8 is H (urolithin B); X 3 is OH and X 1 , X 2 , X 4 , X 5 , X 6 , X 7 , and X 8 is H; X 4 is OH and X 1 , X 2 , X 3 , X 5 , X 6 , X 7 , and X 8 is H; X 5 is OH and X 1 , X 2 , X 3 , X 4 , X 6 , X 7 , and X 8 is H; X 6 is OH and X 1 , X 2 , X 3 , X 4 , X 5 , X 7 , and X 8 is H; X 7 is OH and X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , and X 8 is H; X 8 is OH and X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , and X 7 is H; X 1 and X 2 is OH and X 3 , X 4 , X 5 , X 6 , X 7 , and X 8 is H; X 1 and X 5 is OH and X 2 , X 3 , X 4 , X 6 , X7 , and X 8 is H; X 1 and X 7 is OH and X 2 , X 3 , X 4 , X 5 , X 6 , and X 8 is H; X 1 and X 8 is OH and X 2 , X 3 , X 4 , X 5 , X 6 , and X 7 is H; X 2 and X 3 is OH and X 1 , X 4 , X 5 , X 6 , X 7 , and X 8 is H; X 2 and X 4 is OH and X 1 , X 3 , X 5 , X 6 , X 7 , and X 8 is H; X 2 and X 5 is OH and X 1 , X 3 , X 4 , X 6 , X 7 , and X 8 is H; X 2 and X 6 is OH and X 1 , X 3 , X 4 , X 5 , X 7 , and X 8 is H (urolithin A); X 2 and X 7 is OH and X 1, X 3 , X 4 , X 5 , X 6 , and X 8 is H; X 3 and X 4 is OH and X 1 , X 2 , X 5 , X 6 , X 7 , and X 8 is H; X 3 and X 5 is OH and X 1 , X 2 , X 4 , X 6 , X 7 , and X 8 is H; X 3 and X 6 is OH and X 1 , X 2 , X 4 , X 5 , X 7 , and X 8 is H; X 5 and X 6 is OH and X 1 , X 2 , X 3 , X 4 , X 7 , and X 8 is H; X 5 and X 8 is OH and X 1 , X 2 , X 3 , X 4 , X 6 , and X 7 is H; X 6 and X 7 is OH and X 1 , X 2 , X 3 , X 4 , X 5 , and X 8 is H; X1 , X 2 , and X 5 is OH and X 3 , X 4 , X 6 , X 7 , and X 8 is H; X 1 , X 2 , and X 6 is OH and X 3 , X 4 , X 5 , X 7 , and X 8 is H; X 1 , X 5 , and X 8 is OH and X 2 , X 3 , X 4 , X 6 , and X 7 is H; X 2 , X 4 , and X 6 is OH and X 1 , X 3 , X 5 , X 7 , and X 8 is H; X 2 , X 4 , and X 7 is OH and X 1 , X 3 , X 5 , X 6 , and X 8 is H; X 2 , X 6 , and X 7 is OH and X 1 , X 3 , X 4 , X 5 , and X 8 is H (urolithin C); X 2 , X 6 , and X 8 is OH and X 1 , X 3 , X 4, X 5 , and X 7 is H; X 2 , X 7 , and X 8 is OH and X 1 , X 3 , X 4 , X 5 , and X 6 is H; X 1 , X 2 , X 5 , and X 6 is OH and X 3 , X 4 , X 7 , and X 8 is H; X 1 , X 2 , X 5 , and X 7 is OH and X 3 , X 4 , X 6 , and X 8 is H; X 1 , X 2 , X 6 , and X 7 is OH and X 3 , X 4 , X 5 , and X 8 is H (urolithin D); X 1 , X 6 , X 7 , and X 8 is OH and X 2 , X 3 , X 4 , and X 5 is H; X 2 , X 3 , X 6 , and X 7 is OH and X 1 , X 4 , X 5 , and X 8 is H; X 2 , X 4 , X5 , and X 8 is OH and X 1 , X 3 , X 6 , and X 7 is H; X 2 , X 4 , X 6 , and X 7 is OH and X 1 , X 3 , X 5 , and X 8 is H; X 1 , X 2 , X 4 , X 5 , and X 7 is OH and X 3 , X 6 , and X 8 is H; X 1 , X 2 , X 6 , X 7 , and X 8 is OH and X 3 , X 4 , and X 5 is H; and X 1 , X 2 , X 3 , X 6 , X 7 , and X 8 is OH and X 4 and X 5 is H, Not a compound of formula II.

[0015] One aspect of the invention is a compound of formula III: [ka] During the ceremony, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8is independently selected from the group consisting of H and OR; R is H, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted monosaccharide, or substituted or unsubstituted oligosaccharide; However, the preceding compound is R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 is H; R 1 is OR and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 is H; R 2 is OR and R 1 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 is H; R 3 is OR and R 1 , R 2 , R 4 , R 5 , R 6 , R 7 , and R 8 is H; R 4 is OR and R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , and R 8 is H; R 5 is OR and R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , and R 8is H; R 6 is OR and R 1 , R 2 , R 3 , R 4 , R 5 , R 7 , and R 8 is H; R 7 is OR and R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 8 is H; R 8 is OR and R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 is H; R 1 and R 2 is OR and R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 is H; R 1 and R 5 is OR and R 2 , R 3 , R 4 , R 6 , R 7 , and R 8 is H; R 1 and R 7 is OR and R 2 , R 3 , R 4 , R 5 , R 6 , and R 8 is H; R 1 and R 8 is OR and R 2 , R 3 , R 4 , R5 , R 6 , and R 7 is H; R 2 and R 3 is OR and R 1 , R 4 , R 5 , R 6 , R 7 , and R 8 is H; R 2 and R 4 is OR and R 1 , R 3 , R 5 , R 6 , R 7 , and R 8 is H; R 2 and R 5 is OR and R 1 , R 3 , R 4 , R 6 , R 7 , and R 8 is H; R 2 and R 6 is OR and R 1 , R 3 , R 4 , R 5 , R 7 , and R 8 is H; R 2 and R 7 is OR and R 1 , R 3 , R 4 , R 5 , R 6 , and R 8 is H; R 2 and R 8 is OR and R 1 , R 3 , R 4 , R 5 , R 6 , and R 7 is H; R 3 and R 4 is OR and R1 , R 2 , R 5 , R 6 , R 7 , and R 8 is H; R 3 and R 5 is OR and R 1 , R 2 , R 4 , R 6 , R 7 , and R 8 is H; R 3 and R 6 is OR and R 1 , R 2 , R 4 , R 5 , R 7 , and R 8 is H; R 3 and R 7 is OR and R 1 , R 2 , R 4 , R 5 , R 6 , and R 8 is H; R 3 and R 8 is OR and R 1 , R 2 , R 4 , R 5 , R 6 , and R 7 is H; R 4 and R 8 is OR and R 1 , R 2 , R 3 , R 5 , R 6 , and R 7 is H; R 5 and R 6 is OR and R 1 , R 2 , R 3 , R 4 , R 7 , and R 8 is H; R 5 and R 7 is OR and R 1 , R 2 , R 3 , R 4 , R 6 , and R 8 is H; R 5 and R 8 is OR and R 1 , R 2 , R 3 , R 4 , R 6 , and R 7 is H; R 6 and R 7 is OR and R 1 , R 2 , R 3 , R 4 , R 5 , and R 8 is H; R 6 and R 8 is OR and R 1 , R 2 , R 3 , R 4 , R 5 , and R 7 is H; R 1 , R 2 , and R 3 is OR and R 4 , R 5 , R 6 , R 7 , and R 8 is H; R 1 , R 2 , and R 5 is OR and R 3 , R 4 , R 6 , R 7 , and R 8 is H; R 1 , R 2 , and R 6 is OR and R 3 , R 4 , R 5 , R7 , and R 8 is H; R 1 , R 2 , and R 8 is OR and R 3 , R 4 , R 5 , R 6 , and R 7 is H; R 1 , R 5 , and R 8 is OR and R 2 , R 3 , R 4 , R 6 , and R 7 is H; R 1 , R 7 , and R 8 is OR and R 2 , R 3 , R 4 , R 5 , and R 6 is H; R 2 , R 3 , and R 4 is OR and R 1 , R 5 , R 6 , R 7 , and R 8 is H; R 2 , R 4 , and R 6 is OR and R 1 , R 3 , R 5 , R 7 , and R 8 is H; R 2 , R 4 , and R 7 is OR and R 1 , R 3 , R 5 , R 6 , and R 8 is H; R 2 , R 5 , and R 8is OR and R 1 , R 3 , R 4 , R 6 , and R 7 is H; R 2 , R 6 , and R 7 is OR and R 1 , R 3 , R 4 , R 5 , and R 8 is H; R 2 , R 6 , and R 8 is OR and R 1 , R 3 , R 4 , R 5 , and R 7 is H; R 2 , R 7 , and R 8 is OR and R 1 , R 3 , R 4 , R 5 , and R 6 is H; R 3 , R 5 , and R 8 is OR and R 1 , R 2 , R 4 , R 6 , and R 7 is H; R 3 , R 7 , and R 8 is OR and R 1 , R 2 , R 4 , R 5 , and R 6 is H; R 6 , R 7 , and R 8 is OR and R 1 , R 2 , R 3 , R 4 , and R 5 is H; R 1 , R 2 , R 5 , and R 6 is OR and R 3 , R 4 , R 7 , and R 8 is H; R 1 , R 2 , R 5 , and R 7 is OR and R 3 , R 4 , R 6 , and R 8 is H; R 1 , R 2 , R 6 , and R 7 is OR and R 3 , R 4 , R 5 , and R 8 is H; R 1 , R 6 , R 7 , and R 8 is OR and R 2 , R 3 , R 4 , and R 5 is H; R 2 , R 3 , R 4 , and R 6 is OR and R 1 , R 5 , R 7 , and R 8 is H; R 2 , R 3 , R 5 , and R 7 is OR and R 1 , R 4 , R 6 , and R 8 is H; R 2 , R 3 , R 6 , and R 7 is OR and R 1 , R 4 , R5 , and R 8 is H; R 2 , R 4 , R 5 , and R 8 is OR and R 1 , R 3 , R 6 , and R 7 is H; R 2 , R 4 , R 6 , and R 7 is OR and R 1 , R 3 , R 5 , and R 8 is H; R 2 , R 5 , R 6 , and R 7 is OR and R 1 , R 3 , R 4 , and R 8 is H; R 2 , R 6 , R 7 , and R 8 is OR and R 1 , R 3 , R 4 , and R 5 is H; R 1 , R 2 , R 4 , R 5 , and R 7 is OR and R 3 , R 6 , and R 8 is H; R 1 , R 2 , R 6 , R 7 , and R 8 is OR and R 3 , R 4 , and R 5 is H; R 2 , R 3 , R 4 , R5 , and R 7 is OR and R 1 , R 6 , and R 8 is H; R 2 , R 3 , R 6 , R 7 , and R 8 is OR and R 1 , R 4 , and R 5 is H; R 2 , R 4 , R 6 , R 7 , and R 8 is OR and R 1 , R 3 , and R 5 is H; R 2 , R 5 , R 6 , R 7 , and R 8 is OR and R 1 , R 3 , and R 4 is H; R 1 , R 2 , R 3 , R 6 , R 7 , and R 8 is OR and R 4 and R 5 is H; R 2 , R 3 , R 4 , R 6 , R 7 , and R 8 is OR and R 1 and R 5 is H; and R 2 , R 4 , R 5 , R 6 , R 7 , and R 8 is OR and R 1 and R 3 is H, Not a compound of formula III.

[0016] One aspect of the invention is a compound of formula V: [ka] During the ceremony, X 9 , X 10 , X 11 , X 12 , X 13 , and X 14 is independently selected from the group consisting of H and OH; However, the preceding compound is X 9 , X 10 , X 11 , X 12 , X 13 , and X 14 is H; X 10 is OH and X 9 , X 11 , X 12 , X 13 , and X 14 is H; X 9 and X 12 is OH and X 10 , X 11 , X 13 , and X 14 is H; X 9 and X 13 is OH and X 10 , X 11 , X 12 , and X 14 is H; X 9 and X 14 is OH and X 10 , X 11 , X 12 , and X 13 is H; X 10 and X 13 is OH and X 9 , X 11 , X 12 , and X 14 is H; X 10 , X 11 , and X 13 is OH and X 9 , X 12 , and X 14 is H; X 9 , X 10 , X 12 , and X 14 is OH and X 11 , and X 13 is H; X 9 , X 10 , X 13 , and X 14 is OH and X 11 , and X 12 is H (ellagic acid); X 9 , X 10 , X 11 , X 13 , and X 14 is OH and X 12 is H; and X 9 , X 10 , X 11 , X 12 , X 13 , and X 14 is OH, Not a compound of formula V.

[0017] One aspect of the invention is a compound of formula VI: [ka] During the ceremony, R 9 , R 10 , R 11 , R 12 , R 13 , and R 14 is independently selected from the group consisting of H and OR; R is H, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted monosaccharide, or substituted or unsubstituted oligosaccharide; However, the preceding compound is R9 , R 10 , R 11 , R 12 , R 13 , and R 14 is H; R 10 is OR and R 9 , R 11 , R 12 , R 13 , and R 14 is H; R 9 and R 12 is OR and R 10 , R 11 , R 13 , and R 14 is H; R 9 and R 13 is OR and R 10 , R 11 , R 12 , and R 14 is H; R 9 and R 14 is OR and R 10 , R 11 , R 12 , and R 13 is H; R 10 and R 13 is OR and R 9 , R 11 , R 12 , and R 14 is H; R 9 , R 10 , and R 13 is OR and R 11 , R 12 , and R 14 is H; R 9 , R 10 , and R 14 is OR and R 11 , R 12 , and R 13 is H; R 10 , R 11 , and R 13 is OR and R9 , R 12 , and R 14 is H; R 9 , R 10 , R 12 , and R 13 is OR and R 11 and R 14 is H; R 9 , R 10 , R 12 , and R 14 is OR and R 11 and R 13 is H; R 9 , R 10 , R 13 , and R 14 is OR and R 11 and R 12 is H; R 10 , R 11 , R 12 , and R 13 is OR and R 9 and R 14 is H; R 9 , R 10 , R 11 , R 12 , and R 13 is OR and R 14 is H; R 9 , R 10 , R 11 , R 13 , and R 14 is OR and R 12 is H; and R 9 , R 10 , R 11 , R 12 , R 13 , and R 14 is OR, Not a compound of formula VI.

[0018] One aspect of the present invention is a composition comprising a first compound, which is a compound of any one of Formulas II, III, V, or VI; and a second compound selected from the group consisting of rapamycin, resveratrol, metformin, and spermidine.

[0019] One aspect of the invention is a method of increasing autophagy in a cell, comprising contacting the cell with an effective amount of a compound of any one of Formulas II, III, V, or VI, thereby increasing autophagy in the cell.

[0020] One aspect of the invention is a method for increasing the longevity of an animal, comprising administering to an animal in need thereof an effective amount of a compound of any one of Formulas II, III, V, or VI, thereby increasing the longevity of the animal.

[0021] One aspect of the invention is a method for increasing the lifespan of a eukaryotic cell in vitro, comprising contacting the eukaryotic cell in vitro with an effective amount of a compound of any one of Formulas II, III, V, or VI, thereby increasing the lifespan of the eukaryotic cell in vitro. [Brief explanation of the drawings]

[0022] [Figure 1] Figure 1 is a schematic diagram showing the four stages of macroautophagy (induction and nucleation, proliferation, fusion, and degradation). The proteins involved in each stage are indicated above each stage. The roles of p62 and LC3 are illustrated; p62 helps transport cellular material into the autophagosome by binding to LC3. [Figure 2] Figure 2 shows the structural formulas of urolithin A (UA), ellagic acid (EA), tellimagrandin (TL), punicalagin (PA), and punicalin (PB). [Figure 3] Figure 3 shows ellagic acid (EA) and its metabolites, urolithin D (UD), urolithin C (UC), urolithin A (UA), and urolithin B (UB), which are produced by the intestinal microflora of mammals, including humans. [Figure 4] Figure 4 is a series of five graphs showing the effects of ellagic acid and urolithins A, B, C, and D on C. elegans lifespan. Test agents were administered at 50 μM in DMSO. DMSO (dimethyl sulfoxide) served as a control and vehicle for the test agents. [Figure 5] Figure 5 is a series of graphs showing the lifespan of wild-type C. elegans grown in the presence of the indicated concentrations of urolithin A. [Figure 6] Figure 6 is a group of six graphs (A-F) showing lifespan analysis of wild-type and indicated mutant nematodes grown in the absence (black) or presence (gray) of 50 μM urolithin A. [Figure 7] Figure 7 is a bar graph showing the effect of urolithin A on mitochondria in C. elegans muscle. The transgenic C. elegans strain SJ4103 exhibits fluorescence due to muscle-specific expression of green fluorescent protein (GFP) targeted to the mitochondrial membrane. Mitochondria present in C. elegans muscle are indicated by increased fluorescence. Results are shown as mean ± standard error of the mean. *p=0.0014 (Student's t-test). [Figure 8] Figure 8 shows one line graph and three bar graphs showing the effects of urolithin A (UA) on basal and uncoupled respiration in young (1-day-old) and aged (10-day-old) C. elegans. (A) Basal and uncoupled respiration (FCCP) in 10-week-old control worms treated with 0.1% DMSO and 10-day-old worms treated with 30 μM urolithin A in 0.1% DMSO. (B) Representative area under the curve (AUC) for uncoupled (FCCP) respiration in 10-day-old control worms treated with vehicle (0.1% DMSO) or 30 μM urolithin A in 0.1% DMSO. Results are shown as mean ± standard error of the mean. *p<0.05 (Student's t-test). OCR is oxygen consumption rate. (C) Comparison of basal respiration between 1-day-old worms and 10-day-old worms treated with vehicle (0.1% DMSO). (D) Comparison of basal respiration between 1-day-old and 10-day-old worms treated with UA (30 μM). [Figure 9]Figure 9A is a panel of three confocal images showing the effect of urolithin A on autophagy induction in C. elegans. Figure 9B is a corresponding dot graph showing the effect of urolithin A on autophagy induction. ***p<0.001 (Student's t-test). [Figure 10] Figure 10 is a set of three graphs showing survival curves illustrating the effect of RNAi inactivation of vps-34 and bec-1 on the longevity phenotype induced by urolithin A treatment in C. elegans. Both vps-34 (B) and bec-1 (C) inhibition completely suppress the longevity phenotype observed in worms treated with urolithin A (50 μM) and those fed an empty vector (A). Survival analysis was performed using the Kaplan-Meier method, and the significance of differences between survival curves was calculated using the log-rank test. ***p<0.001 (log-rank test). [Figure 11] Figure 11 is a series of graphs showing the effects of urolithin A (UA), urolithin B (UB), urolithin C (UC), and urolithin D (UD) treatment on pharyngeal pumping in C. elegans 7 and 14 days after treatment (*p<0.05; **p<0.01; ***p<0.001). [Figure 12] Figure 12 shows three line graphs showing the effects of ellagic acid (EA), urolithin A (UA), and urolithin B (UB) treatment on the mobility of young nematodes on days 1, 3, 5, and 8 of treatment (*p<0.05; **p<0.01; ***p<0.001). [Figure 13] Figure 13 is a series of images showing time-lapse tracking of nematode mobility after treatment with ellagic acid (EA), urolithin A (UA), urolithin B (UB), urolithin C (UC), and urolithin D (UD) treatments on days 8, 14, and 16 of treatment. [Figure 14]Figure 14 is a Western blot of ModeK cells, a mouse intestinal epithelial cell line, showing the effect of urolithin A treatment on the autophagy marker ratios LC3-II / LC3-I, p62, and p-AMPKα / AMPKα. Bar graphs show the quantified fold increase in the ratio of LC3-II to LC3-I and p-AMPKα to AMPKα levels observed in the Western blot. ctl is control. [Figure 15] Figure 15 is a Western blot of primary mouse hepatocytes showing the effect of urolithin A treatment on the autophagy marker ratios LC3-II / LC3-I, p62, and p-AMPKα / AMPKα. Bar graphs show the quantified fold increase in the ratio of LC3-II to LC3-I and p-AMPKα to AMPKα levels observed in the Western blot. ctl is control. [Figure 16] Figure 16 is a Western blot of C2C12 mouse muscle cells showing the effect of urolithin A treatment on the autophagy marker ratios LC3-II / LC3-I, p62, and p-AMPKα / AMPKα. Bar graphs show the quantified fold increase in the ratio of LC3-II to LC3-I and p-AMPKα to AMPKα levels observed in the Western blot. ctl is control. [Figure 17] Figure 17 is a Western blot of human primary myoblasts showing the effect of urolithin A treatment on the autophagy marker ratios LC3-II / LC3-I, p62, and p-AMPKα / AMPKα. The bar graph shows the quantified fold increase in the ratio of LC3-II levels to LC3-I levels observed in the Western blot. ctl is the control. [Figure 18]Figure 18 is a Western blot of human primary aortic endothelial cells showing the effect of urolithin A treatment on the autophagy marker ratio LC3-II / LC3-I and protein p62. The bar graph shows the quantified fold increase in the ratio of LC3-II levels to LC3-I levels observed in the Western blot. ctl is the control. [Figure 19] Figure 19 shows Western blots of livers isolated from untreated control mice and mice receiving urolithin A at a dose of 55 mg / kg / day mixed in food. Urolithin A treatment increased the autophagy marker ratio LC3-II / LC3-I, decreased p62, and increased the ratio of p-AMPKα / AMPKα. Bar graphs show the quantified fold-increase in the ratio of LC3-II to LC3-I and the ratio of p-AMPKα to AMPKα levels observed on the Western blot. ctl is control. [Figure 20] Figure 20 is a graph showing the effect of urolithin A orally consumed at 55 mg / kg / day on the motor activity of C57BL / 6J mice. Young treated mice increased their spontaneous voluntary running on the running wheel by at least 25% over the 5-day period tested. [Figure 21] Figure 21 is a bar graph showing the effect of orally consumed urolithin A on running in aged C57BL / 6J mice. [Figure 22] Figure 22 is a bar graph showing the effect of orally consumed urolithin A on grip strength in aged C57BL / 6J mice. [Figure 23] Figure 23 is a pair of graphs showing the effect of orally consumed urolithin A on locomotion and rearing in aged C57BL / 6J mice. HFD is high fat diet; UA is urolithin A. [Figure 24]Figure 24 shows Western blots of skeletal muscle isolated from aged, high-fat diet (HFD)-untreated control mice and aged, high-fat diet mice receiving urolithin A (UA) at a dose of 50 mg / kg / day in their food. Urolithin A treatment increased the autophagy marker ratio LC3-II / LC3-I and decreased p62 levels. Bar graphs show the quantified fold increase in the ratio of LC3-II to LC3-I levels observed on Western blot. ctl is control. [Figure 25] Figure 25 shows the effect of urolithin A (UA) on autophagy in C2C12 myoblasts. Myoblasts incubated with increasing doses of UA for 24 hours showed a dose response with increased autophagy as the UA concentration increased (10 μM, 50 μM, and 100 μM), as indicated by an increased change in histograms representing LC3-B cell levels, a marker of autophagy, compared to untreated controls. [Figure 26] Figure 26 shows the effects of urolithin A (UA), urolithin B (UB), urolithin C (UC), and urolithin D (UD) on autophagy in C2C12 cells. Myoblasts incubated with 100 μM UA, UB, UC, or UD underwent increased autophagy, as indicated by an increased shift in histograms representing LC3-B cellular levels compared to untreated controls. [Figure 27] Figure 27 shows 25 compounds of the present invention. [Figure 28-1] FIG. 28-1 shows a prophetic synthetic route to the compounds in FIG. [Figure 28-2] Figure 28-2 is a continuation of Figure 28-1. [Figure 28-3] Figure 28-3 is a continuation of Figure 28-2. [Figure 28-4] Figure 28-4 is a continuation of Figure 28-3. [Figure 28-5] Figure 28-5 is a continuation of Figure 28-4. [Figure 28-6] Figure 28-6 is a continuation of Figure 28-5. [Figure 28-7] Figure 28-7 is a continuation of Figure 28-6. [Figure 28-8] Figure 28-8 is a continuation of Figure 28-7. [Figure 28-9] Figure 28-9 is a continuation of Figure 28-8. [Figure 28-10] Figure 28-10 is a continuation of Figure 28-9. [Figure 28-11] Figure 28-11 is a continuation of Figure 28-10. [Figure 28-12] Figure 28-12 is a continuation of Figure 28-11. [Figure 28-13] Figure 28-13 is a continuation of Figure 28-12. [Figure 28-14] Figure 28-14 is a continuation of Figure 28-13. DETAILED DESCRIPTION OF THE INVENTION

[0023] Autophagy is the process by which cells degrade their own components and recycle reusable amino acids and other building blocks. Such degradation is carried out by lysosomal acid hydrolases. Autophagy plays an important role in normal cell growth, development, and homeostasis and is a tightly regulated process that helps maintain the balance between the synthesis, degradation, and subsequent recycling of cellular products. Autophagy is the primary mechanism by which starving cells can reallocate nutrients from less essential to more essential processes.

[0024] During nutrient starvation, increased levels of autophagy result in the breakdown of non-essential components and the release of nutrients, ensuring that essential processes can continue. Mutant yeast cells with reduced autophagy capacity rapidly die from nutrient deprivation. A gene known as Atg7 has been linked to nutrient-mediated autophagy, and studies in mice have shown that starvation-induced autophagy is impaired in Atg7-deficient mice. Komatsu M et al. (2005) J Cell Biol. 169:425-434.

[0025] Autophagy degrades damaged organelles, cell membranes, and proteins. Failure of autophagy is thought to be an important factor in the accumulation of cellular damage and, therefore, aging.

[0026] Depending on the pathway that delivers cellular components to lysosomes, autophagy can be divided into three types: macroautophagy, microautophagy, and chaperone-mediated autophagy (CMA).

[0027] Macroautophagy Macroautophagy involves the degradation of long-lived proteins and entire organelles through multiple processes (Figure 1). Macroautophagy initiates the formation of a double-layered isolation membrane (phagophore) that surrounds the molecule and / or organelle to be degraded. The phagophore engulfs cytoplasmic components, trapping their contents and forming an autophagosome. Finally, the autophagosome fuses with a lysosome to develop into an autophagolysosome (or autolysosome), where lysosomal hydrolases digest the cargo. Microautophagy involves the direct sequestration of cytoplasmic components through invaginations or arm-like protrusions of the lysosomal membrane. Microautophagy can aid in the turnover of long-lived proteins; however, the importance and regulation of this type of autophagy remain poorly understood. Finally, chaperone-mediated autophagy is a highly selective process that targets the degradation of soluble cytoplasmic proteins.

[0028] Microtubule-associated protein 1A / 1B-light chain 3 (LC3), the mammalian homolog of yeast Atg8, is a soluble protein with a molecular weight of approximately 17 kDa that is ubiquitously distributed in mammalian tissues and cultured cells. Shortly after its synthesis, LC3 is processed by the cysteine ​​protease Atg4B to expose a C-terminal glycine residue (LC3-I). During autophagy, autophagosomes engulf cytoplasmic components, including cytosolic proteins and organelles. Simultaneously, cytosolic LC3 (LC3-I) complexes with phosphatidylethanolamine (PE) to form the LC3-PE complex (LC3-II), which is then recruited to the autophagosomal membrane (Figure 1).

[0029] p62, also known as sequestosome-1, is a ubiquitously expressed cellular protein that was identified as a novel partner of atypical protein kinase Cs (aPKCs). p62 is known to have domains that interact with and bind to ubiquitinated proteins and has been identified as a component of inclusion bodies observed in human diseases, particularly neurodegenerative diseases (e.g., Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis) and liver diseases. p62 has also been identified as an LC3-interacting protein, and an 11-amino acid sequence in mouse p62 has been shown to recognize the LC3 protein. As shown in Figure 1, LC3 binds to p62 and transports it (and any ubiquitinated proteins or cellular components bound to it) to autophagosomes, where it is degraded. Therefore, one of the hallmarks of autophagy is an increase in the LC3-II / LC3-I ratio, which occurs concomitantly with a decrease in cellular p62 levels.

[0030] Of the three described types of autophagy, macroautophagy is the most well-characterized in mammalian cells. Starvation is the most potent stimulus for macroautophagy. During nutrient depletion, macroautophagy degrades cellular components to generate amino acids, fatty acids, and carbohydrates, which can be utilized for energy production and the synthesis of essential cellular molecules. Macroautophagy is also involved in specific cytosolic reorganization during embryogenesis and postnatal development. Furthermore, macroautophagy is induced during viral or bacterial infection, hypoxia, and under various stress conditions, including radiation exposure and increased production of reactive oxygen species (ROS). In these environments, macroautophagy is essential for maintaining cellular homeostasis by facilitating the removal of damaged components. Indeed, dysfunction in macroautophagy causes premature aging and shortens the lifespan of several organisms, including nematodes, yeast, and Drosophila. Hars ES et al. (2007) Autophagy 3:93-95; Matecic M et al. (2010) PLoS Genet. 6:e1000921; Lee JH et al. (2010) Science 327:1223-1228. Conversely, upregulation of macroautophagy has been proposed to be a key mechanism underlying the lifespan-extending properties of calorie restriction. Toth ML et al. (2008) Autophagy 4:330-338; Morselli E et al. (2010) Cell Death Dis. 1:e10.

[0031] Although more than 35 Atg (autophagy-related) proteins have been identified in yeast and mammals, the precise role each AtG protein plays during autophagy has not yet been fully defined. As shown in Figure 1, the process of macroautophagy can be divided into distinct steps: induction and nucleation, proliferation, fusion, and degradation. Phase I induction is mediated by the ULK1-Atg13-FIP200 kinase complex. The regulation of the nucleation step, which consists of recruitment of AtG proteins to the phagophore assembly site, is not yet fully understood. However, vacuolar protein sorting-34 (Vps34), a class III phosphatidylinositol-3-kinase (PI3K), is required for this step. Vps34 binds to beclin 1, the mammalian homolog of yeast Atg6, and then recruits Atg14 and Vps15 (p150) to preautophagosomal structures. Elongation and expansion of the phagophore membrane require two ubiquitin-like conjugation systems, including Atg12 (which binds to Atg5) and Atg8 / microtubule-associated protein 1 light chain-3 (LC3, which binds to phosphatidylethanolamine), along with other AtG proteins such as Atg9 and Atg16. The fusion of autophagosomes with lysosomes relies on the canonical cell fusion machinery consisting of the Rab-SNARE (Soluble N-ethylmaleimide-sensitive factor Attachment protein REceptor) system and requires the presence of lysosomal membrane-associated protein-2 (LAMP-2) and UV radiation resistance-associated gene (UVRAG). Digestion of the cargo is then achieved by lysosomal hydrolases, and the degraded components are then transported to the cytoplasm by lysosomal efflux transporters such as Atg22.

[0032] Regarding the regulation of macroautophagy, the mammalian target of rapamycin (mTOR) is considered a key checkpoint linking cellular nutritional status with the level of ongoing autophagy. Under nutrient-rich conditions, mTOR is active and inhibits the ULK1-Atg13-FIP200 complex, which is required for the induction of macroautophagy. Energy deficiency leads to the inactivation of mTOR and the stimulation of AMP-activated protein kinase (AMPK), both of which induce macroautophagy. AMPK functions as an energy-sensing kinase and is activated by an increase in the ratio of cellular AMP to cellular ATP. Under such circumstances, AMPK promotes autophagy by directly activating ULK1 and by relieving mTOR-mediated inhibition of macroautophagy.

[0033] Macroautophagy can be selective for the removal of specific targets, such as peroxisomes (pexophagy), endoplasmic reticulum (reticulophagy), intracellular lipids (lipophagy), ribosomes (ribophagy), and intracellular pathogens (xenophagy). Similarly, mitochondria can be selectively targeted for degradation by macroautophagy (mitophagy).

[0034] Mitophagy: a specialized form of macroautophagy Mitophagy is a highly selective process that can facilitate the removal of dysfunctional or unnecessary mitochondria. Wang K et al. (2011) Autophagy 7:297-300. Mitochondrial membrane potential (Δψ m ) is the main trigger of mitophagy. Indeed, laser-induced photodamage of selected mitochondria in live hepatocytes is associated with a decrease in Δψ m This leads to the rapid dissipation of Δψ, followed by the rapid removal of depolarized mitochondria by mitophagy. Furthermore, oxidative injury induces a different Δψm autophagy can lead to the formation of asymmetric daughter mitochondria characterized by a lower Δψ m Apart from the degradation of damaged mitochondria under stress conditions, mitophagy is essential for mitochondrial turnover in basal conditions and during cell differentiation (e.g., maturation of reticulocytes into mature erythrocytes).

[0035] Studies of the molecular regulation of mitophagy have revealed several mitophagy-specific proteins. Parkin and Pink1 are thought to play important roles in the selective degradation of damaged mitochondria, at least under certain circumstances. Parkin is a cytosolic E3-ubiquitin ligase that is specifically recruited to dysfunctional mitochondria and is involved in their removal by mitophagy. Narenda D (2008) J Cell Biol. 183:795-803. Pink1 regulates the Δψ m It is imported into intact mitochondria via a mitochondrial-dependent process and degraded by presenilin-associated rhomboid-like (PARL) proteases. Matsuda N et al. (2010) J Cell Biol. 189:211-221. m Dissipation of mitochondrial ATP leads to the accumulation of Pink1 on the mitochondrial surface, which recruits Parkin, which then ubiquitinates outer membrane proteins, including the voltage-dependent anion channel (VDAC). It has been proposed that ubiquitin-tagged mitochondria are directly targeted to autophagic vacuoles through the interaction of the ubiquitinated protein with the autophagosome marker LC3 (Atg8). Furthermore, Parkin can derepress Beclin 1 by ubiquitinating the inner mitochondrial membrane and the apoptosis-regulating protein B-cell lymphoma-2 (Bcl-2).

[0036] Recent findings also suggest that opening of the mitochondrial permeability transition pore (mPTP) may be necessary for the selective removal of damaged mitochondria. Opening of the mPTP causes a rapid increase in the inner membrane permeability to solutes with molecular weights up to 1500 Da. This leads to mitochondrial depolarization, activation of the mitochondrial ATPase (i.e., the reverse ATP synthase), and swelling and rupture of the outer membrane. Δψ after the permeability transition m A decrease in Δψ targets individual mitochondria for degradation. m The decrease in ATP and activation of macroautophagy are blocked by cyclosporin A, an inhibitor of the mPTP component cyclophilin D. Furthermore, starvation fails to induce macroautophagy in cyclophilin D-deficient mouse cardiomyocytes, whereas autophagy is enhanced in cardiac cells from mice overexpressing cyclophilin D, even under fed conditions. Sirtuin-3 (SIRT3), a nicotinamide adenine dinucleotide (NAD)-dependent deacetylase, appears to be critically involved in regulating mPTP through regulation of cyclophilin D.

[0037] Similar to the mPTP, the apoptotic proteins Bnip3 (Bcl-2 and adenovirus E1B 19-kDa-interacting protein-3) and Nix (Nip3-like protein X) are thought to induce selective mitophagy through mitochondrial depolarization. Furthermore, Bnip3 can induce mitophagy by competitively disrupting the inhibitory interaction between Bcl-2 and Beclin 1. Nix associates with the mitochondrial membrane and directly interacts with LC3 (Atg8).

[0038] Although the molecular control of mitophagy is still not fully understood, the mTOR / AMPK pathway has been proposed to be a key checkpoint. In addition to stimulating mitochondrial removal by autophagic pathway, AMPK stimulates mitochondrial biogenesis by enhancing the activity of sirtuin-1 (SIRT1) and its downstream target, PGC-1α. Therefore, through AMPK activity, mitophagy and mitochondrial biogenesis are coordinately regulated to maintain a healthy and functional mitochondrial pool in cells.

[0039] Lipophagy is a recently recognized alternative pathway of lipid metabolism in which intracellular lipid droplets, triglycerides, and cholesterol, are engulfed by autophagosomes and delivered to lysosomes for degradation by acid hydrolases, releasing free fatty acids. Lipophagy thus functions to regulate intracellular lipid storage, cellular levels of free lipids, including fatty acids, and energy homeostasis.

[0040] Xenophagy is a recently recognized defense mechanism against various types of intracellular pathogens, including Mycobacterium tuberculosis, Salmonella typhimurium, Legionella pneumophila, Brucella spp., Chlamydia spp., Coxiella burnetti, Listeria monocytogenes, Shigella flexneri, Rickettsia spp., Mycobacterium marinum, Burkholderia spp., and Francisella tularensis.

[0041] Microautophagy involves the direct engulfment of cytoplasm by lysosomes through invagination, protrusion, or septation of the lysosomal limiting membrane.

[0042] Chaperone-mediated autophagy Chaperone-mediated autophagy (CMA) involves only proteins with a consensus peptide sequence that can be recognized by the binding of the hsc70-containing chaperone / cochaperone complex. The CMA substrate / chaperone complex then migrates to the lysosome, where the CMA receptor, lysosome-associated membrane protein type-2a (LAMP-2A), recognizes the CMA substrate / chaperone complex. The protein is unfolded and translocated across the lysosomal membrane with the assistance of lysosomal hsc70 on the other side. Thus, CMA substrates are translocated across the lysosomal membrane sequentially, whereas in macroautophagy and microautophagy, CMA substrates are engulfed or sequestered en masse. Furthermore, CMA degrades only certain proteins, not organelles.

[0043] Examples of therapeutic indications for increased autophagy The compounds, compositions, and methods of the present invention can be used to treat and prevent any of the following therapeutic indications for increased autophagy:

[0044] Autophagy protects organisms from metabolic stress Nutrient deprivation, growth factor deprivation, and hypoxia can induce metabolic stress, leading to the induction of autophagy and the generation of free amino acids and fatty acids, which can be recycled cell-autonomously and used: 1) for the de novo synthesis of proteins important in stress responses, and 2) to fuel the TCA cycle to maintain ATP function. The importance of this process is demonstrated by the inability of mice and nematodes lacking ATG proteins, which are important in autophagy, to tolerate starvation. Thus, the critical role of autophagy is the mobilization of intracellular energy resources to meet the cellular and organismal demands for metabolic substrates.

[0045] Induction of autophagy for cardiac therapy Cardiomyocyte function and survival are critically dependent on the presence of a basal level of cardiomyocyte autophagy. Autophagic recycling of damaged cellular components under nutrient-rich conditions constitutes a primary means of protein and organelle quality control, removing defective (e.g., misfolded or oxidized) proteins and dysfunctional organelles from cells. This fact is illustrated by the observation that abrogation of the autophagy pathway in the adult heart by conditional inactivation of the Atg5 or Atg7 genes leads to the rapid development of cardiac hypertrophy, left ventricular dilation, and reduced cardiac output.

[0046] Danon disease, a condition characterized by severe progressive myopathy, results from incomplete fusion of autophagosomes and lysosomes. Disruption of Atg5 during early cardiac development induces intrauterine abnormalities and embryonic lethality. At the other end of the age spectrum, an age-related decline in the efficiency of autophagy clearance can contribute to the progressive accumulation of defective proteins and organelles, ultimately leading to functional deterioration over time. Normal aging is accompanied by a decline in cardiac function, primarily due to impaired relaxation during diastole. Various formulations of calorie restriction (CR) can extend lifespan and improve left ventricular relaxation function; the underlying mechanism is thought to be induction of autophagy. Collectively, these findings highlight the crucial role of cardiomyocyte autophagy as a mechanism for monitoring and quality control of proteins and organelles, essential for survival.

[0047] Autophagy can improve skeletal muscle function under muscle atrophy Skeletal muscle adapts its capacity to the level of load and use, and central to this adaptation is the controlled remodeling of muscle fibers through degeneration or regeneration.

[0048] When muscles are not in use, muscle atrophy occurs, resulting in a decrease in muscle performance. This atrophy has been shown to be caused by increased levels of oxidative stress in disused muscles. Attenuation of this oxidative stress can result in reduced atrophy.

[0049] The autophagy process, specifically mitophagy, is important for removing damaged mitochondria and reducing the impact of increased oxidative stress on muscle functional capacity. A failure of the autophagy process has been shown to be a key factor in muscle disuse atrophy due to the inability to remove damaged mitochondria. This reduction in mitochondrial turnover leads to the accumulation of dysfunctional tissue, resulting in muscle damage.

[0050] Preservation of autophagy function during aging can ameliorate sarcopenia Skeletal muscle atrophy and muscle weakness are important health problems and can result from exercise immobility, disuse, injury, starvation, and aging. In particular, aging is inevitably accompanied by a loss of muscle mass and strength. This condition, known as sarcopenia of aging, has important implications for an individual's health and influences the severity of frailty. Furthermore, muscle weakness is a strong predictor of disability and mortality, and generalized weakness often leads to loss of independence, affecting an individual's quality of life and imposing a high burden on healthcare costs. In addition to aging, skeletal muscle can undergo significant atrophy following disuse.

[0051] Sarcopenia is characterized by the gradual loss of muscle protein. The size of stable postmitotic tissues, such as skeletal and cardiac muscles, is controlled by protein turnover, and skeletal muscle is affected by the balance between protein synthesis and degradation, as well as the turnover of contractile proteins. An important factor affecting the development of sarcopenia is the imbalance between the rates of protein synthesis and degradation. Protein degradation in skeletal muscle cells is essentially mediated by the activity of two highly conserved pathways: the autophagy-lysosomal pathway and the ubiquitin-proteasome pathway.

[0052] Recent studies have shown that impaired autophagy in ATG7-null muscle is characterized by muscle atrophy, weakness, and myofiber degeneration. Consequently, autophagy has been shown to be essential for muscle fiber maintenance and the clearance of damaged proteins and denatured organelles.

[0053] Autophagy, which is activated when skeletal muscle is under nutritional stress (e.g., metabolic stress), is involved in the catabolic condition and degradation of macromolecules and organelles. Catabolic pathways are enhanced during exercise to provide muscles with energy and substrates for continued contraction. Evidence suggests that the oxidation rates of amino acids (relatively small molecules) and glucose increase during endurance exercise, and that increased energy expenditure may require the induction of autophagy. Autophagy has been shown to be necessary for muscle fiber maintenance and the elimination of damaged proteins and denatured organelles.

[0054] Light exercise has been shown to improve muscle function and reduce the decline in muscle function observed in sarcopenia. These clear benefits are at least in part due to exercise-induced improvements in the autophagy process. In aging mice, the autophagy proteins LC3-II, beclin-1, ATG7, and MuRF-1 significantly decrease in muscle with age. However, mice undergoing a training regimen during the aging process show a significant reduction in the loss of these autophagy proteins. In overweight elderly women, light exercise has been shown to increase the transcription levels of the autophagy regulators LCB3, Atg7, and LAMP-2, thereby improving the autophagy process. Therefore, preservation of autophagy may play an important role in skeletal muscle cell homeostasis and optimal mitochondrial turnover in aging muscle.

[0055] Age-related attenuation of autophagy has been shown, resulting in a decrease in the efficiency of protein degradation and clearance of damaged organelles. The reduction in proteolytic activity is thought to be responsible, at least in part, for the accumulation of damaged cellular components in nearly all tissues of aging organisms.

[0056] Improving autophagy as a therapeutic target for myodegenerative diseases Muscular dystrophies are a group of genetic, inherited muscle diseases characterized by abnormalities in muscle proteins. These abnormalities result in progressive skeletal muscle damage accompanied by myofiber necrosis and chronic local inflammation, leading to replacement of muscle fibers with connective and adipose tissue. In the most severe form of these diseases, Duchenne muscular dystrophy (DMD), persistent and progressive skeletal muscle damage leads to complete paralysis and death of the patient, usually due to respiratory and / or cardiac failure.

[0057] Current treatment protocols based on corticosteroid administration result in some delay in disease progression but are associated with severe side effects. Therefore, there is an active search for alternatives to corticosteroids, or at least, treatments that can function as corticosteroid-sparing agents, and the biological mechanisms associated with skeletal muscle homeostasis are being explored to identify new targets.

[0058] Autophagy has emerged as a key process limiting muscle damage. Inhibition or alteration of autophagy contributes to muscle fiber degeneration, resulting in the accumulation of abnormal organelles. Mutations that inactivate Jumpy, a phosphatase that counteracts VPS34 activation for autophagosome formation and reduces autophagy, are associated with centronuclear myopathy. This finding suggests that imbalanced autophagy is the etiology of muscle degeneration. Similarly, hyperactivation of Akt as a result of muscle-specific deletion of the mammalian target of rapamycin (mTOR) results in the inhibition of autophagy and a muscle phenotype similar to that observed in muscular dystrophies. The effectiveness of autophagy modulation as a therapeutic strategy has been demonstrated in a mouse model of Ulrich myopathy, characterized by defective autophagy and the accumulation of dysfunctional organelles. Forced reactivation of autophagy in these animals resulted in a beneficial therapeutic response.

[0059] In vivo and ex vivo analysis has shown that autophagy is defective in both human (DMD) and mouse (mdx) muscular dystrophy, and that this defect contributes to the pathogenesis of the disease.Muscle biopsies obtained from DMD patients have been shown to have significantly lower levels of LC3II and significant accumulation of p62, a protein known to be incorporated into autophagosomes and efficiently degraded, compared to tissue obtained from unaffected control individuals.

[0060] A low-protein diet has been shown to induce prolonged autophagy in mice. In DMD mice fed a low-protein diet, autophagy induction leads to improved and controlled disease progression. Significant improvements in muscle function have been observed, along with improved overall tone, reduced muscle fibrosis, decreased collagen deposition, decreased accumulation of damaged organelles, and decreased apoptosis of muscle fibers.

[0061] This indicates that the induction of autophagy is a critical homoeostatic mechanism that is disrupted in dystrophic muscle, and suggests that novel therapeutic approaches targeting the reactivation of autophagy may be a valuable strategy for reducing muscle damage in DMD.

[0062] Autophagy protects the liver from oxidative stress and disease During liver diseases such as cancer and cirrhosis, the liver can experience tissue hypoxia, a process that induces autophagy, which, when inhibited, has been shown to cause increased apoptosis of hepatocytes.

[0063] Alpha-1 antitrypsin deficiency, the most common genetic cause of human liver disease, results in severe chronic inflammation and ultimately carcinogenesis. In this disease, a point mutation occurs in alpha-1 antitrypsin Z (ATZ), which leads to improper folding and accumulation of aggregates. Deletion of ATG5 in hepatocyte cell lines results in the accumulation of mutant ATZ protein, demonstrating the important role of autophagy in reducing the effects of liver disease.

[0064] Autophagy is important in limiting ischemia-reperfusion injury As patients age, they become more susceptible to primary and secondary hepatic malignancies, which are amenable to surgical resection and transplantation. Although elderly patients may be treated surgically, the aging liver has significantly reduced repair capacity after the ischemia and reperfusion injury associated with these surgeries.

[0065] Ischemic preconditioning is the only promising approach to improve the outcome of liver surgery, but its beneficial effects are limited to young patients. To date, no therapeutic strategy exists that can prevent age-related ischemia and reperfusion injury.

[0066] Decreased autophagy has been observed in aged cells exposed to severe stress, such as ischemia and subsequent reperfusion. Studies have shown that overexpression of autophagy genes in aged mouse livers increased autophagy and prolonged hepatocyte survival after ischemia and reperfusion. Therefore, defective autophagy has been shown to be a causative mechanism of age-related liver reperfusion injury, and enhancing autophagy has been shown to have a therapeutic effect and reduce age-related liver ischemia-reperfusion injury.

[0067] Autophagy in intestinal epithelial cells as a therapeutic target The intestinal epithelium directly interacts with a diverse bacterial community, including benign commensals, opportunistic pathogens, and overt pathogens, and thus represents the first line of defense against bacterial invasion of host tissues. One strategy used by epithelial cells to defend themselves involves secreting antimicrobial proteins. Unfortunately, there are several enteric pathogens, including Salmonella tyhpimurium or opportunistic invasive commensals (e.g., Enterococcus faecalis), that are able to evade this first line of defense and invade epithelial cells.

[0068] Autophagy is essential for the recognition and degradation of intracellular pathogens and has been shown to function as an innate barrier against infection. In cell culture, autophagy has been shown to limit the replication of certain bacterial species.

[0069] Autophagy has been shown to play a key role in intestinal immune homeostasis through genetic studies of inflammatory bowel disease (IBD), a chronic inflammatory disease of the intestine that results from dysregulated interactions with the resident microbiota.

[0070] In recent years, polymorphisms in genes in the autophagy pathway have been shown to be associated with Crohn's disease (CD). Crohn's disease is a chronic form of IBD that can affect any part of the gastrointestinal system, but is usually found in the colon or terminal ileum. The average age of onset in humans is 27 years, and it usually exists throughout an individual's normal lifespan. Crohn's disease is characterized by severe colitis, strictures, and perianal fistulas, and typically requires surgery.

[0071] The chronic inflammatory process typical of CD requires intensive interactions between intestinal epithelial cells and immune cells, resulting in an exacerbated immune response to the gut microbiota, characterized by an abnormal expansion of Th17 cells, which play a key role in autoimmunity, and a downregulation of Treg cells, which are important for regulating the immune response.

[0072] In recent years, intestinal epithelial cell autophagy has been shown to be essential for mammalian intestinal defense against invasive bacteria. Autophagy in epithelial cells protects against the spread of invasive bacteria. After oral infection with the invasive pathogens Salmonella typhimurium and Enterococcus faecalis, mouse epithelial cells activate autophagy as a result of exposure to these pathogens. Autophagy has been shown to be essential for limiting the extraintestinal spread of S. typhimurium. This indicates that autophagy is an important epithelial cell-autonomous mechanism of antibacterial defense that protects against the spread of intestinal bacteria.

[0073] The present invention provides know-how for the use of compounds including urolithins and their precursors as enhancers of autophagy for administration to and treatment of individuals with inflammatory bowel disease (IBD) or Crohn's disease (CD) and in need of increasing autophagy levels in intestinal epithelial cells to treat IBD or CD.

[0074] Autophagy is important in the aging myocardium The impact of autophagy induction on improving the outcome of ischemic injury and muscle maintenance makes it particularly relevant for myocardial maintenance and protection from injury. Myocardium undergoes a progressive decline in mitochondrial function, similar to that observed in skeletal muscle, which leads to increased reactive oxygen species and an increased accumulation of dysfunctional organelles. Clearance of these damaged organelles by autophagy is important for maintaining myocardial function. Because autophagy decreases with age, promoting autophagy may help protect myocardial function.

[0075] Myocardium is also severely exposed to ischemic episodes during myocardial infarction. The level of myocardial injury resulting from these ischemic episodes strongly depends on the ability of cells to mount an efficient autophagy response to eliminate damaged organelles. In aging animals, an incomplete autophagy response leads to increased myocardial injury after an ischemic event. Therefore, promoting autophagy during these acute events may help protect the myocardium from injury.

[0076] Autophagy is important in inflammatory processes Due to the role of autophagy in eliminating dysfunctional organelles, abnormalities in this process lead to the accumulation of necrotic cellular debris and the induction of apoptosis. Autophagy also plays an important role in the defense of organisms against pathogenic microorganisms by inducing their degradation. Furthermore, autophagy plays an important role in trafficking events that activate innate and adaptive immunity.

[0077] Autophagic clearance of apoptotic corpses is crucial for blocking danger signals that can trigger inflammatory responses. In a dysfunctional autophagy response in which apoptotic clearance is insufficient, the resulting induction of inflammation can overcome tolerance to self-antigens and lead to autoimmune diseases such as systemic lupus erythematosus. Therefore, induction of autophagy may help reduce inflammatory responses and the development of autoimmune diseases.

[0078] Application of autophagy to liver disease treatment Several characteristics of hepatocytes and the liver as a whole make this organ particularly dependent on autophagy. Hepatocytes are normally quiescent, but retain the ability to rapidly enter the cell cycle in the event of liver tissue loss due to injury or surgical resection, making the liver quite unique in its repair capacity. This lack of cell turnover makes hepatocytes particularly vulnerable to the effects of impaired autophagy, as long-lived cells accumulate high levels of damaging organelles, protein aggregates, etc., which are normally eliminated by autophagy. This can lead to cellular injury and potentially transformation.

[0079] Lipid metabolism in hepatocytes The liver serves as the second largest reservoir of lipids in the body after adipose tissue. Hepatocytes are the major cellular reservoir of neutral lipids in the form of triglycerides (TG) and cholesterol esters, contained in specialized organelles called lipid droplets (LDs). Autophagy mediates the degradation of intracellular LD stores through the process of lipophagy, allowing hepatocytes to rapidly mobilize their lipid stores upon metabolic demand. Decreased hepatocyte autophagy results in a significant increase in hepatic TG and cholesterol content, indicating that lipophagy limits hepatic lipid accumulation in vivo. Lipophagy also regulates cellular energy homeostasis by providing free fatty acids (FFA) through the breakdown of TG, which subsequently drives mitochondrial β-oxidation and cellular ATP production. The autophagosomal protein LC3, which is crucial for autophagosome membrane formation, has been shown to associate with LDs.

[0080] Autophagy protects against liver disease Serpina1 / α1-antitrypsin deficiency (ATD) is the most common genetic cause of pediatric human liver disease. This disease is caused by homozygosity for the Z allele of SERPINA1 / α1-antitrypsin, a point mutation called SERPINA1-Z, which predisposes the hepatic glycoprotein SERPINA1 to misfolding, polymerization, and aggregation. The mutant SERPINA1-Z protein accumulates in hepatocytes, and SERPINA1 levels in blood and body fluids are reduced to 10–15% of normal levels. Accumulation of mutant SERPINA1-Z in the endoplasmic reticulum (ER) of hepatocytes results in gain-of-function liver injury. The autophagy pathway has been shown to be involved in the intracellular degradation of SERPINA1-Z aggregates and macromolecules.

[0081] The drug carbamazepine, known to induce autophagy, has recently been shown to be effective in cell-based and mouse models of ATD. Carbamazepine increased the autophagic degradation of SERPINA1-Z in cultured cells and, when administered orally to the PiZ mouse model of ATD, reduced the liver burden of SERPINA1-Z. Furthermore, autophagy induction reduced liver fibrosis. Therefore, drugs that enhance autophagy are attractive candidates for ameliorating the liver disease that develops in some ATD patients.

[0082] The present invention provides know-how for using compounds including urolithins and their precursors as enhancers of autophagy to treat individuals with ATD who are in need of increased levels of autophagy in the liver and hepatocytes to reduce liver toxicity.

[0083] Autophagy protects against nonalcoholic fatty liver disease Nonalcoholic fatty liver disease (NAFLD) is a significant component of metabolic syndrome, as well as obesity and diabetes. NAFLD encompasses a spectrum of liver abnormalities ranging from simple fatty liver or steatosis to fatty liver accompanied by hepatocyte injury and inflammation, known as nonalcoholic steatohepatitis (NASH). NAFLD is currently the most prevalent liver disease in the United States, accounting for approximately 75% of all chronic liver diseases.

[0084] The most important role of autophagy in fatty liver disease may be to control the process of excessive lipid accumulation. Indeed, mice consuming a high-fat diet with hepatocyte-specific knockout of Atg7, a protein required for autophagy, developed a significant increase in hepatic TG and cholesterol content, indicating that autophagy abnormalities can induce hepatic steatosis. Regarding NASH, although its exact cause is still unknown, lipotoxicity induced by free fatty acids (FFA) has been linked to the mechanism of hepatocyte injury in this disease. Evidence suggests that hepatocyte autophagy makes cells more resistant to injury by FFA.

[0085] Autophagy is an attractive therapeutic target for treating and preventing both NAFLD and NASH. Therapeutic intervention to increase autophagy can reverse not only the liver symptoms of NAFLD, including hepatocyte steatosis and injury, but also some of the underlying metabolic abnormalities of the disease through its effect on insulin resistance. Furthermore, treatment with autophagy induction can prevent common end-stage complications of NAFLD, such as hepatocellular carcinoma.

[0086] The present invention provides know-how for using compounds including urolithins and their precursors as enhancers of autophagy to treat individuals with NAFLD and who are in need of increased levels of autophagy in the liver and hepatocytes to treat these conditions.

[0087] Autophagy protects against alcoholic liver disease Alcoholic liver disease (ALD) is a major cause of chronic liver disease and, like NAFLD, has a variety of pathogenic features ranging from steatosis to severe acute alcoholic hepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma.

[0088] Autophagy has been shown to be involved in the treatment of ALD. For example, induction of autophagy by rapamycin administration significantly suppresses acute alcohol-induced steatosis. Furthermore, a common feature of chronic alcohol abuse is the formation of hepatic protein aggregates known as Mallory-Denk bodies, which are cytosolic inclusions enriched in proteins including Krt8 / keratin 8, Krt18, and ubiquitin. Rapamycin treatment significantly reduces the number of Mallory-Denk bodies in KRT8 transgenic mice treated with proteasome inhibitors.

[0089] Therefore, enhancing hepatic autophagy is an attractive target for ameliorating alcohol-induced liver disease. The present invention provides know-how for using compounds including urolithins and their precursors as enhancers of autophagy to treat individuals with ALD who are in need of increased autophagy levels in the liver and hepatocytes to treat this condition.

[0090] Autophagy protects against drug-induced liver injury Because most drugs are metabolized and detoxified in the liver, the liver is a major target for drug injury. Drug-induced liver injury is a common cause of withdrawal of commercially approved drugs, and drug-induced hepatotoxicity is thought to be involved in more than half of acute cases of liver failure. Acetaminophen, also known as paracetamol and N-acetyl-p-aminophenol (APAP), is a widely used antipyretic and analgesic and is also the most common cause of severe drug-induced hepatotoxicity. While APAP is safe at therapeutic levels, overdose can result in toxicity, primarily due to its reactive metabolite, N-acetyl-p-benzoquinoneimine (NAPQI). NAPQI can deplete hepatic stores of the intracellular antioxidant glutathione (GSH). After GSH depletion, NAPQI is known to react with cellular and mitochondrial proteins to form protein adducts. These APAP-induced mitochondrial protein adducts can subsequently cause mitochondrial injury and subsequent necrosis.

[0091] When autophagy is enhanced with rapamycin, APAP-induced necrosis is significantly inhibited in both cultured primary mouse hepatocytes and mouse livers. Rapamycin treatment 2 hours after APAP administration significantly ameliorates APAP-induced liver injury, even though APAP metabolism and hepatic GSH depletion have already occurred. This is particularly important because patients at risk for acute APAP overdose hepatotoxicity do not receive treatment until they have passed the metabolic stage. Therefore, pharmacological interventions targeting autophagy enhancement may have promising therapeutic effects for individuals at risk for APAP overdose hepatotoxicity.

[0092] The present invention provides know-how for using compounds including urolithins and their precursors as enhancers of autophagy to treat individuals who are at risk of liver toxicity from adverse drug reactions and who are in need of increased levels of autophagy in the liver and hepatocytes to treat or prevent potential drug toxicity.

[0093] Autophagy is important in limiting ischemia / reperfusion injury Ischemia / reperfusion (I / R) injury is a causative factor contributing to morbidity and mortality. Liver vulnerability to I / R injury is a major obstacle in hepatic resection and transplantation, where reperfusion after persistent ischemia is inevitable during hepatectomy and vascular reconstruction. Mitochondrial dysfunction is known to be one of the crucial downstream events that trigger I / R-induced cell death.

[0094] Autophagy ensures optimal cell function and survival by eliminating abnormal or dysfunctional mitochondria. Dysfunctional or insufficient mitophagy causes cells to accumulate damaged mitochondria, which subsequently leads to uncontrolled ROS formation, mitochondrial DNA mutations, energy insufficiency, and ultimately cell death. Therefore, the inability of mitophagy to remove small numbers of damaged mitochondria during I / R can have a significant impact on hepatocyte function and viability. Mitophagy is essential for liver function and survival after I / R injury.

[0095] Although minimizing I / R injury plays an important role in the prognosis of transplanted young livers, aging livers are even more susceptible to the negative effects of I / R injury. In aging livers, hepatocytes are unable to upregulate the endogenous protective autophagy response in response to I / R stress. Similar to young livers after long-term ischemia, aging livers after short-term ischemia accumulate dysfunctional mitochondria, undergo mitochondrial permeability transition, and lose their viability shortly after reperfusion.

[0096] Methods that enhance autophagy, including pre-ischemia nutrient depletion and overexpression of the autophagy-promoting genes ATG7 or BECN1, result in the suppression of the mitochondrial permeability transition and increase hepatocyte survival after reperfusion.

[0097] This indicates that treatment with autophagy-inducing agents in the liver can help protect against I / R and minimize cellular injury. Such treatments are applicable to both young and aged liver transplantation situations. Treatments can include (i) ex vivo liver tissue pretreatment by perfusion of the liver with a solution containing an autophagy inducer; (ii) treatment of the liver donor with an autophagy inducer; or (iii) treatment of the liver recipient before, during, and / or immediately after surgery. Of course, these treatment modalities can be applied individually or in any combination (e.g., 1 and 2; 2 and 3; 1 and 3; 1, 2, and 3).

[0098] The present invention provides know-how to use compounds, including urolithins and their precursors, as enhancers of autophagy to treat individuals and their livers who may be at risk for I / R injury. These compounds may be given to donors or recipients orally or parenterally, or may be included in a pretreatment solution that can be applied to excised liver tissue.

[0099] Autophagy and Osteoarthritis Osteoarthritis (OA) is the most common age-related joint pathology and is characterized by the degradation of cartilage extracellular matrix (ECM) and reduced cartilage cellularity. Changes in articular cartilage appear to be crucial in the initiation and progression of OA. Chondrocytes are the only cell population in mature articular cartilage. Their ability to regenerate normal cartilage matrix structure is limited and declines with aging due to cell death and abnormal responsiveness to anabolic stimuli. Articular cartilage is characterized by a very low cell turnover rate, and autophagy has been shown to play a critical role in chondrocyte function and survival. In fact, autophagy is a constitutively active protective process that maintains cartilage homeostasis. Studies have shown that decreased expression of autophagy regulators occurs during both joint aging and OA in humans and mice, accompanied by increased chondrocyte apoptosis. Impaired autophagy is thought to contribute to the development of OA. It has been shown that treatment with the compound rapamycin, a known autophagy inducer, was able to reduce the severity of articular cartilage degeneration by increasing LC3 activation in the cartilage of an OA animal model. In the present invention, urolithins and their precursors have been shown to increase autophagy levels in tissues after oral consumption, making them ideal candidates for treating and reducing the severity of osteoarthritis in young and aging humans and mammals.

[0100] Metabolic syndrome, diabetes, and obesity The compounds and methods of the present invention are useful for the treatment and prevention of metabolic syndrome, type 2 diabetes, and obesity. As used herein, the term "metabolic syndrome" refers to a combination of medical disorders that, when occurring together, increase the risk of developing cardiovascular disease and diabetes. It affects one in five people in the United States, and the prevalence increases with age. Some studies have shown that the prevalence in the United States is an estimated 25% of the population. According to the International Diabetes Foundation consensus worldwide definition (2006), metabolic syndrome is central obesity and any two of the following: Elevated triglycerides: greater than 150 mg / dL (1.7 mmol / L) or specific treatment for this lipid abnormality; Reduction of HDL cholesterol: less than 40 mg / dL (1.03 mmol / L) in men and less than 50 mg / dL (1.29 mmol / L) in women, or specific treatment for this lipid abnormality; Elevated blood pressure: systolic blood pressure greater than 130 mmHg or diastolic blood pressure greater than 85 mmHg, or treatment for previously diagnosed hypertension; and Elevated fasting plasma glucose: (FPG) greater than 100 mg / dL (5.6 mmol / L) or previously diagnosed type 2 diabetes.

[0101] Autophagy and Neurodegenerative Diseases In neurodegenerative diseases, brain tissue accumulates autophagosomes, indicating increased autophagy, which has been shown to have a protective effect in model organisms. Increased autophagy plays an important role in eliminating misfolded proteins that accumulate as a result of several neurodegenerative diseases. These include proteins with polyglutamine repeats, which are also seen in Huntington's disease and spinocerebellar ataxia, mutant α-synuclein involved in Parkinson's disease, and tau aggregates.

[0102] Knockdown of ATG genes critical for autophagy in C. elegans resulted in increased aggregate formation and toxicity of polyglutamine proteins. In Alzheimer's disease, the autophagy process is impaired as a result of defects in autophagosome maturation, which may be an important cause of aggregate accumulation. In contrast, induction of autophagy with rapamycin in both Drosophila and mouse models of polyglutamine disease protected these animals from neurotoxicity. These results indicate that autophagy induction may have a protective role in neurons against neurodegeneration.

[0103] The development of neurodegenerative diseases in patients may imply that autophagy has reached a saturation point where its ability to degrade mutant protein aggregates is exceeded, and therefore promoting autophagy may help delay the onset of neurodegenerative diseases.

[0104] Cognitive impairment The compounds and methods of the present invention are useful for treating cognitive disorders. As used herein, cognitive disorders refer to any condition that impairs cognitive function. In one embodiment, "cognitive disorders" refers to any one or more of delirium, dementia, learning disorders, attention deficit disorder (ADD), and attention deficit hyperactivity disorder (ADHD). In one embodiment, the cognitive disorder is a learning disorder. In one embodiment, the cognitive disorder is attention deficit disorder (ADD). In one embodiment, the cognitive disorder is attention deficit hyperactivity disorder (ADHD).

[0105] The compounds and methods of the present invention are useful for improving cognitive function, even in the absence of cognitive impairment. As used herein, "cognitive function" refers to any mental process that involves symbolic operations, such as perception, memory, attention, speech comprehension, speech production, reading comprehension, mental imagery creation, learning, and reasoning. In one embodiment, "cognitive function" refers to any one or more of perception, memory, attention, and reasoning. In one embodiment, "cognitive function" refers to memory.

[0106] The methods for measuring cognitive function are well known, and can include, for example, individual or series of tests for all aspects of cognitive function.One such test is the Prudhoe Cognitive Function Test.Margallo-Lana et al. (2003) J Intellect Disability Res. 47:488-492.Another such test is the Mini Mental State Exam (MMSE), which is designed to evaluate orientation to time and place, registration, attention and calculation, recall, language use and comprehension, repetition, and complex commands.Folstein et al. (1975) J Psych Res. 12:189-198. Other tests useful for measuring cognitive function include the Alzheimer Disease Assessment Scale-Cognitive (ADAS-Cog) (Rosen et al. (1984) Am J Psychiatry. 141(11):1356-64) and the Cambridge Neuropsychological Test Automated Battery (CANTAB) (Robbins et al. (1994) Dementia. 5(5):266-81). Such tests can be used to objectively assess cognitive function, allowing for measurement and comparison of changes in cognitive function in response to treatment, for example, using the methods of the present invention.

[0107] Protein misfolding and aggregation These diseases and disorders are collectively referred to as "amyloid-related diseases" and fall into two major categories: (a) those that affect the brain and other parts of the central nervous system; and (b) those that affect other organs or tissues throughout the body.

[0108] Examples of amyloid-related diseases that fall into these two categories are described in the two sections below; however, many other examples of rare inherited amyloid-related diseases that are not included herein are known, and additional forms of amyloid-related diseases may be discovered in the future.

[0109] Amyloidosis-related neurodegenerative disorders Many different neurodegenerative diseases are associated with the misfolding and aggregation of specific proteins or peptides in specific parts of the brain, or elsewhere in the central nervous system, depending on the particular disease. Examples of such diseases are described below.

[0110] Various forms of Alzheimer's disease (AD), as well as Down's syndrome, hereditary cerebral hemorrhage with amyloidosis (HCHWA, Dutch type), cerebral amyloid angiopathy, and possibly mild cognitive impairment (MCI), as well as other forms of dementia, are associated with the aggregation of a 40 / 42-residue peptide called β-amyloid, Aβ(l-40), or Aβ(l-42), which forms insoluble amyloid fibers and plaques in the cerebral cortex, hippocampus, or elsewhere in the brain, depending on the specific disease. Alzheimer's disease is also associated with the formation of neurofibrillary tangles due to the aggregation of a hyperphosphorylated protein called tau, which also occurs in frontotemporal dementia (Pick's disease).

[0111] Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA) are associated with the aggregation of a protein called α-synuclein, which leads to the formation of insoluble inclusions called Lewy bodies. Huntington's disease (HD), spinal-bulbar muscular atrophy (SBMA, also known as Kennedy's disease), dentatorubral-pallidoluysian atrophy (DRPLA), various forms of spinocerebellar ataxia (SCA, types 1, 2, 3, 6, and 7), and possibly several other inherited neurodegenerative disorders are associated with the aggregation of various proteins and peptides containing abnormally expanded glutamine repeats (polyglutamine stretches). Creutzfeldt-Jakob disease (CJD), bovine spongiform encephalopathy (BSE) in cows, scrapie in sheep, kuru, Gerstmann-Straussler-Scheinker disease (GSS), fatal familial insomnia, and possibly all other forms of infectious brain disease are associated with the self-propagating misfolding and aggregation of prion proteins.

[0112] Amyotrophic lateral sclerosis (ALS), and possibly some other forms of motor neuron disease (MND), are also associated with the aggregation of a protein called superoxide dismutase.

[0113] Familial British Dementia (FBD) and Familial Danish Dementia (FDD) are associated with aggregation of ABri and ADan peptide sequences, respectively, derived from the BRI protein.

[0114] Hereditary cerebral hemorrhage with amyloidosis (HCHWA, Icelandic type) is associated with aggregation of a protein called cystatin C.

[0115] Amyloidosis and related systemic disorders In addition to the neurodegenerative diseases described above, a wide variety of systemic aging-related or degenerative diseases are associated with the misfolding and aggregation of specific proteins or peptides in various other tissues throughout the body (i.e., outside the brain). Examples of such diseases are described below.

[0116] Type II diabetes mellitus (also known as adult-onset diabetes, or non-insulin-dependent diabetes) is associated with the aggregation of a 37-residue peptide called islet amyloid polypeptide (IAPP, or "amylin"), which forms insoluble deposits associated with the progressive destruction of insulin-producing beta cells in the islets of Langerhans within the pancreas.

[0117] Dialysis-related amyloidosis (DRA) and prostatic amyloid are associated with aggregation of a protein called β2-microglobulin in the bones, joints, and tendons in DRA, or within the prostate in the case of prostatic amyloid, which develops during long-term hemodialysis.

[0118] Primary systemic amyloidosis, systemic AL amyloidosis, and multiple myeloma amyloidosis are associated with the aggregation of immunoglobulin light chains (or, in some cases, immunoglobulin heavy chains) into insoluble amyloid deposits that gradually accumulate in various major organs, such as the liver, kidneys, heart, and gastrointestinal (GI) tract.

[0119] Reactive systemic AA amyloidosis, secondary systemic amyloidosis, familial Mediterranean fever, and chronic inflammatory diseases are associated with the aggregation of serum amyloid A, which forms insoluble amyloid deposits that accumulate in major organs such as the liver, kidneys, and spleen. Senile systemic amyloidosis (SSA), familial amyloid polyneuropathy (FAP), and familial amyloid cardiomyopathy (FAC) are associated with the misfolding and aggregation of various variants of transthyretin protein (TTR), which form insoluble inclusions in various organs and tissues, such as the heart (particularly FAC), peripheral nerves (particularly FAP), and gastrointestinal (GI) tract. Another form of familial amyloid polyneuropathy (FAP, type II) is associated with the aggregation of apolipoprotein A-I in peripheral nerves. Familial visceral amyloidosis and hereditary non-neuropathic systemic amyloidosis are associated with the misfolding and aggregation of various variants of lysozyme, which form insoluble deposits in major organs such as the liver, kidneys, and spleen.

[0120] Finnish hereditary systemic amyloidosis is associated with aggregation of a protein called gelsolin in the eye, particularly in the cornea.

[0121] Fibrinogen α-chain amyloidosis is associated with the aggregation of fibrinogen Aα-chain, which forms insoluble amyloid deposits in various organs, such as the liver and kidneys.

[0122] Insulin-associated amyloidosis occurs due to aggregation of insulin at the injection site in diabetes.

[0123] Medullary thyroid carcinoma is associated with the aggregation of calcitonin in surrounding tissues.

[0124] Isolated atrial amyloidosis is associated with aggregation of atrial natriuretic peptide (ANP) in the heart.

[0125] Various forms of cataracts are associated with aggregation of gamma-crystallin proteins in the lens of the eye.

[0126] Autophagy and endothelial cell function and related diseases Endothelial dysfunction Endothelial cell dysfunction occurs in several different diseases, including diabetes, hypertension, chronic kidney disease, and atherosclerosis. In these diseases, endothelial cell dysfunction is thought to occur as a result of stress-induced premature senescence (SIPS). SIPS is characterized by disruption of autophagy and lysosomal dysfunction, accompanied by the accumulation of autolysosomal vacuoles.

[0127] Endothelial cell dysfunction also occurs as a consequence of aging, which is associated with an increased incidence of cardiovascular disease. This increase in cellular dysfunction is associated with a decrease in autophagy. In aged humans, the expression of autophagy markers in arterial endothelial cells was impaired by 50% (P<0.05) and was accompanied by a 30% (P<0.05) decrease in arterial endothelium-dependent dilation (EDD). Similarly, in C57BL / 6 control mice, aging was accompanied by a 40% (P<0.05) decrease in arterial markers of autophagy and a 25% (P<0.05) decrease in EDD, indicating that impaired autophagy contributes to age-related arterial dysfunction.

[0128] In aged mice, treatment with the autophagy enhancer trehalose restored the expression of autophagy markers, rescued NO-mediated EDD by reducing oxidative stress, and normalized inflammatory cytokine expression.The present invention provides know-how for using compounds including urolithins and their precursors as enhancers of autophagy to treat individuals in need of treatment for conditions associated with endothelial cell dysfunction.

[0129] endothelial cell injury Endothelial cell injury can occur as a result of disease processes such as sickle cell anemia or thalassemia, which can result in the release of pathologically high levels of heme and iron. Severe skeletal muscle injury and cardiac ischemic injury cause the release of the heme protein myoglobin, which also causes endothelial cell injury. This injury to vascular endothelial cells can lead to vascular dysfunction and increased cardiovascular complications. Endothelial cell injury caused by heme toxicity is accompanied by a progressive decrease in endothelial cell mitochondrial membrane potential, leading to apoptosis.

[0130] Microvascular and macrovascular complications are common in diabetic patients, and endothelial dysfunction contributes to the onset and progression of these complications. Abnormal function in endothelial cells leads to increased vascular tone and atherosclerosis, subsequent systemic hypertension, and an increased incidence of ischemia and stroke in diabetic patients. Mitochondrial dysfunction appears to play a central role in vascular endothelial dysfunction. Enhanced mitochondrial fission and / or attenuated fusion lead to mitochondrial fragmentation and disruption of endothelial physiological functions. Abnormal mitochondrial biogenesis and impaired mitochondrial autophagy increase the accumulation of damaged mitochondria, such as irreversibly depolarized or leaky mitochondria, and promote cell death. Increased mitochondrial ROS generation and mitochondrial Ca2+ accumulation are also associated with increased risk of endothelial death. 2+ Overload not only causes maladaptive effects on endothelial function but is also potentially detrimental to cell survival.

[0131] Endothelial cell injury can also be caused by cardiac surgery, such as angioplasty, bypass surgery, and valve replacement. Upregulation of autophagy should result in a reduction of the associated damage to endothelial cells.

[0132] Strategies to increase autophagy would have clear therapeutic potential. The present invention provides the know-how to use compounds, including urolithins and their precursors, as enhancers of autophagy to treat individuals with conditions associated with endothelial cell injury resulting from disease processes such as diabetes, sickle cell anemia, or thalassemia, and to protect endothelial cells from the effects of more acute, severe muscle injury.

[0133] Autophagy and Cancer Autophagy and cancer share similar regulatory pathways, including several tumor suppressor genes such as PTEN, TSC1, and TSC2, and upstream inhibition of TOR signaling leads to stimulation of autophagy. Furthermore, the autophagy protein beclin 1 has been identified as a tumor suppressor that is deleted in many human cancers. These results indicate that autophagy plays an important role in tumor suppression.

[0134] aging By far the greatest risk factor for neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS) is aging. Mitochondria are thought to contribute to aging through the accumulation of mitochondrial DNA (mtDNA) mutations and the net production of reactive oxygen species (ROS). Although most mitochondrial proteins are encoded by the nuclear genome, mitochondria contain many copies of their own DNA. Human mtDNA is a circular molecule consisting of 16,569 base pairs that encodes 13 polypeptide components of the respiratory chain, as well as rRNA and tRNA, necessary for mitochondrial protein synthesis using the mitochondrial genetic code. Inherited mutations in mtDNA are known to cause a variety of diseases, most of which affect the brain and muscle (tissues with high energy demands). It is hypothesized that somatic mtDNA mutations acquired during aging contribute to the physiological decline that occurs with aging and age-related neurodegeneration. It is well established that mtDNA accumulates mutations with aging, particularly large deletions and point mutations. In the mtDNA control region, point mutations at specific sites can accumulate to high levels in certain tissues: T414G in cultured fibroblasts, A189G and T408A in muscle, and C150T in leukocytes. However, these control region "hot spots" have not been observed in the brain. Point mutations at individual nucleotides appear to occur at low levels in the brain, although overall levels may be high. Using polymerase chain reaction (PCR) cloning and sequencing, we found that the average level of point mutations in two protein-coding regions of brain mtDNA from aging subjects was approximately 2 mutations per 10 kb. Nontranslated regions, which may be under lower selective pressure, can accumulate two- to four-fold more. The accumulation of these deletions and point mutations with aging correlates with a decline in mitochondrial function. For example, an inverse correlation is observed between brain cytochrome oxidase activity and increased levels of point mutations in the cytochrome oxidase gene (CO1).

[0135] Net ROS production is another important mechanism by which mitochondria are thought to contribute to aging. Mitochondria contain multiple electron carriers capable of generating ROS and an extensive antioxidant defense network. Mitochondrial injury (e.g., oxidative damage itself) can lead to net ROS production by creating an imbalance between ROS production and removal. The importance of net mitochondrial ROS production to aging is supported by the observation that enhancing mitochondrial antioxidant defenses can extend lifespan. In Drosophila, overexpression of the mitochondrial antioxidant enzymes manganese superoxide dismutase (MnSOD) and methionine sulfoxide reductase extends lifespan. This strategy has been most successful in short-lived Drosophila strains and has been ineffective in already long-lived strains. However, recently, experimentally targeted overexpression of catalase to mitochondria has been shown to extend the lifespan of already long-lived mouse strains.

[0136] Improving activity during aging Animal activity is largely driven by circadian rhythms and is entrained to the environment. Disruption of circadian rhythms or desynchronization with the environment can result in increased nighttime wakefulness or daytime sleep.

[0137] Normal aging is accompanied by a decline in locomotor activity, changes in circadian rhythms, and alterations in sleep and food intake patterns. These effects result in decreased alertness and decreased wakefulness in older adults, leading to increased nighttime awakenings and increased daytime sleepiness. Activity patterns can also be disrupted by diseases such as Alzheimer's disease.

[0138] Age-related changes in activity rhythms, along with increased fragmentation and reduced environmental entrainment, have also been observed in other animals, such as rats, hamsters, mice, and dogs. These age-dependent circadian disruptions have been associated with degeneration of the suprachiasmatic nucleus of the hypothalamus. Sleep deprivation in both humans and rodents has been shown to contribute to age-dependent cognitive impairment.

[0139] Increased circadian rhythm disruption is associated with a slow decline in motor activity with age in several species (e.g., humans, mice, monkeys, and dogs). Of particular note is the decline in daytime activity in older dogs (over 10 years of age) compared with young and middle-aged dogs. These changes in activity can be monitored by devices designed to measure activity, such as accelerometers or by using motion-detecting cameras.

[0140] Many of the detriments seen in aging as a result of decreased physical activity are also observed in younger populations, where cultural trends, coupled with increased caloric intake, lead to an obesity epidemic. The resulting calorie imbalance has led to an increase in several medical conditions, including type 2 diabetes, colon cancer, and metabolic syndrome, as well as mental health problems. Several prospective cohort studies and meta-analyses in humans have shown that physical inactivity is associated with an increased risk of developing metabolic syndrome, type 2 diabetes, hypertension, coronary artery disease, stroke, and cardiovascular disease.

[0141] Both humans and animals (especially dogs) will benefit from the present invention and its ability to increase activity in both the early and elderly stages of life.

[0142] In one embodiment, the urolithin or precursor will increase activity in a recipient, human, or animal. In yet another embodiment, the increase in activity is between 1% and 100%. For example, activity may be increased by 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10%. In certain embodiments, the increase in activity is between 5% and 10%, 10% and 15%, 15% and 20%, 20% and 25%, 25% and 30%, 30% and 35%, 35% and 40%, 40% and 45%, 45% and 50%, 50% and 55%, 55% and 60%, 60% and 65%, 65% and 70%, 70% and 75%, 75% and 80%, 80% and 85%, 85% and 90%, 90% and 95%, and 95% and 100%.

[0143] In one embodiment, treatment with a urolithin or its precursor will increase activity and result in a reduced risk of metabolic syndrome. In one embodiment, treatment with a urolithin or its precursor will increase activity and result in a reduced risk of type 2 diabetes. In one embodiment, treatment with a urolithin or its precursor will increase activity and result in a reduced risk of hypertension, coronary artery disease, stroke, and cardiovascular disease. In one embodiment, treatment with a urolithin or its precursor will increase activity and improve cognitive function.

[0144] Mood disorders The compounds and methods of the present invention are useful for treating mood disorders (also known as affective disorders). As used herein, "mood disorder" refers to a disorder in emotional states, such as those described in the Diagnostic and Statistical Manual of Mental Disorders published by the American Psychiatric Association. Mood disorders include, but are not limited to, major depression, postpartum depression, dysthymia, and bipolar disorder. In one embodiment, the mood disorder is major depression.

[0145] The compounds and methods of the present invention are useful for treating or preventing stress-induced or stress-related mood disorders.As used herein, " stress-induced or stress-related mood disorders " refers to the emotional state disorders that are induced by stress or are associated with stress.This type of mood disorder is sometimes called reactive mood disorder, and should be distinguished from other mood disorders (for example, so-called organic mood disorders).

[0146] The compounds and methods of the present invention are useful for treating anxiety disorders.As used herein, "anxiety disorder" refers to a dysfunctional state of fear and anxiety, for example, fear and anxiety that are disproportionate to stressful situations or the anticipation of stressful situations.In one embodiment, the anxiety disorder is any one or combination of generalized anxiety disorder, panic disorder, panic disorder with agoraphobia, agoraphobia, social anxiety disorder, obsessive-compulsive disorder, and post-traumatic stress disorder.In one embodiment, the anxiety disorder is any one or combination of generalized anxiety disorder, obsessive-compulsive disorder, panic disorder, post-traumatic stress disorder, and social anxiety disorder.In one embodiment, the anxiety disorder is generalized stress disorder.In one embodiment, the anxiety disorder is post-traumatic stress disorder.In one embodiment, the anxiety disorder is stress-induced anxiety disorder.

[0147] The compounds and methods of the present invention are useful for treating or preventing stress-induced or stress-related anxiety disorder.As used herein, " stress-induced or stress-related anxiety disorder " refers to the dysfunctional state of fear and anxiety that is induced by stress or is associated with stress.This type of anxiety disorder is sometimes called reactive anxiety disorder, and should be distinguished from other anxiety disorders (for example, so-called organic anxiety disorder).

[0148] For purposes of the present invention, each of the above diseases or conditions is associated with or characterized by reduced or diminished autophagy, or would benefit from increased autophagy, and therefore would benefit from the administration of urolithins and their precursors.

[0149] Table 1 summarizes some cell types affected by autophagy and the beneficial effects of autophagy in those cells.

[0150] [Table 1-1] [Table 1-2] [Table 1-3]

[0151] Exemplary Compounds of the Invention Compounds of the invention include certain urolithins and their precursors, which can be used to carry out any of the methods described herein, for example, but not limited to, increasing autophagy or extending lifespan, and for treating or preventing various diseases and conditions described herein.

[0152] In certain embodiments, the present invention relates to a urolithin. As used herein, "urolithin" refers to a compound of Formula I, [ka] During the ceremony, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 is independently selected from the group consisting of H and OR; R is H, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted monosaccharide, or substituted or unsubstituted oligosaccharide.

[0153] As used herein, the term "alkyl" refers to a straight-chain or branched, acyclic or cyclic, unsaturated or saturated aliphatic hydrocarbon radical containing carbon atoms. Representative saturated straight-chain alkyls include methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, etc.; while saturated branched-chain alkyls include isopropyl, sec-butyl, isobutyl, tert-butyl, isopentyl, etc. Representative saturated cyclic alkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.; while unsaturated cyclic alkyls include cyclopentenyl and cyclohexenyl, etc. Unsaturated alkyls contain at least one double or triple bond between adjacent carbon atoms (referred to as "alkenyl" or "alkynyl," respectively). Representative straight and branched chain alkenyls include ethylenyl, propylenyl, 1-butenyl, 2-butenyl, isobutylenyl, 1-pentenyl, 2-pentenyl, 3-methyl-1-butenyl, 2-methyl-2-butenyl, 2,3-dimethyl-2-butenyl, and the like; while representative straight and branched chain alkynyls include acetylenyl, propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 3-methyl-1-butynyl, and the like.

[0154] As used herein, the term "aryl" refers to a hydrocarbon ring system radical containing hydrogen, 6 to 18 carbon atoms, and at least one aromatic ring. For purposes of this invention, an aryl radical can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, and can include fused or bridged ring systems. Aryl radicals include, but are not limited to, aryl radicals derived from aceanthrylene, fluorene, acephenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene. Unless otherwise stated in the specification, the term "aryl" or the prefix "ar-" (e.g., "aralkyl") is intended to include optionally substituted aryl radicals.

[0155] As used herein, the term "monosaccharide" refers to a sugar having the formula (CHO) n Monosaccharides refer to simple sugars of the formula -CH(OH)-C(=O)-. Monosaccharides can be linear or cyclic and can contain a sucrose unit of the formula -CH(OH)-C(=O)-. Examples of monosaccharides include erythrose, threose, ribose, arabinose, xylose, lyxose, allose, altrose, glucose, mannose, gulose, idose, galactose, talose, erythulose, ribulose, xylulose, psicose, fructose, sorbose, tagatose, erythropentulose, threopentulose, glycerotetrulose, glucopyranose, and fructofuranose. In some embodiments, monosaccharide refers to glucopyranose.

[0156] As used herein, the term "oligosaccharide" refers to a saccharide consisting of at least two and up to ten glycosidically linked monosaccharide units, preferably 2 to 8 monosaccharide units, more preferably 2 to 7 monosaccharide units, and even more preferably 2 to 6 monosaccharide units or 2 to 5 monosaccharide units.

[0157] As used herein, the term "substituted" (e.g., in the context of substituted heterocyclyl or substituted aryl) means that at least one hydrogen atom is replaced with a substituent. For purposes of this invention, "substituents" include halogen, hydroxy, oxo, cyano, nitro, imino, thioxo, amino, alkylamino, dialkylamino, alkyl, alkoxy, alkylthio, haloalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocycle and heterocyclealkyl, and -NR a R b , -NR a C(=O)R b , -NR a C(=O)NR a NR b , -NR a C(=O)OR b -NR a SO2R b, -C(=O)R a , -C(=O)OR a , -C(=O)NR a R b , -OC(=O)NR a R b , -OR a , -SR a , -SOR a , -S(=O)2R a , -OS(=O)2R a , -S(=O)2OR a , =NSO2R a and -SO2NR a R b In the above, R in this context a and R b may be the same or different and independently may be hydrogen, alkyl, haloalkyl, cycloalkyl, aryl, aralkyl, heterocyclyl. Additionally, the above substituents may be further substituted with one or more of the above substituents.

[0158] In one embodiment, the urolithin is urolithin A.

[0159] In one embodiment, the urolithin is urolithin B.

[0160] In one embodiment, the urolithin is urolithin C.

[0161] In one embodiment, the urolithin is urolithin D.

[0162] In one embodiment, "urolithin" refers to any one of urolithin A, urolithin B, urolithin C, and urolithin D, or a combination thereof (see, e.g., Figures 2 and 3). In one embodiment, the urolithin is urolithin A, urolithin B, urolithin C, urolithin D, or any combination of urolithin A, urolithin B, urolithin C, and urolithin D. In one embodiment, the urolithin is urolithin A, urolithin B, urolithin C, or any combination of urolithin A, urolithin B, and urolithin C. In one embodiment, the urolithin is urolithin A, urolithin B, or any combination of urolithin A and urolithin B. In one embodiment, the urolithin is urolithin A.

[0163] In one embodiment, the urolithin is provided as an isolated urolithin (e.g., isolated from a natural source or prepared by total synthesis). Isolated urolithins may also be synthesized de novo. See Examples 1-4.

[0164] In one embodiment, the urolithin is provided as a purified urolithin.

[0165] In one embodiment, "urolithin" as used herein may be or include a glucuronidated, methylated, or sulfated urolithin.

[0166] In one embodiment, the present invention relates to a compound of formula II: [ka] During the ceremony, X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , and X 8 is independently selected from the group consisting of H and OH; However, the compound is X 1 , X 2 , X3 , X 4 , X 5 , X 6 , X 7 , and X 8 is H; X 1 is OH and X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , and X 8 is H; X 2 is OH and X 1 , X 3 , X 4 , X 5 , X 6 , X 7 , and X 8 is H (urolithin B); X 3 is OH and X 1 , X 2 , X 4 , X 5 , X 6 , X 7 , and X 8 is H; X 4 is OH and X 1 , X 2 , X 3 , X 5 , X 6 , X 7 , and X 8 is H; X 5 is OH and X 1 , X 2 , X 3 , X 4 , X 6 , X 7 , and X 8 is H; X 6 is OH and X 1 , X 2 , X 3 , X 4 , X 5 , X 7 , and X 8 is H; X7 is OH and X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , and X 8 is H; X 8 is OH and X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , and X 7 is H; X 1 and X 2 is OH and X 3 , X 4 , X 5 , X 6 , X 7 , and X 8 is H; X 1 and X 5 is OH and X 2 , X 3 , X 4 , X 6 , X 7 , and X 8 is H; X 1 and X 7 is OH and X 2 , X 3 , X 4 , X 5 , X 6 , and X 8 is H; X 1 and X 8 is OH and X 2 , X 3 , X 4 , X 5 , X 6 , and X 7 is H; X 2 and X 3 is OH and X 1 , X 4 , X 5 , X 6 , X 7, and X 8 is H; X 2 and X 4 is OH and X 1 , X 3 , X 5 , X 6 , X 7 , and X 8 is H; X 2 and X 5 is OH and X 1 , X 3 , X 4 , X 6 , X 7 , and X 8 is H; X 2 and X 6 is OH and X 1 , X 3 , X 4 , X 5 , X 7 , and X 8 is H (urolithin A); X 2 and X 7 is OH and X 1 , X 3 , X 4 , X 5 , X 6 , and X 8 is H; X 3 and X 4 is OH and X 1 , X 2 , X 5 , X 6 , X 7 , and X 8 is H; X 3 and X 5 is OH and X 1 , X 2 , X 4 , X 6 , X 7 , and X 8 is H; X 3 and X 6 is OH and X 1 , X2 , X 4 , X 5 , X 7 , and X 8 is H; X 5 and X 6 is OH and X 1 , X 2 , X 3 , X 4 , X 7 , and X 8 is H; X 5 and X 8 is OH and X 1 , X 2 , X 3 , X 4 , X 6 , and X 7 is H; X 6 and X 7 is OH and X 1 , X 2 , X 3 , X 4 , X 5 , and X 8 is H; X 1 , X 2 , and X 5 is OH and X 3 , X 4 , X 6 , X 7 , and X 8 is H; X 1 , X 2 , and X 6 is OH and X 3 , X 4 , X 5 , X 7 , and X 8 is H; X 1 , X 5 , and X 8 is OH and X 2 , X 3 , X 4 , X 6 , and X 7 is H; X2 , X 4 , and X 6 is OH and X 1 , X 3 , X 5 , X 7 , and X 8 is H; X 2 , X 4 , and X 7 is OH and X 1 , X 3 , X 5 , X 6 , and X 8 is H; X 2 , X 6 , and X 7 is OH and X 1 , X 3 , X 4 , X 5 , and X 8 is H (urolithin C); X 2 , X 6 , and X 8 is OH and X 1 , X 3 , X 4 , X 5 , and X 7 is H; X 2 , X 7 , and X 8 is OH and X 1 , X 3 , X 4 , X 5 , and X 6 is H; X 1 , X 2 , X 5 , and X 6 is OH and X 3 , X 4 , X 7 , and X 8 is H; X 1 , X 2 , X 5 , and X 7 is OH and X 3 , X 4, X 6 , and X 8 is H; X 1 , X 2 , X 6 , and X 7 is OH and X 3 , X 4 , X 5 , and X 8 is H (urolithin D); X 1 , X 6 , X 7 , and X 8 is OH and X 2 , X 3 , X 4 , and X 5 is H; X 2 , X 3 , X 6 , and X 7 is OH and X 1 , X 4 , X 5 , and X 8 is H; X 2 , X 4 , X 5 , and X 8 is OH and X 1 , X 3 , X 6 , and X 7 is H; X 2 , X 4 , X 6 , and X 7 is OH and X 1 , X 3 , X 5 , and X 8 is H; X 1 , X 2 , X 4 , X 5 , and X 7 is OH and X 3 , X 6 , and X 8 is H; X 1 , X 2 , X6 , X 7 , and X 8 is OH and X 3 , X 4 , and X 5 is H; or X 1 , X 2 , X 3 , X 6 , X 7 , and X 8 is OH and X 4 and X 5 is H, Not a compound of formula II.

[0167] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a cancer patient, a method for treating a cancer patient, a cancer patient comprising administering to a subject a cancer patient, a method for treating ... 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , and X 8 wherein at least two of are OH.

[0168] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a cancer patient, a method for treating a cancer patient, a cancer patient comprising administering to a subject a cancer patient, a method for treating ... 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , and X 8 wherein at least three of are OH.

[0169] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a cancer patient, a method for treating a cancer patient, a cancer patient comprising administering to a subject a cancer patient, a method for treating ... 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , and X 8 wherein at least four of are OH.

[0170] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a cancer patient, a method for treating a cancer patient, a cancer patient comprising administering to a subject a cancer patient, a method for treating ... 1 , X 2 , X3 , X 4 , X 5 , X 6 , X 7 , and X 8 wherein at least five of are OH.

[0171] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a cancer patient, a method for treating a cancer patient, a cancer patient comprising administering to a subject a cancer patient, a method for treating ... 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , and X 8 wherein at least six of are OH.

[0172] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a cancer patient, a method for treating a cancer patient, a cancer patient comprising administering to a subject a cancer patient, a method for treating ... 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , and X 8 wherein at least seven of are OH.

[0173] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a cancer patient, a method for treating a cancer patient, a cancer patient comprising administering to a subject a cancer patient, a method for treating ... 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , and X 8 is OH.

[0174] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a cancer patient, a method for treating a cancer patient, a cancer patient comprising administering to a subject a cancer patient, a method for treating ... 1 and X 3 is OH;X 2 , X 4 , X 5 , X 6 , X 7 , and X 8 is H.

[0175] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a cancer patient, a method for treating a cancer patient, a cancer patient comprising administering to a subject a cancer patient, a method for treating ...1 and X 4 is OH;X 2 , X 3 , X 5 , X 6 , X 7 , and X 8 is H.

[0176] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a 1 and X 6 is OH;X 2 , X 3 , X 4 , X 5 , X 7 , and X 8 is H.

[0177] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a 2 and X 8 is OH;X 1 , X 3 , X 4 , X 5 , X 6 , and X 7 is H.

[0178] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a 3 and X 7 is OH;X 1 , X 2 , X 4 , X 5 , X 6 , and X 8 is H.

[0179] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a 3 and X 8 is OH;X 1 , X 2 , X 4 , X 5 , X 6 , and X 7 is H.

[0180] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a 4 and X 5 is OH;X 1 , X 2 , X 3 , X 6 , X 7 , and X 8 is H.

[0181] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a 4 and X 6 is OH;X 1 , X 2 , X 3 , X 5 , X 7 , and X 8 is H.

[0182] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a 4 and X 7 is OH;X 1 , X 2 , X 3 , X 5 , X 6 , and X 8 is H.

[0183] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a 4 and X 8 is OH;X 1 , X 2 , X 3 , X 5 , X 6 , and X 7 is H.

[0184] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a 5 and X 7 is OH;X 1 , X 2 , X 3 , X 4 , X 6 , and X 8is H.

[0185] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a cancer patient, a method for treating a cancer patient, a cancer patient comprising administering to a subject a cancer patient, a method for treating ... 6 and X 8 is OH;X 1 , X 2 , X 3 , X 4 , X 5 , and X 7 is H.

[0186] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a cancer patient, a method for treating a cancer patient, a cancer patient comprising administering to a subject a cancer patient, a method for treating ... 7 and X 8 is OH;X 1 , X 2 , X 3 , X 4 , X 5 , and X 6 is H.

[0187] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a cancer patient, a method for treating a cancer patient, a cancer patient comprising administering to a subject a cancer patient, a method for treating ... 1 , X 2 , and X 3 is OH;X 4 , X 5 , X 6 , X 7 , and X 8 is H.

[0188] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a cancer patient, a method for treating a cancer patient, a cancer patient comprising administering to a subject a cancer patient, a method for treating ... 1 , X 2 , and X 4 is OH;X 3 , X 5 , X 6 , X 7 , and X 8 is H.

[0189] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a cancer patient, a method for treating a cancer patient, a cancer patient comprising administering to a subject a cancer patient, a method for treating ... 1 , X 2 , and X 7 is OH;X 3 , X 4 , X 5, X 6 , and X 8 is H.

[0190] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a 1 , X 2 , and X 8 is OH;X 3 , X 4 , X 5 , X 6 , and X 7 is H.

[0191] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a 1 , X 3 , and X 4 is OH;X 2 , X 5 , X 6 , X 7 , and X 8 is H.

[0192] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a 1 , X 3 , and X 5 is OH;X 2 , X 4 , X 6 , X 7 , and X 8 is H.

[0193] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a 1 , X 3 , and X 6 is OH;X 2 , X 4 , X 5 , X 7 , and X 8 is H.

[0194] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a 1 , X 3 , and X 7 is OH;X2 , X 4 , X 5 , X 6 , and X 8 is H.

[0195] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a 1 , X 3 , and X 8 is OH;X 2 , X 4 , X 5 , X 6 , and X 7 is H.

[0196] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a 1 , X 4 , and X 5 is OH;X 2 , X 3 , X 6 , X 7 , and X 8 is H.

[0197] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a 1 , X 4 , and X 6 is OH;X 2 , X 3 , X 5 , X 7 , and X 8 is H.

[0198] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a 1 , X 4 , and X 7 is OH;X 2 , X 3 , X 5 , X 6 , and X 8 is H.

[0199] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a 1 , X4 , and X 8 is OH;X 2 , X 3 , X 5 , X 6 , and X 7 is H.

[0200] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a cancer patient, a method for treating a cancer patient, a cancer patient comprising administering to a subject a cancer patient, a method for treating ... 1 , X 5 , and X 6 is OH;X 2 , X 3 , X 4 , X 7 , and X 8 is H.

[0201] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a cancer patient, a method for treating a cancer patient, a cancer patient comprising administering to a subject a cancer patient, a method for treating ... 1 , X 5 , and X 7 is OH;X 2 , X 3 , X 4 , X 6 , and X 8 is H.

[0202] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a cancer patient, a method for treating a cancer patient, a cancer patient comprising administering to a subject a cancer patient, a method for treating ... 1 , X 6 , and X 7 is OH;X 2 , X 3 , X 4 , X 5 , and X 8 is H.

[0203] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a cancer patient, a method for treating a cancer patient, a cancer patient comprising administering to a subject a cancer patient, a method for treating ... 1 , X 6 , and X 8 is OH;X 2 , X 3 , X 4 , X 5 , and X 7 is H.

[0204] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a 1 , X 7 , and X 8 is OH;X 2 , X 3 , X 4 , X 5 , and X 6 is H.

[0205] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a 2 , X 3 , and X 4 is OH;X 1 , X 5 , X 6 , X 7 , and X 8 is H.

[0206] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a 2 , X 3 , and X 5 is OH;X 1 , X 4 , X 6 , X 7 , and X 8 is H.

[0207] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a 2 , X 3 , and X 6 is OH;X 1 , X 4 , X 5 , X 7 , and X 8 is H.

[0208] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a 2 , X 3 , and X 7 is OH;X 1 , X 4 , X 5 , X 6 , and X 8 is H.

[0209] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a 2 , X 3 , and X 8 is OH;X 1 , X 4 , X 5 , X 6 , and X 7 is H.

[0210] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a 2 , X 4 , and X 5 is OH;X 1 , X 3 , X 6 , X 7 , and X 8 is H.

[0211] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a 2 , X 4 , and X 8 is OH;X 1 , X 3 , X 5 , X 6 , and X 7 is H.

[0212] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a 2 , X 5 , and X 6 is OH;X 1 , X 3 , X 4 , X 7 , and X 8 is H.

[0213] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a 2 , X 5 , and X 7 is OH;X 1 , X 3 , X 4 , X 6 , and X8 is H.

[0214] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a 2 , X 5 , and X 8 is OH;X 1 , X 3 , X 4 , X 6 , and X 7 is H.

[0215] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a 3 , X 4 , and X 5 is OH;X 1 , X 2 , X 6 , X 7 , and X 8 is H.

[0216] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a 3 , X 4 , and X 6 is OH;X 1 , X 2 , X 5 , X 7 , and X 8 is H.

[0217] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a 3 , X 4 , and X 7 is OH;X 1 , X 2 , X 5 , X 6 , and X 8 is H.

[0218] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a 3 , X 4 , and X 8 is OH;X 1 , X 2 , X5 , X 6 , and X 7 is H.

[0219] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a 3 , X 5 , and X 6 is OH;X 1 , X 2 , X 4 , X 7 , and X 8 is H.

[0220] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a 3 , X 5 , and X 7 is OH;X 1 , X 2 , X 4 , X 6 , and X 8 is H.

[0221] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a 3 , X 5 , and X 8 is OH;X 1 , X 2 , X 4 , X 6 , and X 7 is H.

[0222] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a 3 , X 6 , and X 7 is OH;X 1 , X 2 , X 4 , X 5 , and X 8 is H.

[0223] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a 3 , X 6 , and X 8is OH;X 1 , X 2 , X 4 , X 5 , and X 7 is H.

[0224] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a cancer patient, a method for treating a cancer patient, a cancer patient comprising administering to a subject a cancer patient, a method for treating ... 3 , X 7 , and X 8 is OH;X 1 , X 2 , X 4 , X 5 , and X 6 is H.

[0225] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a cancer patient, a method for treating a cancer patient, a cancer patient comprising administering to a subject a cancer patient, a method for treating ... 4 , X 5 , and X 6 is OH;X 1 , X 2 , X 3 , X 7 , and X 8 is H.

[0226] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a cancer patient, a method for treating a cancer patient, a cancer patient comprising administering to a subject a cancer patient, a method for treating ... 4 , X 5 , and X 7 is OH;X 1 , X 2 , X 3 , X 6 , and X 8 is H.

[0227] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a cancer patient, a method for treating a cancer patient, a cancer patient comprising administering to a subject a cancer patient, a method for treating ... 4 , X 5 , and X 8 is OH;X 1 , X 2 , X 3 , X 6 , and X 7 is H.

[0228] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a cancer patient, a method for treating a cancer patient, a cancer patient comprising administering to a subject a cancer patient, a method for treating ... 4, X 6 , and X 7 is OH;X 1 , X 2 , X 3 , X 5 , and X 8 is H.

[0229] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a 4 , X 6 , and X 8 is OH;X 1 , X 2 , X 3 , X 5 , and X 7 is H.

[0230] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a 4 , X 7 , and X 8 is OH;X 1 , X 2 , X 3 , X 5 , and X 6 is H.

[0231] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a 5 , X 6 , and X 7 is OH;X 1 , X 2 , X 3 , X 4 , and X 8 is H.

[0232] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a 5 , X 6 , and X 8 is OH;X 1 , X 2 , X 3 , X 4 , and X 7 is H.

[0233] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a cancer patient, a method for treating a cancer patient, a cancer patient comprising administering to a subject a cancer patient, a method for treating ... 5 , X 7 , and X 8 is OH;X 1 , X 2 , X 3 , X 4 , and X 6 is H.

[0234] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a cancer patient, a method for treating a cancer patient, a cancer patient comprising administering to a subject a cancer patient, a method for treating ... 6 , X 7 , and X 8 is OH;X 1 , X 2 , X 3 , X 4 , and X 5 is H.

[0235] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a cancer patient, a method for treating a cancer patient, a cancer patient comprising administering to a subject a cancer patient, a method for treating ... 1 , X 2 , X 3 , and X 4 is OH;X 5 , X 6 , X 7 , and X 8 is H.

[0236] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a cancer patient, a method for treating a cancer patient, a cancer patient comprising administering to a subject a cancer patient, a method for treating ... 1 , X 2 , X 3 , and X 5 is OH;X 4 , X 6 , X 7 , and X 8 is H.

[0237] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a cancer patient, a method for treating a cancer patient, a cancer patient comprising administering to a subject a cancer patient, a method for treating ... 1 , X 2 , X 3 , and X 6 is OH;X 4 , X 5 , X 7 , and X 8is H.

[0238] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a cancer patient, a method for treating a cancer patient, a cancer patient comprising administering to a subject a cancer patient, a method for treating ... 1 , X 2 , X 3 , and X 7 is OH;X 4 , X 5 , X 6 , and X 8 is H.

[0239] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a cancer patient, a method for treating a cancer patient, a cancer patient comprising administering to a subject a cancer patient, a method for treating ... 1 , X 2 , X 3 , and X 8 is OH;X 4 , X 5 , X 6 , and X 7 is H.

[0240] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a cancer patient, a method for treating a cancer patient, a cancer patient comprising administering to a subject a cancer patient, a method for treating ... 1 , X 2 , X 4 , and X 5 is OH;X 3 , X 6 , X 7 , and X 8 is H.

[0241] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a cancer patient, a method for treating a cancer patient, a cancer patient comprising administering to a subject a cancer patient, a method for treating ... 1 , X 2 , X 4 , and X 6 is OH;X 3 , X 5 , X 7 , and X 8 is H.

[0242] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a cancer patient, a method for treating a cancer patient, a cancer patient comprising administering to a subject a cancer patient, a method for treating ... 1 , X 2 , X 4 , and X 7 is OH;X 3 , X 5, X 6 , and X 8 is H.

[0243] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a 1 , X 2 , X 4 , and X 8 is OH;X 3 , X 5 , X 6 , and X 7 is H.

[0244] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a 1 , X 2 , X 5 , and X 8 is OH;X 3 , X 4 , X 6 , and X 7 is H.

[0245] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a 1 , X 2 , X 6 , and X 8 is OH;X 3 , X 4 , X 5 , and X 7 is H.

[0246] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a 1 , X 2 , X 7 , and X 8 is OH;X 3 , X 4 , X 5 , and X 6 is H.

[0247] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a 1 , X 3 , X 4 , and X 5is OH;X 2 , X 6 , X 7 , and X 8 is H.

[0248] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a cancer patient, a method for treating a cancer patient, a cancer patient comprising administering to a subject a cancer patient, a method for treating ... 1 , X 3 , X 4 , and X 6 is OH;X 2 , X 5 , X 7 , and X 8 is H.

[0249] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a cancer patient, a method for treating a cancer patient, a cancer patient comprising administering to a subject a cancer patient, a method for treating ... 1 , X 3 , X 4 , and X 7 is OH;X 2 , X 5 , X 6 , and X 8 is H.

[0250] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a cancer patient, a method for treating a cancer patient, a cancer patient comprising administering to a subject a cancer patient, a method for treating ... 1 , X 3 , X 4 , and X 8 is OH;X 2 , X 5 , X 6 , and X 7 is H.

[0251] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a cancer patient, a method for treating a cancer patient, a cancer patient comprising administering to a subject a cancer patient, a method for treating ... 1 , X 3 , X 5 , and X 6 is OH;X 2 , X 4 , X 7 , and X 8 is H.

[0252] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a cancer patient, a method for treating a cancer patient, a cancer patient comprising administering to a subject a cancer patient, a method for treating ... 1 , X 3, X 5 , and X 7 is OH;X 2 , X 4 , X 6 , and X 8 is H.

[0253] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a 1 , X 3 , X 5 , and X 8 is OH;X 2 , X 4 , X 6 , and X 7 is H.

[0254] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a 1 , X 3 , X 6 , and X 7 is OH;X 2 , X 4 , X 5 , and X 8 is H.

[0255] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a 1 , X 3 , X 6 , and X 8 is OH;X 2 , X 4 , X 5 , and X 7 is H.

[0256] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a 1 , X 3 , X 7 , and X 8 is OH;X 2 , X 4 , X 5 , and X 6 is H.

[0257] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a cancer patient, a method for treating a cancer patient, a cancer patient comprising administering to a subject a cancer patient, a method for treating ... 1 , X 4 , X 5 , and X 6 is OH;X 2 , X 3 , X 7 , and X 8 is H.

[0258] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a cancer patient, a method for treating a cancer patient, a cancer patient comprising administering to a subject a cancer patient, a method for treating ... 1 , X 4 , X 5 , and X 7 is OH;X 2 , X 3 , X 6 , and X 8 is H.

[0259] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a cancer patient, a method for treating a cancer patient, a cancer patient comprising administering to a subject a cancer patient, a method for treating ... 1 , X 4 , X 5 , and X 8 is OH;X 2 , X 3 , X 6 , and X 7 is H.

[0260] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a cancer patient, a method for treating a cancer patient, a cancer patient comprising administering to a subject a cancer patient, a method for treating ... 1 , X 4 , X 6 , and X 7 is OH;X 2 , X 3 , X 5 , and X 8 is H.

[0261] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a cancer patient, a method for treating a cancer patient, a cancer patient comprising administering to a subject a cancer patient, a method for treating ... 1 , X 4 , X 6 , and X 8 is OH;X 2 , X 3 , X 5 , and X 7 is H.

[0262] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a 1 , X 4 , X 7 , and X 8 is OH;X 2 , X 3 , X 5 , and X 6 is H.

[0263] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a 1 , X 5 , X 6 , and X 7 is OH;X 2 , X 3 , X 4 , and X 8 is H.

[0264] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a 1 , X 5 , X 6 , and X 8 is OH;X 2 , X 3 , X 4 , and X 7 is H.

[0265] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a 1 , X 5 , X 7 , and X 8 is OH;X 2 , X 3 , X 4 , and X 6 is H.

[0266] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a 2 , X 3 , X 4 , and X 5 is OH;X 1 , X 6 , X 7 , and X8 is H.

[0267] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a cancer patient, a method for treating a cancer patient, a cancer patient comprising administering to a subject a cancer patient, a method for treating ... 2 , X 3 , X 4 , and X 6 is OH;X 1 , X 5 , X 7 , and X 8 is H.

[0268] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a cancer patient, a method for treating a cancer patient, a cancer patient comprising administering to a subject a cancer patient, a method for treating ... 2 , X 3 , X 4 , and X 7 is OH;X 1 , X 5 , X 6 , and X 8 is H.

[0269] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a cancer patient, a method for treating a cancer patient, a cancer patient comprising administering to a subject a cancer patient, a method for treating ... 2 , X 3 , X 4 , and X 8 is OH;X 1 , X 5 , X 6 , and X 7 is H.

[0270] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a cancer patient, a method for treating a cancer patient, a cancer patient comprising administering to a subject a cancer patient, a method for treating ... 2 , X 3 , X 5 , and X 6 is OH;X 1 , X 4 , X 7 , and X 8 is H.

[0271] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a cancer patient, a method for treating a cancer patient, a cancer patient comprising administering to a subject a cancer patient, a method for treating ... 2 , X 3 , X 5 , and X 7 is OH;X 1 , X4 , X 6 , and X 8 is H.

[0272] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a 2 , X 3 , X 5 , and X 8 is OH;X 1 , X 4 , X 6 , and X 7 is H.

[0273] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a 2 , X 3 , X 6 , and X 8 is OH;X 1 , X 4 , X 5 , and X 7 is H.

[0274] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a 2 , X 3 , X 7 , and X 8 is OH;X 1 , X 4 , X 6 , and X 7 is H.

[0275] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a 2 , X 4 , X 5 , and X 6 is OH;X 1 , X 3 , X 7 , and X 8 is H.

[0276] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a 2 , X 4 , X 5 , and X7 is OH;X 1 , X 3 , X 6 , and X 8 is H.

[0277] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a 2 , X 4 , X 6 , and X 8 is OH;X 1 , X 3 , X 5 , and X 7 is H.

[0278] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a 2 , X 4 , X 7 , and X 8 is OH;X 1 , X 3 , X 5 , and X 6 is H.

[0279] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a 2 , X 5 , X 6 , and X 7 is OH;X 1 , X 3 , X 4 , and X 8 is H.

[0280] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a 2 , X 5 , X 6 , and X 8 is OH;X 1 , X 3 , X 4 , and X 7 is H.

[0281] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a 2 , X5 , X 7 , and X 8 is OH;X 1 , X 3 , X 4 , and X 6 is H.

[0282] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a cancer patient, a method for treating a cancer patient, a cancer patient comprising administering to a subject a cancer patient, a method for treating ... 2 , X 6 , X 7 , and X 8 is OH;X 1 , X 3 , X 4 , and X 5 is H.

[0283] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a cancer patient, a method for treating a cancer patient, a cancer patient comprising administering to a subject a cancer patient, a method for treating ... 3 , X 4 , X 5 , and X 6 is OH;X 1 , X 2 , X 7 , and X 8 is H.

[0284] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a cancer patient, a method for treating a cancer patient, a cancer patient comprising administering to a subject a cancer patient, a method for treating ... 3 , X 4 , X 5 , and X 7 is OH;X 1 , X 2 , X 6 , and X 8 is H.

[0285] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a cancer patient, a method for treating a cancer patient, a cancer patient comprising administering to a subject a cancer patient, a method for treating ... 3 , X 4 , X 5 , and X 8 is OH;X 1 , X 2 , X 6 , and X 7 is H.

[0286] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a 3 , X 4 , X 6 , and X 7 is OH;X 1 , X 2 , X 5 , and X 8 is H.

[0287] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a 3 , X 4 , X 6 , and X 8 is OH;X 1 , X 2 , X 5 , and X 7 is H.

[0288] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a 3 , X 4 , X 7 , and X 8 is OH;X 1 , X 2 , X 5 , and X 6 is H.

[0289] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a 3 , X 5 , X 6 , and X 7 is OH;X 1 , X 2 , X 4 , and X 8 is H.

[0290] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a 3 , X 5 , X 6 , and X 8 is OH;X 1 , X 2 , X 4 , and X 7 is H.

[0291] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a 3 , X 5 , X 7 , and X 8 is OH;X 1 , X 2 , X 4 , and X 6 is H.

[0292] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a 3 , X 6 , X 7 , and X 8 is OH;X 1 , X 2 , X 4 , and X 5 is H.

[0293] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a 4 , X 5 , X 6 , and X 7 is OH;X 1 , X 2 , X 3 , and X 8 is H.

[0294] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a 4 , X 5 , X 6 , and X 8 is OH;X 1 , X 2 , X 3 , and X 7 is H.

[0295] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a 4 , X 5 , X 7 , and X 8 is OH;X 1 , X 2 , X 3 , and X6 is H.

[0296] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a 4 , X 6 , X 7 , and X 8 is OH;X 1 , X 2 , X 3 , and X 5 is H.

[0297] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a 5 , X 6 , X 7 , and X 8 is OH;X 1 , X 2 , X 3 , and X 4 is H.

[0298] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a 1 , X 2 , X 3 , X 4 , and X 5 is OH;X 6 , X 7 , and X 8 is H.

[0299] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a 1 , X 2 , X 3 , X 4 , and X 6 is OH;X 5 , X 7 , and X 8 is H.

[0300] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a 1 , X 2 , X 3 , X 4 , and X 7 is OH;X5 , X 6 , and X 8 is H.

[0301] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a 1 , X 2 , X 3 , X 4 , and X 8 is OH;X 5 , X 6 , and X 7 is H.

[0302] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a 1 , X 2 , X 3 , X 5 , and X 6 is OH;X 4 , X 7 , and X 8 is H.

[0303] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a 1 , X 2 , X 3 , X 5 , and X 7 is OH;X 4 , X 6 , and X 8 is H.

[0304] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a 1 , X 2 , X 3 , X 5 , and X 8 is OH;X 4 , X 6 , and X 7 is H.

[0305] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a 1 , X 2 , X 3 , X6 , and X 7 is OH;X 4 , X 5 , and X 8 is H.

[0306] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a cancer patient, a method for treating a cancer patient, a cancer patient comprising administering to a subject a cancer patient, a method for treating ... 1 , X 2 , X 3 , X 6 , and X 8 is OH;X 4 , X 5 , and X 7 is H.

[0307] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a cancer patient, a method for treating a cancer patient, a cancer patient comprising administering to a subject a cancer patient, a method for treating ... 1 , X 2 , X 3 , X 7 , and X 8 is OH;X 4 , X 5 , and X 6 is H.

[0308] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a cancer patient, a method for treating a cancer patient, a cancer patient comprising administering to a subject a cancer patient, a method for treating ... 1 , X 2 , X 4 , X 5 , and X 6 is OH;X 3 , X 7 , and X 8 is H.

[0309] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a cancer patient, a method for treating a cancer patient, a cancer patient comprising administering to a subject a cancer patient, a method for treating ... 1 , X 2 , X 4 , X 5 , and X 8 is OH;X 3 , X 6 , and X 7 is H.

[0310] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a cancer patient, a method for treating a cancer patient, a cancer patient comprising administering to a subject a cancer patient, a method for treating ... 1, X 2 , X 4 , X 6 , and X 7 is OH;X 3 , X 5 , and X 8 is H.

[0311] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a 1 , X 2 , X 4 , X 6 , and X 8 is OH;X 3 , X 5 , and X 7 is H.

[0312] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a 1 , X 2 , X 4 , X 7 , and X 8 is OH;X 3 , X 5 , and X 6 is H.

[0313] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a 1 , X 2 , X 5 , X 6 , and X 7 is OH;X 3 , X 4 , and X 8 is H.

[0314] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a 1 , X 2 , X 5 , X 6 , and X 8 is OH;X 3 , X 4 , and X 7 is H.

[0315] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a cancer patient, a method for treating a cancer patient, a cancer patient comprising administering to a subject a cancer patient, a method for treating ... 1 , X 2 , X 5 , X 7 , and X 8 is OH;X 3 , X 4 , and X 6 is H.

[0316] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a cancer patient, a method for treating a cancer patient, a cancer patient comprising administering to a subject a cancer patient, a method for treating ... 1 , X 3 , X 4 , X 5 , and X 6 is OH;X 2 , X 7 , and X 8 is H.

[0317] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a cancer patient, a method for treating a cancer patient, a cancer patient comprising administering to a subject a cancer patient, a method for treating ... 1 , X 3 , X 4 , X 5 , and X 7 is OH;X 2 , X 6 , and X 8 is H.

[0318] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a cancer patient, a method for treating a cancer patient, a cancer patient comprising administering to a subject a cancer patient, a method for treating ... 1 , X 3 , X 4 , X 5 , and X 8 is OH;X 2 , X 6 , and X 7 is H.

[0319] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a cancer patient, a method for treating a cancer patient, a cancer patient comprising administering to a subject a cancer patient, a method for treating ... 1 , X 3 , X 4 , X 6 , and X 7 is OH;X 2 , X 5 , and X 8is H.

[0320] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a cancer patient, a method for treating a cancer patient, a cancer patient comprising administering to a subject a cancer patient, a method for treating ... 1 , X 3 , X 4 , X 6 , and X 8 is OH;X 2 , X 5 , and X 7 is H.

[0321] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a cancer patient, a method for treating a cancer patient, a cancer patient comprising administering to a subject a cancer patient, a method for treating ... 1 , X 3 , X 4 , X 7 , and X 8 is OH;X 2 , X 5 , and X 7 is H.

[0322] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a cancer patient, a method for treating a cancer patient, a cancer patient comprising administering to a subject a cancer patient, a method for treating ... 1 , X 3 , X 5 , X 6 , and X 7 is OH;X 2 , X 4 , and X 8 is H.

[0323] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a cancer patient, a method for treating a cancer patient, a cancer patient comprising administering to a subject a cancer patient, a method for treating ... 1 , X 3 , X 5 , X 6 , and X 8 is OH;X 2 , X 4 , and X 7 is H.

[0324] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a cancer patient, a method for treating a cancer patient, a cancer patient comprising administering to a subject a cancer patient, a method for treating ... 1 , X 3 , X 5 , X 7 , and X 8 is OH;X 2, X 4 , and X 6 is H.

[0325] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a cancer patient, a method for treating a cancer patient, a cancer patient comprising administering to a subject a cancer patient, a method for treating ... 1 , X 3 , X 6 , X 7 , and X 8 is OH;X 2 , X 4 , and X 5 is H.

[0326] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a cancer patient, a method for treating a cancer patient, a cancer patient comprising administering to a subject a cancer patient, a method for treating ... 1 , X 4 , X 5 , X 6 , and X 7 is OH;X 2 , X 3 , and X 8 is H.

[0327] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a cancer patient, a method for treating a cancer patient, a cancer patient comprising administering to a subject a cancer patient, a method for treating ... 1 , X 4 , X 5 , X 6 , and X 8 is OH;X 2 , X 3 , and X 7 is H.

[0328] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a cancer patient, a method for treating a cancer patient, a cancer patient comprising administering to a subject a cancer patient, a method for treating ... 1 , X 4 , X 5 , X 7 , and X 8 is OH;X 2 , X 3 , and X 6 is H.

[0329] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a cancer patient, a method for treating a cancer patient, a cancer patient comprising administering to a subject a cancer patient, a method for treating ... 1 , X 4 , X 6 , X 7 , and X8 is OH;X 2 , X 3 , and X 6 is H.

[0330] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a cancer patient, a method for treating a cancer patient, a cancer patient comprising administering to a subject a cancer patient, a method for treating ... 1 , X 5 , X 6 , X 7 , and X 8 is OH;X 2 , X 3 , and X 4 is H.

[0331] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a cancer patient, a method for treating a cancer patient, a cancer patient comprising administering to a subject a cancer patient, a method for treating ... 2 , X 3 , X 4 , X 5 , and X 6 is OH;X 1 , X 7 , and X 8 is H.

[0332] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a cancer patient, a method for treating a cancer patient, a cancer patient comprising administering to a subject a cancer patient, a method for treating ... 2 , X 3 , X 4 , X 5 , and X 7 is OH;X 1 , X 6 , and X 8 is H.

[0333] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a cancer patient, a method for treating a cancer patient, a cancer patient comprising administering to a subject a cancer patient, a method for treating ... 2 , X 3 , X 4 , X 5 , and X 8 is OH;X 1 , X 6 , and X 7 is H.

[0334] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a cancer patient, a method for treating a cancer patient, a cancer patient comprising administering to a subject a cancer patient, a method for treating ... 2 , X 3 , X4 , X 6 , and X 7 is OH;X 1 , X 5 , and X 8 is H.

[0335] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a 2 , X 3 , X 4 , X 6 , and X 8 is OH;X 1 , X 5 , and X 7 is H.

[0336] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a 2 , X 3 , X 4 , X 7 , and X 8 is OH;X 1 , X 5 , and X 6 is H.

[0337] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a 2 , X 3 , X 5 , X 6 , and X 7 is OH;X 1 , X 4 , and X 8 is H.

[0338] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a 2 , X 3 , X 5 , X 6 , and X 8 is OH;X 1 , X 4 , and X 7 is H.

[0339] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a cancer patient, a method for treating a cancer patient, a cancer patient comprising administering to a subject a cancer patient, a method for treating ... 2 , X 3 , X 5 , X 7 , and X 8 is OH;X 1 , X 4 , and X 6 is H.

[0340] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a cancer patient, a method for treating a cancer patient, a cancer patient comprising administering to a subject a cancer patient, a method for treating ... 2 , X 3 , X 6 , X 7 , and X 8 is OH;X 1 , X 4 , and X 5 is H.

[0341] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a cancer patient, a method for treating a cancer patient, a cancer patient comprising administering to a subject a cancer patient, a method for treating ... 2 , X 4 , X 5 , X 6 , and X 7 is OH;X 1 , X 3 , and X 8 is H.

[0342] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a cancer patient, a method for treating a cancer patient, a cancer patient comprising administering to a subject a cancer patient, a method for treating ... 2 , X 4 , X 5 , X 6 , and X 8 is OH;X 1 , X 3 , and X 7 is H.

[0343] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a cancer patient, a method for treating a cancer patient, a cancer patient comprising administering to a subject a cancer patient, a method for treating ... 2 , X 4 , X 5 , X 7 , and X 8 is OH;X 1 , X 3 , and X 6 is H.

[0344] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a cancer patient, a method for treating a cancer patient, a cancer patient comprising administering to a subject a cancer patient, a method for treating ... 2 , X 4 , X 6 , X 7 , and X 8 is OH;X 1 , X 3 , and X 5 is H.

[0345] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a cancer patient, a method for treating a cancer patient, a cancer patient comprising administering to a subject a cancer patient, a method for treating ... 2 , X 5 , X 6 , X 7 , and X 8 is OH;X 1 , X 3 , and X 5 is H.

[0346] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a cancer patient, a method for treating a cancer patient, a cancer patient comprising administering to a subject a cancer patient, a method for treating ... 3 , X 4 , X 5 , X 6 , and X 7 is OH;X 1 , X 2 , and X 8 is H.

[0347] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a cancer patient, a method for treating a cancer patient, a cancer patient comprising administering to a subject a cancer patient, a method for treating ... 3 , X 4 , X 5 , X 6 , and X 8 is OH;X 1 , X 2 , and X 7 is H.

[0348] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a cancer patient, a method for treating a cancer patient, a cancer patient comprising administering to a subject a cancer patient, a method for treating ... 3 , X 4 , X 5 , X 7 , and X 8 is OH;X 1 , X 2 , and X6 is H.

[0349] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a 3 , X 4 , X 6 , X 7 , and X 8 is OH;X 1 , X 2 , and X 5 is H.

[0350] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a 3 , X 5 , X 6 , X 7 , and X 8 is OH;X 1 , X 2 , and X 4 is H.

[0351] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a 4 , X 5 , X 6 , X 7 , and X 8 is OH;X 1 , X 2 , and X 3 is H.

[0352] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a 1 , X 2 , X 3 , X 4 , X 5 , and X 6 is OH;X 7 and X 8 is H.

[0353] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a 1 , X 2 , X 3 , X 4 , X 5 , and X7 is OH;X 6 and X 8 is H.

[0354] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a 1 , X 2 , X 3 , X 4 , X 5 , and X 8 is OH;X 6 and X 7 is H.

[0355] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a 1 , X 2 , X 3 , X 4 , X 6 , and X 7 is OH;X 5 and X 8 is H.

[0356] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a 1 , X 2 , X 3 , X 4 , X 6 , and X 8 is OH;X 5 and X 7 is H.

[0357] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a 1 , X 2 , X 3 , X 4 , X 7 , and X 8 is OH;X 5 and X 6 is H.

[0358] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a 1 , X 2 , X 3 , X5 , X 6 , and X 7 is OH;X 4 and X 8 is H.

[0359] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a 1 , X 2 , X 3 , X 5 , X 6 , and X 8 is OH;X 4 and X 7 is H.

[0360] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a 1 , X 2 , X 3 , X 5 , X 7 , and X 8 is OH;X 4 and X 6 is H.

[0361] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a 1 , X 2 , X 4 , X 5 , X 6 , and X 7 is OH;X 3 and X 8 is H.

[0362] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a 1 , X 2 , X 4 , X 5 , X 6 , and X 8 is OH;X 3 and X 7 is H.

[0363] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a 1 , X2 , X 4 , X 5 , X 7 , and X 8 is OH;X 3 and X 6 is H.

[0364] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a cancer patient, a method for treating a cancer patient, a cancer patient comprising administering to a subject a cancer patient, a method for treating ... 1 , X 2 , X 4 , X 6 , X 7 , and X 8 is OH;X 3 and X 5 is H.

[0365] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a cancer patient, a method for treating a cancer patient, a cancer patient comprising administering to a subject a cancer patient, a method for treating ... 1 , X 2 , X 5 , X 6 , X 7 , and X 8 is OH;X 3 and X 4 is H.

[0366] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a cancer patient, a method for treating a cancer patient, a cancer patient comprising administering to a subject a cancer patient, a method for treating ... 1 , X 3 , X 4 , X 5 , X 6 , and X 7 is OH;X 2 and X 8 is H.

[0367] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a cancer patient, a method for treating a cancer patient, a cancer patient comprising administering to a subject a cancer patient, a method for treating ... 1 , X 3 , X 4 , X 5 , X 6 , and X 8 is OH;X 2 and X 7 is H.

[0368] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a 1 , X 3 , X 4 , X 5 , X 7 , and X 8 is OH;X 2 and X 6 is H.

[0369] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a 1 , X 3 , X 4 , X 6 , X 7 , and X 8 is OH;X 2 and X 5 is H.

[0370] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a 1 , X 3 , X 5 , X 6 , X 7 , and X 8 is OH;X 2 and X 4 is H.

[0371] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a 1 , X 4 , X 5 , X 6 , X 7 , and X 8 is OH;X 2 and X 3 is H.

[0372] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a 2 , X 3 , X 4 , X 5 , X 6 , and X 7 is OH;X 1 and X 8 is H.

[0373] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a 2 , X 3 , X 4 , X 5 , X 6 , and X 8 is OH;X 1 and X 7 is H.

[0374] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a 2 , X 3 , X 4 , X 5 , X 7 , and X 8 is OH;X 1 and X 6 is H.

[0375] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a 2 , X 3 , X 4 , X 6 , X 7 , and X 8 is OH;X 1 and X 5 is H.

[0376] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a 2 , X 3 , X 5 , X 6 , X 7 , and X 8 is OH;X 1 and X 4 is H.

[0377] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a 2 , X 4 , X 5 , X 6 , X 7 , and X 8 is OH;X 1 and X3 is H.

[0378] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a cancer patient, a method for treating a cancer patient, a cancer patient comprising administering to a subject a cancer patient, a method for treating ... 3 , X 4 , X 5 , X 6 , X 7 , and X 8 is OH;X 1 and X 2 is H.

[0379] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a cancer patient, a method for treating a cancer patient, a cancer patient comprising administering to a subject a cancer patient, a method for treating ... 1 , X 2 , X 3 , X 4 , X 5 , X 6 , and X 7 is OH;X 8 is H.

[0380] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a cancer patient, a method for treating a cancer patient, a cancer patient comprising administering to a subject a cancer patient, a method for treating ... 1 , X 2 , X 3 , X 4 , X 5 , X 6 , and X 8 is OH;X 7 is H.

[0381] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a cancer patient, a method for treating a cancer patient, a cancer patient comprising administering to a subject a cancer patient, a method for treating ... 1 , X 2 , X 3 , X 4 , X 5 , X 7 , and X 8 is OH;X 6 is H.

[0382] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a cancer patient, a method for treating a cancer patient, a cancer patient comprising administering to a subject a cancer patient, a method for treating ... 1 , X 2 , X 3 , X 4 , X 6 , X 7 , and X8 is OH;X 5 is H.

[0383] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a cancer patient, a method for treating a cancer patient, a cancer patient comprising administering to a subject a cancer patient, a method for treating ... 1 , X 2 , X 3 , X 5 , X 6 , X 7 , and X 8 is OH;X 4 is H.

[0384] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a cancer patient, a method for treating a cancer patient, a cancer patient comprising administering to a subject a cancer patient, a method for treating ... 1 , X 2 , X 4 , X 5 , X 6 , X 7 , and X 8 is OH;X 3 is H.

[0385] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a cancer patient, a method for treating a cancer patient, a cancer patient comprising administering to a subject a cancer patient, a method for treating ... 1 , X 3 , X 4 , X 5 , X 6 , X 7 , and X 8 is OH;X 2 is H.

[0386] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a cancer patient, a method for treating a cancer patient, a cancer patient comprising administering to a subject a cancer patient, a method for treating ... 2 , X 3 , X 4 , X 5 , X 6 , X 7 , and X 8 is OH;X 1 is H.

[0387] In one embodiment, the present invention relates to a compound of formula III: [ka] During the ceremony, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 is independently selected from the group consisting of H and OR; R is H, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted monosaccharide, or substituted or unsubstituted oligosaccharide; However, the compound is R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 is H; R 1 is OR and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 is H; R 2 is OR and R 1 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 is H; R 3 is OR and R 1 , R 2 , R 4 , R 5 , R 6 , R 7 , and R 8 is H; R 4 is OR and R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , and R 8 is H; R 5 is OR and R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , and R 8 is H; R 6 is OR and R 1 , R 2 , R 3 , R 4 , R 5 , R 7 , and R 8 is H; R 7 is OR and R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 8 is H; R 8 is OR and R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 is H; R 1 and R 2 is OR and R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 is H; R 1 and R 5 is OR and R 2 , R 3 , R 4 , R 6 , R 7 , and R 8 is H; R 1 and R 7 is OR and R 2 , R 3 , R 4 , R 5 , R6 , and R 8 is H; R 1 and R 8 is OR and R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 is H; R 2 and R 3 is OR and R 1 , R 4 , R 5 , R 6 , R 7 , and R 8 is H; R 2 and R 4 is OR and R 1 , R 3 , R 5 , R 6 , R 7 , and R 8 is H; R 2 and R 5 is OR and R 1 , R 3 , R 4 , R 6 , R 7 , and R 8 is H; R 2 and R 6 is OR and R 1 , R 3 , R 4 , R 5 , R 7 , and R 8 is H; R 2 and R 7 is OR and R 1 , R 3 , R 4 , R 5 , R 6 , and R 8 is H; R 2 and R 8 is OR and R 1 , R3 , R 4 , R 5 , R 6 , and R 7 is H; R 3 and R 4 is OR and R 1 , R 2 , R 5 , R 6 , R 7 , and R 8 is H; R 3 and R 5 is OR and R 1 , R 2 , R 4 , R 6 , R 7 , and R 8 is H; R 3 and R 6 is OR and R 1 , R 2 , R 4 , R 5 , R 7 , and R 8 is H; R 3 and R 7 is OR and R 1 , R 2 , R 4 , R 5 , R 6 , and R 8 is H; R 3 and R 8 is OR and R 1 , R 2 , R 4 , R 5 , R 6 , and R 7 is H; R 4 and R 8 is OR and R 1 , R 2 , R 3 , R 5 , R 6 , and R 7 is H; R 5and R 6 is OR and R 1 , R 2 , R 3 , R 4 , R 7 , and R 8 is H; R 5 and R 7 is OR and R 1 , R 2 , R 3 , R 4 , R 6 , and R 8 is H; R 5 and R 8 is OR and R 1 , R 2 , R 3 , R 4 , R 6 , and R 7 is H; R 6 and R 7 is OR and R 1 , R 2 , R 3 , R 4 , R 5 , and R 8 is H; R 6 and R 8 is OR and R 1 , R 2 , R 3 , R 4 , R 5 , and R 7 is H; R 1 , R 2 , and R 3 is OR and R 4 , R 5 , R 6 , R 7 , and R 8 is H; R 1 , R 2 , and R 5 is OR and R 3 , R 4 , R 6 , R 7 , and R8 is H; R 1 , R 2 , and R 6 is OR and R 3 , R 4 , R 5 , R 7 , and R 8 is H; R 1 , R 2 , and R 8 is OR and R 3 , R 4 , R 5 , R 6 , and R 7 is H; R 1 , R 5 , and R 8 is OR and R 2 , R 3 , R 4 , R 6 , and R 7 is H; R 1 , R 7 , and R 8 is OR and R 2 , R 3 , R 4 , R 5 , and R 6 is H; R 2 , R 3 , and R 4 is OR and R 1 , R 5 , R 6 , R 7 , and R 8 is H; R 2 , R 4 , and R 6 is OR and R 1 , R 3 , R 5 , R 7 , and R 8 is H; R 2 , R 4 , and R 7 is OR and R 1 , R3 , R 5 , R 6 , and R 8 is H; R 2 , R 5 , and R 8 is OR and R 1 , R 3 , R 4 , R 6 , and R 7 is H; R 2 , R 6 , and R 7 is OR and R 1 , R 3 , R 4 , R 5 , and R 8 is H; R 2 , R 6 , and R 8 is OR and R 1 , R 3 , R 4 , R 5 , and R 7 is H; R 2 , R 7 , and R 8 is OR and R 1 , R 3 , R 4 , R 5 , and R 6 is H; R 3 , R 5 , and R 8 is OR and R 1 , R 2 , R 4 , R 6 , and R 7 is H; R 3 , R 7 , and R 8 is OR and R 1 , R 2 , R 4 , R 5 , and R 6 is H; R 6 , R7 , and R 8 is OR and R 1 , R 2 , R 3 , R 4 , and R 5 is H; R 1 , R 2 , R 5 , and R 6 is OR and R 3 , R 4 , R 7 , and R 8 is H; R 1 , R 2 , R 5 , and R 7 is OR and R 3 , R 4 , R 6 , and R 8 is H; R 1 , R 2 , R 6 , and R 7 is OR and R 3 , R 4 , R 5 , and R 8 is H; R 1 , R 6 , R 7 , and R 8 is OR and R 2 , R 3 , R 4 , and R 5 is H; R 2 , R 3 , R 4 , and R 6 is OR and R 1 , R 5 , R 7 , and R 8 is H; R 2 , R 3 , R 5 , and R 7 is OR and R 1 , R 4 , R 6 , and R8 is H; R 2 , R 3 , R 6 , and R 7 is OR and R 1 , R 4 , R 5 , and R 8 is H; R 2 , R 4 , R 5 , and R 8 is OR and R 1 , R 3 , R 6 , and R 7 is H; R 2 , R 4 , R 6 , and R 7 is OR and R 1 , R 3 , R 5 , and R 8 is H; R 2 , R 5 , R 6 , and R 7 is OR and R 1 , R 3 , R 4 , and R 8 is H; R 2 , R 6 , R 7 , and R 8 is OR and R 1 , R 3 , R 4 , and R 5 is H; R 1 , R 2 , R 4 , R 5 , and R 7 is OR and R 3 , R 6 , and R 8 is H; R 1 , R 2 , R 6 , R 7 , and R8 is OR and R 3 , R 4 , and R 5 is H; R 2 , R 3 , R 4 , R 5 , and R 7 is OR and R 1 , R 6 , and R 8 is H; R 2 , R 3 , R 6 , R 7 , and R 8 is OR and R 1 , R 4 , and R 5 is H; R 2 , R 4 , R 6 , R 7 , and R 8 is OR and R 1 , R 3 , and R 5 is H; R 2 , R 5 , R 6 , R 7 , and R 8 is OR and R 1 , R 3 , and R 4 is H; R 1 , R 2 , R 3 , R 6 , R 7 , and R 8 is OR and R 4 and R 5 is H; R 2 , R 3 , R 4 , R 6 , R 7 , and R 8 is OR and R 1 and R 5 is H; and R 2 , R4 , R 5 , R 6 , R 7 , and R 8 is OR and R 1 and R 3 is H, Not a compound of formula III.

[0388] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 wherein at least two of are OR.

[0389] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 wherein at least three of are OR.

[0390] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 wherein at least four of are OR.

[0391] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 any one of the aforementioned compounds, wherein at least five of are OR.

[0392] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 wherein at least six of are OR.

[0393] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 wherein at least seven of are OR.

[0394] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 is OR.

[0395] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 1 and R 3 is OR;R 2 , R 4 , R 5 , R 6 , R 7 , and R 8 is H.

[0396] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 1 and R 4 is OR;R 2 , R 3 , R 5 , R 6 , R 7 , and R 8is H.

[0397] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 1 and R 6 is OR;R 2 , R 3 , R 4 , R 5 , R 7 , and R 8 is H.

[0398] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 4 and R 5 is OR;R 1 , R 2 , R 3 , R 6 , R 7 , and R 8 is H.

[0399] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 4 and R 6 is OR;R 1 , R 2 , R 3 , R 5 , R 7 , and R 8 is H.

[0400] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 4 and R 7 is OR;R 1 , R 2 , R 3 , R 5 , R 6 , and R 8 is H.

[0401] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 7 and R 8 is OR;R 1 , R 2 , R 3 , R 4 , R5 , and R 6 is H.

[0402] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 1 , R 2 , and R 4 is OR;R 3 , R 5 , R 6 , R 7 , and R 8 is H.

[0403] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 1 , R 2 , and R 7 is OR;R 3 , R 4 , R 5 , R 6 , and R 8 is H.

[0404] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 1 , R 3 , and R 4 is OR;R 2 , R 5 , R 6 , R 7 , and R 8 is H.

[0405] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 1 , R 3 , and R 5 is OR;R 2 , R 4 , R 6 , R 7 , and R 8 is H.

[0406] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 1 , R 3 , and R 6 is OR;R 2, R 4 , R 5 , R 7 , and R 8 is H.

[0407] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 1 , R 3 , and R 7 is OR;R 2 , R 4 , R 5 , R 6 , and R 8 is H.

[0408] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 1 , R 3 , and R 8 is OR;R 2 , R 4 , R 5 , R 6 , and R 7 is H.

[0409] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 1 , R 4 , and R 5 is OR;R 2 , R 3 , R 6 , R 7 , and R 8 is H.

[0410] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 1 , R 4 , and R 6 is OR;R 2 , R 3 , R 5 , R 7 , and R 8 is H.

[0411] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 1 , R 4 , and R7 is OR;R 2 , R 3 , R 5 , R 6 , and R 8 is H.

[0412] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 1 , R 4 , and R 8 is OR;R 2 , R 3 , R 5 , R 6 , and R 7 is H.

[0413] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 1 , R 5 , and R 6 is OR;R 2 , R 3 , R 4 , R 7 , and R 8 is H.

[0414] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 1 , R 5 , and R 7 is OR;R 2 , R 3 , R 4 , R 6 , and R 8 is H.

[0415] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 1 , R 6 , and R 7 is OR;R 2 , R 3 , R 4 , R 5 , and R 8 is H.

[0416] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a1 , R 6 , and R 8 is OR;R 2 , R 3 , R 4 , R 5 , and R 7 is H.

[0417] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 2 , R 3 , and R 5 is OR;R 1 , R 4 , R 6 , R 7 , and R 8 is H.

[0418] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 2 , R 3 , and R 6 is OR;R 1 , R 4 , R 5 , R 7 , and R 8 is H.

[0419] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 2 , R 3 , and R 7 is OR;R 1 , R 4 , R 5 , R 6 , and R 8 is H.

[0420] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 2 , R 3 , and R 8 is OR;R 1 , R 4 , R 5 , R 6 , and R 7 is H.

[0421] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 2 , R 4 , and R 5 is OR;R 1 , R 3 , R 6 , R 7 , and R 8 is H.

[0422] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 2 , R 4 , and R 8 is OR;R 1 , R 3 , R 5 , R 6 , and R 7 is H.

[0423] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 2 , R 5 , and R 6 is OR;R 1 , R 3 , R 4 , R 7 , and R 8 is H.

[0424] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 2 , R 5 , and R 7 is OR;R 1 , R 3 , R 4 , R 6 , and R 8 is H.

[0425] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 3 , R 4 , and R 5 is OR;R 1 , R 2 , R 6 , R 7 , and R 8is H.

[0426] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 3 , R 4 , and R 6 is OR;R 1 , R 2 , R 5 , R 7 , and R 8 is H.

[0427] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 3 , R 4 , and R 7 is OR;R 1 , R 2 , R 5 , R 6 , and R 8 is H.

[0428] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 3 , R 4 , and R 8 is OR;R 1 , R 2 , R 5 , R 6 , and R 7 is H.

[0429] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 3 , R 5 , and R 6 is OR;R 1 , R 2 , R 4 , R 7 , and R 8 is H.

[0430] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 3 , R 5 , and R 7 is OR;R 1 , R 2 , R 4, R 6 , and R 8 is H.

[0431] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 3 , R 6 , and R 7 is OR;R 1 , R 2 , R 4 , R 5 , and R 8 is H.

[0432] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 3 , R 6 , and R 8 is OR;R 1 , R 2 , R 4 , R 5 , and R 7 is H.

[0433] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 4 , R 5 , and R 6 is OR;R 1 , R 2 , R 3 , R 7 , and R 8 is H.

[0434] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 4 , R 5 , and R 7 is OR;R 1 , R 2 , R 3 , R 6 , and R 8 is H.

[0435] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 4 , R 5 , and R 8 is OR;R1 , R 2 , R 3 , R 6 , and R 7 is H.

[0436] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 4 , R 6 , and R 7 is OR;R 1 , R 2 , R 3 , R 5 , and R 8 is H.

[0437] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 4 , R 6 , and R 8 is OR;R 1 , R 2 , R 3 , R 5 , and R 7 is H.

[0438] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 4 , R 7 , and R 8 is OR;R 1 , R 2 , R 3 , R 5 , and R 6 is H.

[0439] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 5 , R 6 , and R 7 is OR;R 1 , R 2 , R 3 , R 4 , and R 8 is H.

[0440] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 5 , R6 , and R 8 is OR;R 1 , R 2 , R 3 , R 4 , and R 7 is H.

[0441] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 5 , R 7 , and R 8 is OR;R 1 , R 2 , R 3 , R 4 , and R 6 is H.

[0442] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 1 , R 2 , R 3 , and R 4 is OR;R 5 , R 6 , R 7 , and R 8 is H.

[0443] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 1 , R 2 , R 3 , and R 5 is OR;R 4 , R 6 , R 7 , and R 8 is H.

[0444] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 1 , R 2 , R 3 , and R 6 is OR;R 4 , R 5 , R 7 , and R 8 is H.

[0445] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 1 , R 2 , R 3 , and R 7 is OR;R 4 , R 5 , R 6 , and R 8 is H.

[0446] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 1 , R 2 , R 3 , and R 8 is OR;R 4 , R 5 , R 6 , and R 7 is H.

[0447] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 1 , R 2 , R 4 , and R 5 is OR;R 3 , R 6 , R 7 , and R 8 is H.

[0448] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 1 , R 2 , R 4 , and R 6 is OR;R 3 , R 5 , R 7 , and R 8 is H.

[0449] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 1 , R 2 , R 4 , and R 7 is OR;R 3 , R 5 , R 6 , and R 8 is H.

[0450] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 1 , R 2 , R 4 , and R 8 is OR;R 3 , R 5 , R 6 , and R 7 is H.

[0451] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 1 , R 2 , R 5 , and R 8 is OR;R 3 , R 4 , R 6 , and R 7 is H.

[0452] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 1 , R 2 , R 6 , and R 8 is OR;R 3 , R 4 , R 5 , and R 7 is H.

[0453] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 1 , R 2 , R 7 , and R 8 is OR;R 3 , R 4 , R 5 , and R 6 is H.

[0454] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 1 , R 3 , R 4 , and R 5 is OR;R 2 , R 6 , R 7 , and R8 is H.

[0455] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 1 , R 3 , R 4 , and R 6 is OR;R 2 , R 5 , R 7 , and R 8 is H.

[0456] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 1 , R 3 , R 4 , and R 7 is OR;R 2 , R 5 , R 6 , and R 8 is H.

[0457] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 1 , R 3 , R 4 , and R 8 is OR;R 2 , R 5 , R 6 , and R 7 is H.

[0458] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 1 , R 3 , R 5 , and R 6 is OR;R 2 , R 4 , R 7 , and R 8 is H.

[0459] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 1 , R 3 , R 5 , and R 7 is OR;R 2 , R4 , R 6 , and R 8 is H.

[0460] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 1 , R 3 , R 5 , and R 8 is OR;R 2 , R 4 , R 6 , and R 7 is H.

[0461] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 1 , R 3 , R 6 , and R 7 is OR;R 2 , R 4 , R 5 , and R 8 is H.

[0462] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 1 , R 3 , R 6 , and R 8 is OR;R 2 , R 4 , R 5 , and R 7 is H.

[0463] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 1 , R 3 , R 7 , and R 8 is OR;R 2 , R 4 , R 5 , and R 6 is H.

[0464] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 1 , R 4 , R 5 , and R6 is OR;R 2 , R 3 , R 7 , and R 8 is H.

[0465] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 1 , R 4 , R 5 , and R 7 is OR;R 2 , R 3 , R 6 , and R 8 is H.

[0466] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 1 , R 4 , R 5 , and R 8 is OR;R 2 , R 3 , R 6 , and R 7 is H.

[0467] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 1 , R 4 , R 6 , and R 7 is OR;R 2 , R 3 , R 5 , and R 8 is H.

[0468] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 1 , R 4 , R 6 , and R 8 is OR;R 2 , R 3 , R 5 , and R 7 is H.

[0469] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 1 , R4 , R 7 , and R 8 is OR;R 2 , R 3 , R 5 , and R 6 is H.

[0470] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 1 , R 5 , R 6 , and R 7 is OR;R 2 , R 3 , R 4 , and R 8 is H.

[0471] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 1 , R 5 , R 6 , and R 8 is OR;R 2 , R 3 , R 4 , and R 7 is H.

[0472] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 1 , R 5 , R 7 , and R 8 is OR;R 2 , R 3 , R 4 , and R 6 is H.

[0473] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 2 , R 3 , R 4 , and R 5 is OR;R 1 , R 6 , R 7 , and R 8 is H.

[0474] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 2 , R 3 , R 4 , and R 7 is OR;R 1 , R 5 , R 6 , and R 8 is H.

[0475] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 2 , R 3 , R 4 , and R 8 is OR;R 1 , R 5 , R 6 , and R 7 is H.

[0476] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 2 , R 3 , R 5 , and R 6 is OR;R 1 , R 4 , R 7 , and R 8 is H.

[0477] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 2 , R 3 , R 5 , and R 8 is OR;R 1 , R 4 , R 6 , and R 7 is H.

[0478] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 2 , R 3 , R 6 , and R 8 is OR;R 1 , R 4 , R 5 , and R 7 is H.

[0479] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 2 , R 3 , R 7 , and R 8 is OR;R 1 , R 4 , R 6 , and R 7 is H.

[0480] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 2 , R 4 , R 5 , and R 6 is OR;R 1 , R 3 , R 7 , and R 8 is H.

[0481] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 2 , R 4 , R 5 , and R 7 is OR;R 1 , R 3 , R 6 , and R 8 is H.

[0482] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 2 , R 4 , R 6 , and R 8 is OR;R 1 , R 3 , R 5 , and R 7 is H.

[0483] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 2 , R 4 , R 7 , and R 8 is OR;R 1 , R 3 , R 5 , and R6 is H.

[0484] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 2 , R 5 , R 6 , and R 8 is OR;R 1 , R 3 , R 4 , and R 7 is H.

[0485] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 2 , R 5 , R 7 , and R 8 is OR;R 1 , R 3 , R 4 , and R 6 is H.

[0486] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 3 , R 4 , R 5 , and R 6 is OR;R 1 , R 2 , R 7 , and R 8 is H.

[0487] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 3 , R 4 , R 5 , and R 7 is OR;R 1 , R 2 , R 6 , and R 8 is H.

[0488] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 3 , R 4 , R 5 , and R 8 is OR;R 1 , R2 , R 6 , and R 7 is H.

[0489] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 3 , R 4 , R 6 , and R 7 is OR;R 1 , R 2 , R 5 , and R 8 is H.

[0490] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 3 , R 4 , R 6 , and R 8 is OR;R 1 , R 2 , R 5 , and R 7 is H.

[0491] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 3 , R 4 , R 7 , and R 8 is OR;R 1 , R 2 , R 5 , and R 6 is H.

[0492] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 3 , R 5 , R 6 , and R 7 is OR;R 1 , R 2 , R 4 , and R 8 is H.

[0493] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 3 , R 5 , R 6 , and R8 is OR;R 1 , R 2 , R 4 , and R 7 is H.

[0494] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 3 , R 5 , R 7 , and R 8 is OR;R 1 , R 2 , R 4 , and R 6 is H.

[0495] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 3 , R 6 , R 7 , and R 8 is OR;R 1 , R 2 , R 4 , and R 5 is H.

[0496] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 4 , R 5 , R 6 , and R 7 is OR;R 1 , R 2 , R 3 , and R 8 is H.

[0497] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 4 , R 5 , R 6 , and R 8 is OR;R 1 , R 2 , R 3 , and R 7 is H.

[0498] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 4 , R5 , R 7 , and R 8 is OR;R 1 , R 2 , R 3 , and R 6 is H.

[0499] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 4 , R 6 , R 7 , and R 8 is OR;R 1 , R 2 , R 3 , and R 5 is H.

[0500] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 5 , R 6 , R 7 , and R 8 is OR;R 1 , R 2 , R 3 , and R 4 is H.

[0501] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 1 , R 2 , R 3 , R 4 , and R 5 is OR;R 6 , R 7 , and R 8 is H.

[0502] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 1 , R 2 , R 3 , R 4 , and R 6 is OR;R 5 , R 7 , and R 8 is H.

[0503] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 1 , R 2 , R 3 , R 4 , and R 7 is OR;R 5 , R 6 , and R 8 is H.

[0504] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 1 , R 2 , R 3 , R 4 , and R 8 is OR;R 5 , R 6 , and R 7 is H.

[0505] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 1 , R 2 , R 3 , R 5 , and R 6 is OR;R 4 , R 7 , and R 8 is H.

[0506] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 1 , R 2 , R 3 , R 5 , and R 7 is OR;R 4 , R 6 , and R 8 is H.

[0507] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 1 , R 2 , R 3 , R 5 , and R 8 is OR;R 4 , R 6 , and R 7 is H.

[0508] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 1 , R 2 , R 3 , R 6 , and R 7 is OR;R 4 , R 5 , and R 8 is H.

[0509] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 1 , R 2 , R 3 , R 6 , and R 8 is OR;R 4 , R 5 , and R 7 is H.

[0510] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 1 , R 2 , R 3 , R 7 , and R 8 is OR;R 4 , R 5 , and R 6 is H.

[0511] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 1 , R 2 , R 4 , R 5 , and R 6 is OR;R 3 , R 7 , and R 8 is H.

[0512] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 1 , R 2 , R 4 , R 5 , and R 8 is OR;R 3 , R 6 , and R7 is H.

[0513] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 1 , R 2 , R 4 , R 6 , and R 7 is OR;R 3 , R 5 , and R 8 is H.

[0514] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 1 , R 2 , R 4 , R 6 , and R 8 is OR;R 3 , R 5 , and R 7 is H.

[0515] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 1 , R 2 , R 4 , R 7 , and R 8 is OR;R 3 , R 5 , and R 6 is H.

[0516] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 1 , R 2 , R 5 , R 6 , and R 7 is OR;R 3 , R 4 , and R 8 is H.

[0517] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 1 , R 2 , R 5 , R 6 , and R 8 is OR;R3 , R 4 , and R 7 is H.

[0518] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 1 , R 2 , R 5 , R 7 , and R 8 is OR;R 3 , R 4 , and R 6 is H.

[0519] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 1 , R 3 , R 4 , R 5 , and R 6 is OR;R 2 , R 7 , and R 8 is H.

[0520] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 1 , R 3 , R 4 , R 5 , and R 7 is OR;R 2 , R 6 , and R 8 is H.

[0521] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 1 , R 3 , R 4 , R 5 , and R 8 is OR;R 2 , R 6 , and R 7 is H.

[0522] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 1 , R 3 , R 4 , R6 , and R 7 is OR;R 2 , R 5 , and R 8 is H.

[0523] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 1 , R 3 , R 4 , R 6 , and R 8 is OR;R 2 , R 5 , and R 7 is H.

[0524] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 1 , R 3 , R 4 , R 7 , and R 8 is OR;R 2 , R 5 , and R 7 is H.

[0525] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 1 , R 3 , R 5 , R 6 , and R 7 is OR;R 2 , R 4 , and R 8 is H.

[0526] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 1 , R 3 , R 5 , R 6 , and R 8 is OR;R 2 , R 4 , and R 7 is H.

[0527] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 1, R 3 , R 5 , R 7 , and R 8 is OR;R 2 , R 4 , and R 6 is H.

[0528] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 1 , R 3 , R 6 , R 7 , and R 8 is OR;R 2 , R 4 , and R 5 is H.

[0529] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 1 , R 4 , R 5 , R 6 , and R 7 is OR;R 2 , R 3 , and R 8 is H.

[0530] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 1 , R 4 , R 5 , R 6 , and R 8 is OR;R 2 , R 3 , and R 7 is H.

[0531] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 1 , R 4 , R 5 , R 7 , and R 8 is OR;R 2 , R 3 , and R 6 is H.

[0532] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 1 , R 4 , R 6 , R 7 , and R 8 is OR;R 2 , R 3 , and R 6 is H.

[0533] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 1 , R 5 , R 6 , R 7 , and R 8 is OR;R 2 , R 3 , and R 4 is H.

[0534] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 2 , R 3 , R 4 , R 5 , and R 6 is OR;R 1 , R 7 , and R 8 is H.

[0535] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 2 , R 3 , R 4 , R 5 , and R 8 is OR;R 1 , R 6 , and R 7 is H.

[0536] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 2 , R 3 , R 4 , R 6 , and R 7 is OR;R 1 , R 5 , and R 8is H.

[0537] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 2 , R 3 , R 4 , R 6 , and R 8 is OR;R 1 , R 5 , and R 7 is H.

[0538] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 2 , R 3 , R 4 , R 7 , and R 8 is OR;R 1 , R 5 , and R 6 is H.

[0539] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 2 , R 3 , R 5 , R 6 , and R 7 is OR;R 1 , R 4 , and R 8 is H.

[0540] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 2 , R 3 , R 5 , R 6 , and R 8 is OR;R 1 , R 4 , and R 7 is H.

[0541] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 2 , R 3 , R 5 , R 7 , and R 8 is OR;R 1, R 4 , and R 6 is H.

[0542] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 2 , R 4 , R 5 , R 6 , and R 7 is OR;R 1 , R 3 , and R 8 is H.

[0543] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 2 , R 4 , R 5 , R 6 , and R 8 is OR;R 1 , R 3 , and R 7 is H.

[0544] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 2 , R 4 , R 5 , R 7 , and R 8 is OR;R 1 , R 3 , and R 6 is H.

[0545] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 3 , R 4 , R 5 , R 6 , and R 7 is OR;R 1 , R 2 , and R 8 is H.

[0546] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 3 , R 4 , R 5 , R 6 , and R8 is OR;R 1 , R 2 , and R 7 is H.

[0547] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 3 , R 4 , R 5 , R 7 , and R 8 is OR;R 1 , R 2 , and R 6 is H.

[0548] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 3 , R 4 , R 6 , R 7 , and R 8 is OR;R 1 , R 2 , and R 5 is H.

[0549] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 3 , R 5 , R 6 , R 7 , and R 8 is OR;R 1 , R 2 , and R 4 is H.

[0550] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 4 , R 5 , R 6 , R 7 , and R 8 is OR;R 1 , R 2 , and R 3 is H.

[0551] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 1 , R 2 , R3 , R 4 , R 5 , and R 6 is OR;R 7 and R 8 is H.

[0552] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 1 , R 2 , R 3 , R 4 , R 5 , and R 7 is OR;R 6 and R 8 is H.

[0553] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 1 , R 2 , R 3 , R 4 , R 5 , and R 8 is OR;R 6 and R 7 is H.

[0554] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 1 , R 2 , R 3 , R 4 , R 6 , and R 7 is OR;R 5 and R 8 is H.

[0555] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 1 , R 2 , R 3 , R 4 , R 6 , and R 8 is OR;R 5 and R 7 is H.

[0556] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a1 , R 2 , R 3 , R 4 , R 7 , and R 8 is OR;R 5 and R 6 is H.

[0557] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 1 , R 2 , R 3 , R 5 , R 6 , and R 7 is OR;R 4 and R 8 is H.

[0558] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 1 , R 2 , R 3 , R 5 , R 6 , and R 8 is OR;R 4 and R 7 is H.

[0559] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 1 , R 2 , R 3 , R 5 , R 7 , and R 8 is OR;R 4 and R 6 is H.

[0560] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 1 , R 2 , R 4 , R 5 , R 6 , and R 7 is OR;R 3 and R 8 is H.

[0561] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 1 , R 2 , R 4 , R 5 , R 6 , and R 8 is OR;R 3 and R 7 is H.

[0562] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 1 , R 2 , R 4 , R 5 , R 7 , and R 8 is OR;R 3 and R 6 is H.

[0563] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 1 , R 2 , R 4 , R 6 , R 7 , and R 8 is OR;R 3 and R 5 is H.

[0564] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 1 , R 2 , R 5 , R 6 , R 7 , and R 8 is OR;R 3 and R 4 is H.

[0565] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 1 , R 3 , R 4 , R 5 , R 6 , and R 7 is OR;R 2 and R 8is H.

[0566] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 1 , R 3 , R 4 , R 5 , R 6 , and R 8 is OR;R 2 and R 7 is H.

[0567] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 1 , R 3 , R 4 , R 5 , R 7 , and R 8 is OR;R 2 and R 6 is H.

[0568] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 1 , R 3 , R 4 , R 6 , R 7 , and R 8 is OR;R 2 and R 5 is H.

[0569] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 1 , R 3 , R 5 , R 6 , R 7 , and R 8 is OR;R 2 and R 4 is H.

[0570] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 1 , R 4 , R 5 , R 6 , R 7 , and R 8 is OR;R2 and R 3 is H.

[0571] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 2 , R 3 , R 4 , R 5 , R 6 , and R 7 is OR;R 1 and R 8 is H.

[0572] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 2 , R 3 , R 4 , R 5 , R 6 , and R 8 is OR;R 1 and R 7 is H.

[0573] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 2 , R 3 , R 4 , R 5 , R 7 , and R 8 is OR;R 1 and R 6 is H.

[0574] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 2 , R 3 , R 5 , R 6 , R 7 , and R 8 is OR;R 1 and R 4 is H.

[0575] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 3 , R 4 , R 5 , R 6 , R 7, and R 8 is OR;R 1 and R 2 is H.

[0576] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 is OR;R 8 is H.

[0577] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 8 is OR;R 7 is H.

[0578] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 1 , R 2 , R 3 , R 4 , R 5 , R 7 , and R 8 is OR;R 6 is H.

[0579] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 1 , R 2 , R 3 , R 4 , R 6 , R 7 , and R 8 is OR;R 5 is H.

[0580] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 1 , R 2 , R 3 , R5 , R 6 , R 7 , and R 8 is OR;R 4 is H.

[0581] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 1 , R 2 , R 4 , R 5 , R 6 , R 7 , and R 8 is OR;R 3 is H.

[0582] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 1 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 is OR;R 2 is H.

[0583] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 is OR;R 1 is H.

[0584] In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R is H.

[0585] As used herein, the term "urolithin precursor" refers to ellagic acid and any ellagitannin that can be converted to one or more urolithins after administration to an animal. In one embodiment, a "urolithin precursor" is a compound of formula IV: [ka] During the ceremony, R 9 , R 10 , R 11 , R 12 , R 13 , and R 14 is independently selected from the group consisting of H and OR; R is H, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted monosaccharide, or substituted or unsubstituted oligosaccharide.

[0586] In one embodiment, the present invention relates to a compound of formula V: [ka] During the ceremony, X 9 , X 10 , X 11 , X 12 , X 13 , and X 14 is independently selected from the group consisting of H and OH; However, the compound is X 9 , X 10 , X 11 , X 12 , X 13 , and X 14 is H; X 10 is OH and X 9 , X 11 , X 12 , X 13 , and X 14 is H; X 9 and X 12 is OH and X 10 , X 11 , X 13 , and X 14 is H; X 9 and X 13 is OH and X 10 , X 11 , X 12 , and X 14 is H; X9 and X 14 is OH and X 10 , X 11 , X 12 , and X 13 is H; X 10 and X 13 is OH and X 9 , X 11 , X 12 , and X 14 is H; X 10 , X 11 , and X 13 is OH and X 9 , X 12 , and X 14 is H; X 9 , X 10 , X 12 , and X 14 is OH and X 11 , and X 13 is H; X 9 , X 10 , X 13 , and X 14 is OH and X 11 , and X 12 is H (ellagic acid); X 9 , X 10 , X 11 , X 13 , and X 14 is OH and X 12 is H; and X 9 , X 10 , X 11 , X 12 , X 13 , and X 14 is OH, Not a compound of formula V.

[0587] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a cancer patient, a method for treating a cancer patient, a cancer patient comprising administering to a subject a cancer patient, a method for treating ... 9 , X 10 , X 11 , X 12 , X 13 , and X 14wherein at least one of is OH.

[0588] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a cancer patient, a method for treating a cancer patient, a cancer patient comprising administering to a subject a cancer patient, a method for treating ... 9 , X 10 , X 11 , X 12 , X 13 , and X 14 wherein at least two of are OH.

[0589] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a cancer patient, a method for treating a cancer patient, a cancer patient comprising administering to a subject a cancer patient, a method for treating ... 9 , X 10 , X 11 , X 12 , X 13 , and X 14 wherein at least three of are OH.

[0590] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a cancer patient, a method for treating a cancer patient, a cancer patient comprising administering to a subject a cancer patient, a method for treating ... 9 , X 10 , X 11 , X 12 , X 13 , and X 14 wherein at least four of are OH.

[0591] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a cancer patient, a method for treating a cancer patient, a cancer patient comprising administering to a subject a cancer patient, a method for treating ... 9 , X 10 , X 11 , X 12 , X 13 , and X 14 wherein five of the are OH.

[0592] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a cancer patient, a method for treating a cancer patient, a cancer patient comprising administering to a subject a cancer patient, a method for treating ... 9 is OH;X 10 , X 11 , X 12 , X 13 , and X 14 is H.

[0593] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a cancer patient, a method for treating a cancer patient, a cancer patient comprising administering to a subject a cancer patient, a method for treating ... 11 is OH;X9 , X 10 , X 12 , X 13 , and X 14 is H.

[0594] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a cancer patient, a method for treating a cancer patient, a cancer patient comprising administering to a subject a cancer patient, a method for treating ... 9 and X 10 is OH;X 11 , X 12 , X 13 , and X 14 is H.

[0595] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a cancer patient, a method for treating a cancer patient, a cancer patient comprising administering to a subject a cancer patient, a method for treating ... 9 and X 11 is OH;X 10 , X 12 , X 13 , and X 14 is H.

[0596] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a cancer patient, a method for treating a cancer patient, a cancer patient comprising administering to a subject a cancer patient, a method for treating ... 10 and X 11 is OH;X 9 , X 12 , X 13 , and X 14 is H.

[0597] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a cancer patient, a method for treating a cancer patient, a cancer patient comprising administering to a subject a cancer patient, a method for treating ... 10 and X 12 is OH;X 9 , X 11 , X 13 , and X 14 is H.

[0598] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a cancer patient, a method for treating a cancer patient, a cancer patient comprising administering to a subject a cancer patient, a method for treating ... 11 and X 12 is OH;X 9 , X 10 , X 13 , and X 14 is H.

[0599] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a 9 , X 10 , and X 11 is OH;X 12 , X 13 , and X 14 is H.

[0600] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a 9 , X 10 , and X 12 is OH;X 11 , X 13 , and X 14 is H.

[0601] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a 9 , X 10 , and X 13 is OH;X 11 , X 12 , and X 14 is H.

[0602] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a 9 , X 10 , and X 14 is OH;X 11 , X 12 , and X 13 is H.

[0603] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a 9 , X 11 , and X 12 is OH;X 10 , X 13 , and X 14 is H.

[0604] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a 9 , X 11 , and X 13 is OH;X 10 , X 12 , and X14 is H.

[0605] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a 9 , X 11 , and X 14 is OH;X 10 , X 12 , and X 13 is H.

[0606] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a 9 , X 12 , and X 13 is OH;X 10 , X 11 , and X 14 is H.

[0607] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a 10 , X 11 , and X 12 is OH;X 9 , X 13 , and X 14 is H.

[0608] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a 9 , X 10 , X 11 , and X 12 is OH;X 13 and X 14 is H.

[0609] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a 9 , X 10 , X 11 , and X 13 is OH;X 12 and X 14 is H.

[0610] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a 9 , X 10 , X11 , and X 14 is OH;X 12 and X 13 is H.

[0611] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a cancer patient, a method for treating a cancer patient, a cancer patient comprising administering to a subject a cancer patient, a method for treating ... 9 , X 10 , X 12 , and X 13 is OH;X 11 and X 14 is H.

[0612] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a cancer patient, a method for treating a cancer patient, a cancer patient comprising administering to a subject a cancer patient, a method for treating ... 9 , X 11 , X 12 , and X 13 is OH;X 10 and X 14 is H.

[0613] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a cancer patient, a method for treating a cancer patient, a cancer patient comprising administering to a subject a cancer patient, a method for treating ... 9 , X 11 , X 12 , and X 14 is OH;X 10 and X 13 is H.

[0614] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a cancer patient, a method for treating a cancer patient, a cancer patient comprising administering to a subject a cancer patient, a method for treating ... 10 , X 11 , X 12 , and X 13 is OH;X 9 and X 14 is H.

[0615] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a cancer patient, a method for treating a cancer patient, a cancer patient comprising administering to a subject a cancer patient, a method for treating ... 9 , X 10 , X 11 , X 12 , and X 13 is OH;X 14 is H.

[0616] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a subject a cancer patient, comprising administering to a subject a 9 , X 10 , X 11 , X 12 , and X 14 is OH;X 13 is H.

[0617] In one embodiment, the present invention relates to a compound of formula VI: [ka] During the ceremony, R 9 , R 10 , R 11 , R 12 , R 13 , and R 14 is independently selected from the group consisting of H and OR; R is H, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted monosaccharide, or substituted or unsubstituted oligosaccharide; However, the compound is R 9 , R 10 , R 11 , R 12 , R 13 , and R 14 is H; R 10 is OR and R 9 , R 11 , R 12 , R 13 , and R 14 is H; R 9 and R 12 is OR and R 10 , R 11 , R 13 , and R 14 is H; R 9 and R 13 is OR and R 10 , R 11 , R 12 , and R 14 is H; R9 and R 14 is OR and R 10 , R 11 , R 12 , and R 13 is H; R 10 and R 13 is OR and R 9 , R 11 , R 12 , and R 14 is H; R 9 , R 10 , and R 13 is OR and R 11 , R 12 , and R 14 is H; R 9 , R 10 , and R 14 is OR and R 11 , R 12 , and R 13 is H; R 10 , R 11 , and R 13 is OR and R 9 , R 12 , and R 14 is H; R 9 , R 10 , R 12 , and R 13 is OR and R 11 and R 14 is H; R 9 , R 10 , R 12 , and R 14 is OR and R 11 and R 13 is H; R 9 , R 10 , R 13 , and R 14 is OR and R 11 and R 12 is H; R 10 , R 11 , R 12 , and R13 is OR and R 9 and R 14 is H; R 9 , R 10 , R 11 , R 12 , and R 13 is OR and R 14 is H; R 9 , R 10 , R 11 , R 13 , and R 14 is OR and R 12 is H; and R 9 , R 10 , R 11 , R 12 , R 13 , and R 14 is OR, Not a compound of formula VI.

[0618] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 9 , R 10 , R 11 , R 12 , R 13 , and R 14 wherein at least one of is OR.

[0619] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 9 , R 10 , R 11 , R 12 , R 13 , and R 14 wherein at least two of are OR.

[0620] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 9 , R 10 , R 11 , R 12 , R 13 , and R 14 wherein at least three of are OR.

[0621] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 9 , R 10 , R 11 , R 12 , R 13 , and R 14 wherein at least four of are OR.

[0622] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 9 , R 10 , R 11 , R 12 , R 13 , and R 14 wherein five of are OR.

[0623] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 9 is OR;R 10 , R 11 , R 12 , R 13 , and R 14 is H.

[0624] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 11 is OR;R 9 , R 10 , R 12 , R 13 , and R 14 is H.

[0625] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 9 and R 10 is OR;R 11 , R 12 , R 13 , and R 14 is H.

[0626] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 9 and R 11 is OR;R 10 , R 12 , R 13 , and R 14is H.

[0627] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 10 and R 11 is OR;R 9 , R 12 , R 13 , and R 14 is H.

[0628] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 10 and R 12 is OR;R 9 , R 11 , R 13 , and R 14 is H.

[0629] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 11 and R 12 is OR;R 9 , R 10 , R 13 , and R 14 is H.

[0630] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 9 , R 10 , and R 11 is OR;R 12 , R 13 , and R 14 is H.

[0631] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 9 , R 10 , and R 12 is OR;R 11 , R 13 , and R 14 is H.

[0632] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 9 , R 11 , and R12 is OR;R 10 , R 13 , and R 14 is H.

[0633] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 9 , R 11 , and R 13 is OR;R 10 , R 12 , and R 14 is H.

[0634] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 9 , R 11 , and R 14 is OR;R 10 , R 12 , and R 13 is H.

[0635] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 9 , R 12 , and R 13 is OR;R 10 , R 11 , and R 14 is H.

[0636] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 10 , R 11 , and R 12 is OR;R 9 , R 13 , and R 14 is H.

[0637] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 9 , R 10 , R 11 , and R 12 is OR;R 13 and R 14 is H.

[0638] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 9 , R 10 , R 11 , and R 13 is OR;R 12 and R 14 is H.

[0639] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 9 , R 10 , R 11 , and R 14 is OR;R 12 and R 13 is H.

[0640] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 9 , R 11 , R 12 , and R 13 is OR;R 10 and R 14 is H.

[0641] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 9 , R 11 , R 12 , and R 14 is OR;R 10 and R 13 is H.

[0642] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 9 , R 10 , R 11 , R 12 , and R 14 is OR;R 13 is H.

[0643] In certain embodiments, the present invention relates to any one of the aforementioned compounds, wherein R is H.

[0644] In one embodiment, the urolithin precursor is punicalagin (PA). In one embodiment, the urolithin precursor is punicalin (PB). See, e.g., Figure 2. In one embodiment, the urolithin precursor is ellagic acid (EA). In one embodiment, the urolithin precursor is provided as an isolated urolithin precursor, e.g., isolated from a natural food source or prepared by total synthesis. Isolated urolithin precursors are typically purified from natural sources or synthesized de novo; some urolithin precursors, including EA, are commercially available from suppliers such as Sigma-Aldrich.

[0645] Also according to the present invention, precursors of urolithins include natural foods containing ellagitannins and ellagic acid, particularly natural foods rich in ellagitannins, ellagic acid, or both ellagitannins and ellagic acid. Such foods include, but are not limited to, certain berries, grapes, pomegranates, rose hips, and nuts. In one embodiment, the natural food is pomegranate.

[0646] Additionally, precursors of urolithins include processed foods and beverages made from such naturally occurring foods. The processed foods can be in any form, including, for example, jams, jellies, preserves, pastas, spreads, juices, wines, extracts, concentrates, etc. In one embodiment, the processed food is pomegranate juice.

[0647] In one embodiment, the urolithin precursor is provided as an extract (e.g., a fruit extract).

[0648] In one embodiment, the urolithin precursor is provided as a concentrate (e.g., a fruit concentrate or a fruit juice concentrate).

[0649] In one embodiment, the urolithin precursor is an isolated urolithin precursor.

[0650] In one embodiment, the urolithin precursor is a purified urolithin precursor.

[0651] In one embodiment, the urolithin precursor is selected from the group consisting of ellagic acid, ellagitannin, and any combination thereof.

[0652] In one embodiment, the urolithin precursor is ellagic acid.

[0653] In one embodiment, the urolithin precursor is an ellagitannin.

[0654] In one embodiment, the ellagitannin is selected from the group consisting of castalagin, castalin, casuarictin, chebulagic acid, chebulinic acid, gemin D, grandinin, pedunculagin, punicalagin, punicalin, lobulin A, strictinin, tellimagrandin I, tellimagrandin II, terflavin A, terflavin B, tergallagin, lambertianin C, sanguiine H-6, sanguiine H-10, and vescalagin.

[0655] Ellagitannins Of the more than 500 hydrolyzable tannins characterized to date, ellagitannins, which produce ellagic acid upon hydrolysis, constitute the largest group; the remaining group is comprised of gallotannins (galloylglucose). Ellagitannins include (1) monomeric ellagitannins, (2) C-glycosidic ellagitannins with an open-chain glucose core, (3) condensations of C-glycosidic tannins with flavan-3-ols (complex tannins), (4) oligomers formed via intermolecular CO or C-C bonds between monomers, and (5) other ellagitannins. Unlike condensed tannins, which are widespread throughout the plant kingdom, ellagitannins have been found exclusively in dicotyledonous angiosperms. Plant families rich in ellagitannins include the Myrtaceae, Lythraceae, Onagraceae, Melastomataceae, and Combriaceae. These families belong to the Myrtaceae order according to the New Engler, Cronquist, and APGII (Angiosperm Phylogenetic Group) plant classification systems.

[0656] Ellagitannins are characterized by the presence of one or more hexahydroxydiphenoyl (HHDP) units on the glucopyranose core. The HHDP group is biosynthetically formed via intramolecular oxidative C-C bond formation between adjacent galloyl groups in galloylglucose. The HHDP group is readily hydrolyzed enzymatically or with acid to release stable ellagic acid as the dilactone form of hexahydroxydiphenic acid. In addition to the HHDP group, other constitutive acyl units within ellagitannins include galloyl groups and HHDP metabolites such as valoneoyl, dehydrohexahydroxydiphenoyl (DHHDP), and chebuloyl groups. Referring to Table 2, differences in the number and position of these acyl units on the glucose core give rise to various analogs, such as tellimagrandin I (1), tellimagrandin II (2), pedunculagin (6), casualictin (7), chebulagic acid (14), and chebulinic acid (15).

[0657] [Table 2] [ka] [ka]

[0658] Table 3 lists the natural sources of representative monomeric ellagitannins 1–15.

[0659] [Table 3-1] [Table 3-2]

[0660] C-glycosidic ellagitannins have been found in many plant families, including Lythraceae, Myrtaceae, Combretaceae, Melastomataceae, and Pomegranate families, as well as Fagaceae, Birchaceae, Casuarinae, Rosaceae, Theaceae, and Elaeaceae. C-glycosidic ellagitannins are classified into two groups: the castalagin type, which contains a flavogalloyl unit involved in a C-glycosidic bond, e.g., castalagin (16) and its C-1 epimer, vescalagin (18), and the casuarinine type, which contains a HHDP unit, e.g., casuarinine (20) and stachyurin (21).

[0661] [Table 4]

[0662] Table 5 lists the natural sources of representative C-glycoside ellagitannins 16–28.

[0663] [Table 5-1] [Table 5-2]

[0664] Complex tannins (flavono-ellagitannins) are characterized by a unique C-C condensation structure between C-glycosidic tannins (vescalagin-type or stachyurin-type) and flavan-3-ols (catechin or epicatechin). Unlike C-glycosidic tannins, these tannins are found in a fairly limited number of plant species belonging to the families Combretaceae, Myrtaceae, Melastomataceae, Fagaceae, and Theaceae. Table 6 lists representative complex ellagitannins.

[0665] [Table 6]

[0666] Oligomeric ellagitannins are widespread in many plant families, including Fagaceae, Rosaceae, Columbaceae, Onagraceae, Melastomataceae, Myrtaceae, and Lythraceae. This class of tannins is divided into three subgroups based on structural features: (1) oligomers containing a valoneoyl group or its equivalent, formed by intermolecular C-O bonding between the HHDP group and the galloyl group of adjacent monomers; (2) macrocyclic oligomers formed by two C-O bonds; and (3) C-glycosidic tannin oligomers, produced by intermolecular C-C bond formation between the C-1 of one monomer and the aromatic ring of another. Table 7 lists representative examples of oligomeric ellagitannins.

[0667] [Table 7]

[0668] Table 8 lists other representative ellagitannins.

[0669] [Table 8]

[0670] Table 9 lists further representative examples of ellagitannins, including some commonly known natural sources of ellagitannins.

[0671] [Table 9-1] [Table 9-2]

[0672] Unfortunately, for the most part, ellagitannins are poorly absorbed by the human intestine, but some metabolites derived from ellagitannins are absorbed by the human intestine, including certain metabolites ultimately formed in the intestine by commensal microorganisms (i.e., intestinal microflora).

[0673] Ellagitannins liberate ellagic acid under physiological conditions in vivo, which is then progressively metabolized in the intestine by the intestinal microflora to produce urolithin A (UA), urolithin B, urolithin C, and urolithin D. After absorption, these metabolites are further metabolized to produce urolithin glucuronides and / or sulfates, resulting in a combination of metabolites that are secreted into the bile.

[0674] Ellagic acid is usually present in relatively small amounts in plant tissues. It is thought to be derived from ellagitannins, which, when degraded, form hexahydroxydiphenic acid, which is naturally converted to ellagic acid. Some additional sources of ellagic acid are listed in Table 10.

[0675] [Table 10]

[0676] Pomegranate (Punica granatum) fruit is an ancient medicinal ingredient that has been used for centuries in folk medicine. Consumed whole and as juice, pomegranate is an excellent source of ellagitannins and ellagic acid. Ellagitannins in the pomegranate fruit rind and juice include punicalin, punicalagin, corilagin, casuarinin, terminalin / gallagyldilacton, pedunculagin, tellimagrandin, granatin A, and granatin B. Other parts of the pomegranate plant contain additional ellagitannins, including punicaforin, punicacortein A, punicacortein B, punicacortein C, punicacortein D, and punigluconin. Commercially available pomegranate juice contains gallagyl-type ellagitannins, including punicalagin isomers (1500–1900 mg / L), undefined hydrolyzable tannins (400–500 mg / L), and ellagic acid and its glycosides (120–260 mg / L). Gil et al. (2000) J. Agric. Food Chem. 48:4581–4589. Punicalagins are ellagitannins in which gallagic acid and ellagic acid are linked to glucose molecules and are abundant in pomegranate peel. Punicalagin isomers and ellagic acid derivatives are not present in aril juice, but during industrial juice processing, they are extracted from the rind and membranes surrounding the aril and released in large amounts into the juice.

[0677] Urolithins are metabolites of ellagic acid, punicalagin (PA), punicalin (PB), tellimagrandin (TL), and other ellagitannins. Ellagic acid (EA) is abundant in pomegranate juice. Gil et al. (2000) J. Agric. Food Chem. 48:4581-4589. The ellagitannin tellimagrandin (TL) has previously been isolated from pomegranate and other plants. The structural formulas of UA, PA, PB, EA, and TL are shown in Figure 2.

[0678] As mentioned above, ellagitannins are not normally absorbed in the intestine. Instead, they liberate EA, which is only poorly absorbed in the stomach and small intestine. EA is largely metabolized by unidentified bacteria in the intestinal lumen to produce urolithins. Microbial metabolism begins in the small intestine, and the first metabolites produced retain four phenolic hydroxyls (urolithin D, four hydroxyl groups). These are further metabolized during intestinal passage, removing hydroxyl units to yield urolithins C (three hydroxyls), A (two hydroxyls), and B (one hydroxyl) in the distal colon (Figure 3). Absorbed metabolites are conjugated with glucuronic acid (one or two units) and / or methyl ethers (if ortho-dihydroxyl groups are present). Urolithin A conjugates and urolithin B conjugates are the predominant metabolites detected in plasma and urine, although some trihydroxy derivatives (hydroxyl-UA) or EA-dimethyl ether glucuronides are also detected in smaller amounts. While tetrahydroxy-urolithins, trihydroxy-urolithins, and EA derivatives are typically found in the terminal plasma, they are absorbed in the small intestine, transported to the liver, where they are further metabolized, and excreted with bile back into the small intestine, establishing an enterohepatic circulation that accounts for the relatively long lifetime of urolithins in plasma and urine.

[0679] Numerous papers on the biosynthesis, isolation, and biological activity of tannins, particularly ellagitannins, in addition to natural food sources, have appeared over the past 20 years. Accessing pure ellagitannins by isolation from natural sources can be cumbersome and may yield only relatively small amounts of the pure natural product. See, for example, Okuda et al. (1982) Chem Pharm Bull. 30:4230-4233; Okuda et al. (1982) Chem Pharm Bull. 30:234-4236. It is therefore noteworthy that methods for the total synthesis of many ellagitannins are known. See, for example, Khanbabaee, K., "Strategies for the synthesis of ellagitannins," in Chemistry and Biology of Ellagitannins, Ed. S. Quideau, World Scientific Publishing, Singapore, 2009, pp. 152-202, including the references therein.

[0680] Methods of increasing autophagy, extending lifespan, and treating or preventing diseases and disorders using urolithins and related compounds In certain embodiments, the present invention provides methods for increasing or decreasing autophagy both in vivo and in vitro, for extending lifespan, and for treating or preventing various diseases and conditions using urolithins and their precursors. In certain embodiments, the diseases or disorders treated or prevented in accordance with the present invention are diseases or disorders associated with decreased autophagy or that would benefit from increased autophagy, including, but not limited to, any of the diseases and conditions described herein.

[0681] One aspect of the invention is a method of treating or preventing a disease or condition associated with or characterized by reduced or diminished autophagy, or that would benefit from increased autophagy. The method includes administering to a subject in need thereof a therapeutically effective amount of a urolithin or a precursor thereof. In certain embodiments, any of the urolithins or precursors thereof described herein can be used to practice any aspect of the invention.

[0682] As used herein, unless otherwise clear by context, "treat," and similar terms such as "treatment," "treated," "treating," and the like, refer to an approach for obtaining beneficial or desired results (e.g., clinical results). Treatment can optionally include reducing or ameliorating symptoms of a disease or condition, or slowing the progression of a disease or condition. In some embodiments, treatment is achieved by reducing the duration of a disease or condition. Administration of a compound described herein can, in some embodiments, treat one or more of such symptoms.

[0683] As used herein, unless otherwise clear by context, "prevent," and similar words such as "prevention," "prevented," "preventing," and the like, refer to an approach for preventing, inhibiting, or reducing the likelihood of the occurrence or recurrence of a disease or condition. Prevention also refers to preventing, inhibiting, or reducing the likelihood of the occurrence or recurrence of symptoms of a disease or condition, or, as desired, refers to an approach for delaying the occurrence or recurrence of a disease or condition, or for delaying the occurrence or recurrence of symptoms of a disease or condition. As used herein, "prevent" and similar words also include reducing the intensity, impact, symptoms, or burden of a disease or condition prior to the occurrence or recurrence of the disease or condition.

[0684] One aspect of the invention is a method for increasing autophagy in a cell, comprising contacting the cell with an effective amount of a urolithin or a precursor thereof, thereby increasing autophagy in the cell. In certain embodiments, the cell is present in a subject (e.g., a mammal). Furthermore, the invention includes a method for increasing autophagy in a cell, wherein the cell is present in a subject (e.g., a mammal), comprising providing the subject with an effective amount of a urolithin or a precursor thereof, thereby increasing autophagy in the cell.

[0685] One aspect of the invention is a method of increasing autophagy in a cell, comprising contacting the cell with an effective amount of a urolithin or a precursor thereof, thereby increasing autophagy in the cell.

[0686] In certain embodiments, the urolithin is a compound having a structure set forth in Formula I, Formula II, or Formula III, such as any one of the specific compounds of Formula II or Formula III described herein. As used herein, an "effective amount" refers to an amount sufficient to achieve or realize a particular or desired biological effect. For example, an effective amount of a urolithin for increasing autophagy in a cell is an amount of urolithin sufficient to increase autophagy in the cell.

[0687] Increased intracellular autophagy can be measured using any suitable assay for measuring autophagy. For example, autophagosome formation can be measured using the fluorescent dye monodansylcadaverine (MDC) (Sigma-Aldrich, 30432). This dye selectively labels autophagic vacuoles. (Biederbick A et al. (1995) Eur. J. Cell. Biol. 66:3-14) Autophagy can also be measured by examining changes in the ratio of proteins involved in autophagy (e.g., the ratio of LC3-II to LC3-I), for example, using Western blot analysis. Using such methods, an increase in the LC3-II / LC3-I ratio in treated cells over the baseline LC3-II / LC3-I ratio in untreated cells would be considered an increase in autophagy. Examination of other protein levels, such as p62, can also be helpful in confirmation. For calculation, the increase percentage (%) of intracellular autophagy can be calculated using the LC3-II / LC3-I ratio at baseline (B-ratio) and the LC3-II / LC3-I ratio during treatment (T-ratio). The increase percentage (%) can be calculated mathematically, for example, by the formula 100 x [((T-ratio) - (B-ratio)) / (B-ratio)].

[0688] Autophagy is said to be increased in a cell when it is measurably greater than the autophagy present or would be present in untreated or placebo-controlled cells. In one embodiment, autophagy is said to be increased in a cell when it is a statistically significant amount or degree greater than the autophagy present or would be present in untreated or placebo-controlled cells. In some embodiments, the increase in autophagy is at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 100%, at least 150%, at least 200%, at least 300%, at least 400%, at least 500%, at least 600%, at least 700%, at least 800%, at least 900%, at least 1,000%, or more than 1,000% compared to the level of autophagy present in untreated cells or placebo-treated cells.

[0689] In certain embodiments, the increase in autophagy is 5-500%, 10-500%, 15-500%, 20-500%, 25-500%, 30-500%, 40-500%, 50-500%, 60-500%, at least 70-500%, 80-500%, 90-500%, 100-500%, 150-500%, 200-500%, 300-500%, or 400-500%, 5-1,000%, 10-500%, or 150-500% compared to the level of autophagy present in untreated cells or cells treated with a placebo. An increase of 0%, 15-1,000%, 20-1,000%, 25-1,000%, 30-1,000%, 40-1,000%, 50-1,000%, 60-1,000%, at least 70-1,000%, 80-1,000%, 90-1,000%, 100-1,000%, 150-1,000%, 200-1,000%, 300-1,000%, 400-1,000%, 500-1,000%, 600-1,000%, 700-1,000%, 800-1,000%, or 900-1,000%.

[0690] In one embodiment, the autophagy is mitophagy.

[0691] In one embodiment, the urolithin is an isolated urolithin.

[0692] In one embodiment, the urolithin is a purified urolithin.

[0693] In one embodiment, the urolithin is selected from the group consisting of urolithin A, urolithin B, urolithin C, urolithin D, and any combination thereof.

[0694] In one embodiment, the urolithin is urolithin A.

[0695] In one embodiment, the urolithin is urolithin B.

[0696] In one embodiment, the urolithin is urolithin C.

[0697] In one embodiment, the urolithin is urolithin D.

[0698] In some embodiments, the urolithin is a compound of Formula I, Formula II, or Formula III, including any one of the specific compounds of these formulas described herein.

[0699] In one embodiment, the urolithin precursor is an isolated urolithin precursor.

[0700] In one embodiment, the urolithin precursor is a purified urolithin precursor.

[0701] In some embodiments, the urolithin precursor is a compound of Formula IV, Formula V, or Formula VI, including any one of the specific compounds of these formulas described herein.

[0702] In one embodiment, the urolithin precursor is selected from the group consisting of ellagic acid, ellagitannin, and any combination thereof.

[0703] In one embodiment, the urolithin precursor is ellagic acid.

[0704] In one embodiment, the urolithin precursor is an ellagitannin.

[0705] In one embodiment, the ellagitannin is selected from the group consisting of castalagin, castalin, casuarictin, chebulagic acid, chebulinic acid, gemin D, grandinin, pedunculagin, punicalagin, punicalin, lobulin A, strictinin, tellimagrandin I, tellimagrandin II, terflavin A, terflavin B, tergallagin, lambertianin C, sanguiine H-6, sanguiine H-10, and vescalagin.

[0706] In one embodiment, the cell is selected from the group consisting of an embryonic stem cell, an induced pluripotent stem cell, an adult stem cell, a differentiated cell, a blood cell, a hematopoietic cell, an epithelial cell, an exocrine cell, an endocrine cell, a connective tissue cell, an adipocyte, a bone cell, a smooth muscle cell, a striated muscle cell, a neuronal cell, a sensory cell, a cardiac cell, a hepatic cell, a gastric cell, an intestinal cell, a lung cell, a kidney cell, and a germ cell. In one embodiment, the cells are selected from the group consisting of endothelial cells, cells of the central and peripheral nervous system (neurons (all types) and glial cells (microglia, astrocytes and oligodendrocytes, Schwann cells), keratinocytes (skin cells), retinal cells, immune cells, also hair cells and follicle stem cells, and cancer stem cells. In some embodiments, the cells are embryonic stem cells. In some embodiments, the cells are induced pluripotent stem cells. In some embodiments, the cells are adult stem cells. In some embodiments, the cells are hematopoietic stem cells. In some embodiments, the cells are cancer cells. In some embodiments, the cells are present in an isolated organ or organ bloc, such as an organ or organ bloc isolated for transplantation or maintained ex vivo. In some embodiments, the cells are present in a tissue or tissue section. In various embodiments, the cells are contacted with a urolithin or a precursor thereof in vivo, ex vivo, or in vitro.

[0707] One aspect of the invention is a method of increasing longevity in an animal, comprising the step of administering to an animal in need thereof an effective amount of a urolithin or a precursor thereof, thereby increasing autophagy in the animal, and thereby increasing the longevity of the animal.

[0708] The term "lifespan" as used herein in relation to animal lifespan refers to the lifespan of an individual organism. While lifespan can be measured in individual organisms, it is more common to measure and compare the mean or median lifespan of a population of individual organisms. For example, lifespan may be measured and compared as the average survival in an experimentally treated group and an appropriately selected untreated or placebo control group. Lifespan may also be considered in a population of individuals suffering from a health condition requiring autophagy. Treatment of such individuals increases their lifespan compared to their untreated counterparts. In one embodiment, the lifespan is actual lifespan. In one embodiment, the lifespan is actuarial lifespan.

[0709] As used herein in reference to the lifespan of eukaryotic cells in vitro, the term "lifespan" refers to the lifespan of an individual cell. While lifespan can be measured for individual cells, it is more common to measure and compare the mean or median lifespan of a population of individual cells. For example, lifespan may be measured and compared as the average survival in an experimentally treated group and an appropriately selected untreated or placebo control group. The term "lifespan" also refers to the lifespan of cells subjected to a particular metabolic stress. In one embodiment, the metabolic stress is due to nutrient deprivation, growth factor deprivation, or hypoxia. For example, treatment of metabolically stressed cells with a urolithin or precursor, either directly in vitro, ex vivo, or in vivo by administration to a subject, will result in an extension of the lifespan of these metabolically stressed cells, and in the case of ex vivo and in vivo treatment, the extension of the lifespan of these metabolically stressed cells will improve the function of the tissue containing them.

[0710] In one embodiment, lifespan is said to be extended if it is at least 5 percent longer than an untreated control group. In various specific embodiments, lifespan is said to be extended if it is at least 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 percent longer than an untreated control group. In some embodiments, lifespan is extended by at least 10 percent compared to an untreated control group. In some embodiments, lifespan is extended by at least 20 percent compared to an untreated control group. In some embodiments, lifespan is extended by at least 30 percent compared to an untreated control group. In some embodiments, lifespan is increased by at least 40 percent compared to an untreated control group, hi some embodiments, lifespan is increased by at least 50 percent compared to an untreated control group.

[0711] In one embodiment, lifespan is said to be extended if it is at least 5 percent longer than a placebo control. In various specific embodiments, lifespan is said to be extended if it is at least 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 percent longer than a placebo control. In some embodiments, lifespan is extended by at least 10 percent compared to a placebo control. In some embodiments, lifespan is extended by at least 20 percent compared to a placebo control. In some embodiments, lifespan is extended by at least 30 percent compared to a placebo control. In some embodiments, lifespan is increased by at least 40 percent compared to a placebo control, hi some embodiments, lifespan is increased by at least 50 percent compared to a placebo control.

[0712] In one embodiment, lifespan is said to be extended if it is longer by a statistically significant difference compared to an untreated control group. In one embodiment, the statistical significance of the difference is p≦0.05. In one embodiment, the statistical significance of the difference is p≦0.01. In one embodiment, the statistical significance of the difference is p≦0.005. In one embodiment, the statistical significance of the difference is p≦0.001.

[0713] In one embodiment, lifespan is said to be extended if it is increased by a statistically significant difference compared to a placebo control. In one embodiment, the statistical significance of the difference is p≦0.05. In one embodiment, the statistical significance of the difference is p≦0.01. In one embodiment, the statistical significance of the difference is p≦0.005. In one embodiment, the statistical significance of the difference is p≦0.001.

[0714] An animal is any multicellular eukaryotic organism belonging to the kingdom Animalia. In one embodiment, the animal is an invertebrate, such as a nematode (e.g., C. elegans) or a fruit fly (e.g., D. melanogaster). In one embodiment, the animal is a vertebrate, such as a fish or a mammal. In one embodiment, the animal is a mammal. In one embodiment, the animal is a primate. In one embodiment, the animal is a human. In some embodiments, the animal is a domestic animal, such as a dog or cat. In some embodiments, the animal is livestock, such as a horse, cow, or sheep.

[0715] In one embodiment, the urolithin is an isolated urolithin.

[0716] In one embodiment, the urolithin is a purified urolithin.

[0717] In one embodiment, the urolithin is selected from the group consisting of urolithin A, urolithin B, urolithin C, urolithin D, and any combination thereof.

[0718] In one embodiment, the urolithin is urolithin A.

[0719] In one embodiment, the urolithin is urolithin B.

[0720] In one embodiment, the urolithin is urolithin C.

[0721] In one embodiment, the urolithin is urolithin D.

[0722] In some embodiments, the urolithin is a compound of Formula I, Formula II, or Formula III, including any one of the specific compounds of these formulas described herein.

[0723] In one embodiment, the urolithin precursor is an isolated urolithin precursor.

[0724] In one embodiment, the urolithin precursor is a purified urolithin precursor.

[0725] In some embodiments, the urolithin precursor is a compound of Formula IV, Formula V, or Formula VI, including any one of the specific compounds of these formulas described herein.

[0726] In one embodiment, the urolithin precursor is selected from the group consisting of ellagic acid, ellagitannin, and any combination thereof.

[0727] In one embodiment, the urolithin precursor is ellagic acid.

[0728] In one embodiment, the urolithin precursor is an ellagitannin.

[0729] In one embodiment, the ellagitannin is selected from the group consisting of castalagin, castalin, casuarictin, chebulagic acid, chebulinic acid, gemin D, grandinin, pedunculagin, punicalagin, punicalin, lobulin A, strictinin, tellimagrandin I, tellimagrandin II, terflavin A, terflavin B, tergallagin, lambertianin C, sanguiine H-6, sanguiine H-10, and vescalagin.

[0730] One aspect of the invention is a method of increasing the lifespan of a eukaryotic cell in vitro, comprising the step of contacting a eukaryotic cell in vitro with an effective amount of a urolithin to increase autophagy in the cell, thereby increasing the lifespan of the eukaryotic cell in vitro.

[0731] According to the present invention, urolithins can be used as cell culture reagents to promote the growth and preservation of cells and tissues in culture. Urolithins are believed to have the ability to maintain primary cells and tissues viably for extended periods, meaning they can be used in a variety of in vitro applications, such as (i) routine laboratory cell culture of cell lines, primary cells of any origin (i.e., freshly isolated from humans or animals); and (ii) maintaining tissues or organs in culture. For both cells and tissues maintained in culture, this can also be used for in vitro diagnostic and therapeutic applications, such as tissue expansion, protection during transport (for human transplantation), and for cell therapy applications using primary cells that require cryopreservation, it can be part of a special solution for cell freezing. The present invention also includes methods for culturing or preserving cells or tissues, including growing or culturing the cells or tissues in a medium containing urolithins. Cell culture media suitable for culturing and growing various cells and tissues are known in the art and are commercially available.

[0732] Urolithins and their precursors can be useful as positive controls when studying autophagy and improved mitochondrial function in cells, tissues, or organisms. For example, urolithins can be used separately or included as part of useful kits to examine mitochondrial function or pathways associated with longevity, such as the mTOR pathway.

[0733] In one embodiment, the autophagy is mitophagy.

[0734] In one embodiment, the urolithin is an isolated urolithin.

[0735] In one embodiment, the urolithin is a purified urolithin.

[0736] In one embodiment, the urolithin is selected from the group consisting of urolithin A, urolithin B, urolithin C, urolithin D, and any combination thereof.

[0737] In one embodiment, the urolithin is urolithin A.

[0738] In one embodiment, the urolithin is urolithin B.

[0739] In one embodiment, the urolithin is urolithin C.

[0740] In one embodiment, the urolithin is urolithin D.

[0741] In some embodiments, the urolithin is a compound of Formula I, Formula II, or Formula III, including any one of the specific compounds of these formulas described herein.

[0742] In one embodiment, the urolithin precursor is an isolated urolithin precursor.

[0743] In one embodiment, the urolithin precursor is a purified urolithin precursor.

[0744] In some embodiments, the urolithin precursor is a compound of Formula IV, Formula V, or Formula VI, including any one of the specific compounds of these formulas described herein.

[0745] In one embodiment, the urolithin precursor is selected from the group consisting of ellagic acid, ellagitannin, and any combination thereof.

[0746] In one embodiment, the urolithin precursor is ellagic acid.

[0747] In one embodiment, the urolithin precursor is an ellagitannin.

[0748] In one embodiment, the ellagitannin is selected from the group consisting of castalagin, castalin, casuarictin, chebulagic acid, chebulinic acid, gemin D, grandinin, pedunculagin, punicalagin, punicalin, lobulin A, strictinin, tellimagrandin I, tellimagrandin II, terflavin A, terflavin B, tergallagin, lambertianin C, sanguiine H-6, sanguiine H-10, and vescalagin.

[0749] In one embodiment, the eukaryotic cells are primary culture eukaryotic cells.

[0750] In one embodiment, the eukaryotic cell is part of a cell line.

[0751] In one embodiment, the eukaryotic cell is selected from the group consisting of embryonic stem cells, induced pluripotent stem cells, adult stem cells, differentiated cells, blood cells, hematopoietic cells, epithelial cells, exocrine cells, endocrine cells, connective tissue cells, adipocytes, bone cells, smooth muscle cells, striated muscle cells, neural cells, sensory cells, cardiac cells, hepatic cells, gastric cells, intestinal cells, lung cells, kidney cells, and germ cells. In some embodiments, the cell is an embryonic stem cell. In some embodiments, the cell is an induced pluripotent stem cell. In one embodiment, the cell is selected from the group consisting of endothelial cells, cells of the central and peripheral nervous system (neurons (all types) and glial cells (microglia, astrocytes and oligodendrocytes, Schwann cells)), keratinocytes (skin cells), retinal cells, immune cells, also hair cell and follicle stem cells, and cancer stem cells. In some embodiments, the cell is an adult stem cell. In some embodiments, the cell is a hematopoietic stem cell. In some embodiments, the cell is a cancer cell.

[0752] In some embodiments, the cells are present in an excised tissue or organ, or a portion or specimen thereof. In some embodiments, the cells are present in an excised organ or organ bloc, such as an organ or organ bloc excised for transplantation or maintained ex vivo. In some embodiments, the cells are present in a tissue or tissue section.

[0753] In certain embodiments, the cells are in a primary culture, i.e., "primary cells." As used herein, "primary culture" refers to cells cultured directly from a tissue or subject. In one embodiment, a primary culture includes more than one cell type. In one embodiment, a primary culture includes a single cell type (e.g., endothelial cells). Cells in a primary culture are often only able to undergo a limited number of passages or divisions.

[0754] In certain embodiments, the cells are present in a cell line. As used herein, a "cell line" is an established, immortalized, and genetically homogeneous population of cells derived from a eukaryotic animal and maintained in vitro. In one embodiment, the cell line is of mammalian origin. In one embodiment, the cell line is of human origin. Many types of cell lines are available from several commercial suppliers, including, for example, the American Type Culture Collection (ATCC) (Manassas, VA).

[0755] In certain embodiments, the present invention relates to a method of increasing autophagy in a cell, comprising contacting the cell with an effective amount of a compound selected from the group consisting of a compound of formula II, a compound of formula III, a compound of formula V, a compound of formula VI, urolithin A, urolithin B, urolithin C, urolithin D, and ellagic acid, thereby increasing autophagy in the cell.

[0756] In certain embodiments, the invention relates to any one of the aforementioned methods, wherein the autophagy is mitophagy.

[0757] In certain embodiments, the invention relates to any one of the aforementioned methods, wherein the compound is urolithin A.

[0758] In certain embodiments, the invention relates to any one of the aforementioned methods, wherein the compound is urolithin B.

[0759] In certain embodiments, the invention relates to any one of the aforementioned methods, wherein the compound is urolithin C.

[0760] In certain embodiments, the invention relates to any one of the aforementioned methods, wherein the compound is urolithin D.

[0761] In certain embodiments, the present invention relates to any one of the aforementioned methods, wherein the compound is ellagic acid.

[0762] In certain embodiments, the invention relates to any one of the aforementioned methods, wherein the cell is selected from the group consisting of an embryonic stem cell, an induced pluripotent stem cell, an adult stem cell, a differentiated cell, a blood cell, a hematopoietic cell, an epithelial cell, an exocrine cell, an endocrine cell, a connective tissue cell, an adipocyte, a bone cell, a smooth muscle cell, a striated muscle cell, a nerve cell, a sensory cell, a cardiac cell, a liver cell, a stomach cell, an intestinal cell, a lung cell, a kidney cell, and a germ cell.

[0763] In certain embodiments, the present invention relates to a method of increasing the longevity of an animal, comprising administering to an animal in need thereof an effective amount of a compound selected from the group consisting of a compound of formula II, a compound of formula III, a compound of formula V, a compound of formula VI, urolithin A, urolithin B, urolithin C, urolithin D, and ellagic acid, thereby increasing the longevity of the animal.

[0764] In certain embodiments, the invention relates to any one of the aforementioned methods, wherein the compound is urolithin A.

[0765] In certain embodiments, the invention relates to any one of the aforementioned methods, wherein the compound is urolithin B.

[0766] In certain embodiments, the invention relates to any one of the aforementioned methods, wherein the compound is urolithin C.

[0767] In certain embodiments, the invention relates to any one of the aforementioned methods, wherein the compound is urolithin D.

[0768] In certain embodiments, the present invention relates to any one of the aforementioned methods, wherein the compound is ellagic acid.

[0769] In certain embodiments, the invention relates to any one of the aforementioned methods, wherein the animal is a mammal.

[0770] In certain embodiments, the invention relates to any one of the aforementioned methods, wherein the mammal is a human.

[0771] In certain embodiments, the present invention relates to a method of increasing the lifespan of a eukaryotic cell in vitro, comprising contacting the eukaryotic cell in vitro with an effective amount of a compound selected from the group consisting of a compound of formula II, a compound of formula III, a compound of formula V, a compound of formula VI, urolithin A, urolithin B, urolithin C, urolithin D, and ellagic acid, thereby increasing the lifespan of the eukaryotic cell in vitro.

[0772] In certain embodiments, the invention relates to any one of the aforementioned methods, wherein the compound is urolithin A.

[0773] In certain embodiments, the invention relates to any one of the aforementioned methods, wherein the compound is urolithin B.

[0774] In certain embodiments, the invention relates to any one of the aforementioned methods, wherein the compound is urolithin C.

[0775] In certain embodiments, the invention relates to any one of the aforementioned methods, wherein the compound is urolithin D.

[0776] In certain embodiments, the present invention relates to any one of the aforementioned methods, wherein the compound is ellagic acid.

[0777] In certain embodiments, the invention relates to any one of the aforementioned methods, wherein the eukaryotic cells are primary culture eukaryotic cells.

[0778] In certain embodiments, the invention relates to any one of the aforementioned methods, wherein the eukaryotic cell is part of a cell line.

[0779] In certain embodiments, the invention relates to any one of the aforementioned methods, wherein the eukaryotic cell is a cell selected from the group consisting of an embryonic stem cell, an induced pluripotent stem cell, an adult stem cell, a differentiated cell, a blood cell, a hematopoietic cell, an epithelial cell, an exocrine cell, an endocrine cell, a connective tissue cell, an adipocyte, a bone cell, a smooth muscle cell, a striated muscle cell, a nerve cell, a sensory cell, a cardiac cell, a liver cell, a stomach cell, an intestinal cell, a lung cell, a kidney cell, and a germ cell.

[0780] In certain embodiments, the invention relates to any one of the aforementioned methods, wherein the eukaryotic cell is a cell selected from the group consisting of an embryonic stem cell, an induced pluripotent stem cell, and an adult stem cell.

[0781] In one embodiment, the present invention relates to a method for increasing autophagy in a cell, comprising contacting the cell with an effective amount of a compound of formula I, thereby increasing autophagy in the cell; The compound of formula I is [ka] wherein: R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 is independently selected from the group consisting of H and OR; R is H, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted monosaccharide, or substituted or unsubstituted oligosaccharide.

[0782] In certain embodiments, the invention relates to any one of the aforementioned methods, wherein the autophagy is mitophagy.

[0783] In certain embodiments, the invention relates to any one of the aforementioned methods, wherein the cell is selected from the group consisting of an embryonic stem cell, an induced pluripotent stem cell, an adult stem cell, a differentiated cell, a blood cell, a hematopoietic cell, an epithelial cell, an exocrine cell, an endocrine cell, a connective tissue cell, an adipocyte, a bone cell, a smooth muscle cell, a striated muscle cell, a nerve cell, a sensory cell, a cardiac cell, a liver cell, a stomach cell, an intestinal cell, a lung cell, a kidney cell, and a germ cell.

[0784] In one embodiment, the present invention relates to a method for increasing the longevity of an animal, comprising administering to an animal in need thereof an effective amount of a compound of formula I, thereby increasing the longevity of the animal; The compound of formula I is [ka] wherein: R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 is independently selected from the group consisting of H and OR; R is H, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted monosaccharide, or substituted or unsubstituted oligosaccharide.

[0785] In certain embodiments, the invention relates to any one of the aforementioned methods, wherein the animal is a mammal.

[0786] In certain embodiments, the invention relates to any one of the aforementioned methods, wherein the mammal is a human.

[0787] In one embodiment, the present invention relates to a method of increasing the longevity of a eukaryotic cell in vitro, comprising contacting the eukaryotic cell in vitro with an effective amount of a compound of Formula I, thereby increasing the longevity of the eukaryotic cell in vitro, The compound of formula I is [ka] wherein: R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 is independently selected from the group consisting of H and OR; R is H, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted monosaccharide, or substituted or unsubstituted oligosaccharide.

[0788] In certain embodiments, the invention relates to any one of the aforementioned methods, wherein the eukaryotic cells are primary culture eukaryotic cells.

[0789] In certain embodiments, the invention relates to any one of the aforementioned methods, wherein the eukaryotic cell is part of a cell line.

[0790] In certain embodiments, the invention relates to any one of the aforementioned methods, wherein the eukaryotic cell is a cell selected from the group consisting of an embryonic stem cell, an induced pluripotent stem cell, an adult stem cell, a differentiated cell, a blood cell, a hematopoietic cell, an epithelial cell, an exocrine cell, an endocrine cell, a connective tissue cell, an adipocyte, a bone cell, a smooth muscle cell, a striated muscle cell, a nerve cell, a sensory cell, a cardiac cell, a liver cell, a stomach cell, an intestinal cell, a lung cell, a kidney cell, and a germ cell.

[0791] In certain embodiments, the invention relates to any one of the aforementioned methods, wherein the eukaryotic cell is a cell selected from the group consisting of an embryonic stem cell, an induced pluripotent stem cell, and an adult stem cell.

[0792] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 is H.

[0793] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 any one of the aforementioned methods, wherein at least one of is OR.

[0794] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 1 , R 2 , R 3 , R 4 , R 5 , R6 , R 7 , and R 8 any one of the aforementioned methods, wherein at least two of are OR.

[0795] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 wherein at least three of are OR.

[0796] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 any one of the aforementioned methods, wherein at least four of said are OR.

[0797] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 any one of the aforementioned methods, wherein at least five of said are OR.

[0798] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 any one of the aforementioned methods, wherein at least six of are OR.

[0799] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 1 , R 2 , R3 , R 4 , R 5 , R 6 , R 7 , and R 8 any one of the aforementioned methods, wherein at least seven of said are OR.

[0800] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 is OR.

[0801] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 1 is OR;R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 is H.

[0802] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 2 is OR;R 1 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 is H.

[0803] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 3 is OR;R 1 , R 2 , R 4 , R 5 , R 6 , R 7 , and R 8 is H.

[0804] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 4is OR;R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , and R 8 is H.

[0805] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 5 is OR;R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , and R 8 is H.

[0806] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 6 is OR;R 1 , R 2 , R 3 , R 4 , R 5 , R 7 , and R 8 is H.

[0807] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 7 is OR;R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 8 is H.

[0808] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 8 is OR;R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 is H.

[0809] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 1 and R 2 is OR;R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 is H.

[0810] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 1 and R 3 is OR;R 2 , R 4 , R 5 , R 6 , R 7 , and R 8 is H.

[0811] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 1 and R 4 is OR;R 2 , R 3 , R 5 , R 6 , R 7 , and R 8 is H.

[0812] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 1 and R 5 is OR;R 2 , R 3 , R 4 , R 6 , R 7 , and R 8 is H.

[0813] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 1 and R 6 is OR;R 2 , R 3 , R 4 , R 5 , R 7 , and R 8 is H.

[0814] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 1 and R 7 is OR;R 2 , R 3 , R 4 , R 5 , R 6 , and R 8 is H.

[0815] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 1 and R 8 is OR;R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 is H.

[0816] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 2 and R 3 is OR;R 1 , R 4 , R 5 , R 6 , R 7 , and R 8 is H.

[0817] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 2 and R 4 is OR;R 1 , R 3 , R 5 , R 6 , R 7 , and R 8 is H.

[0818] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 2 and R 5 is OR;R 1 , R 3 , R 4 , R 6 , R 7 , and R 8is H.

[0819] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 2 and R 6 is OR;R 1 , R 3 , R 4 , R 5 , R 7 , and R 8 is H.

[0820] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 2 and R 7 is OR;R 1 , R 3 , R 4 , R 5 , R 6 , and R 8 is H.

[0821] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 2 and R 8 is OR;R 1 , R 3 , R 4 , R 5 , R 6 , and R 7 is H.

[0822] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 3 and R 4 is OR;R 1 , R 2 , R 5 , R 6 , R 7 , and R 8 is H.

[0823] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 3 and R 5 is OR;R 1 , R 2 , R 4 , R 6 , R7 , and R 8 is H.

[0824] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 3 and R 6 is OR;R 1 , R 2 , R 4 , R 5 , R 7 , and R 8 is H.

[0825] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 3 and R 7 is OR;R 1 , R 2 , R 4 , R 5 , R 6 , and R 8 is H.

[0826] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 3 and R 8 is OR;R 1 , R 2 , R 4 , R 5 , R 6 , and R 7 is H.

[0827] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 4 and R 5 is OR;R 1 , R 2 , R 3 , R 6 , R 7 , and R 8 is H.

[0828] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 4 and R 6 is OR;R 1 , R 2 , R3 , R 5 , R 7 , and R 8 is H.

[0829] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 4 and R 7 is OR;R 1 , R 2 , R 3 , R 5 , R 6 , and R 8 is H.

[0830] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 4 and R 8 is OR;R 1 , R 2 , R 3 , R 5 , R 6 , and R 7 is H.

[0831] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 5 and R 6 is OR;R 1 , R 2 , R 3 , R 4 , R 7 , and R 8 is H.

[0832] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 5 and R 7 is OR;R 1 , R 2 , R 3 , R 4 , R 6 , and R 8 is H.

[0833] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 5 and R 8 is OR;R1 , R 2 , R 3 , R 4 , R 6 , and R 7 is H.

[0834] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 6 and R 7 is OR;R 1 , R 2 , R 3 , R 4 , R 5 , and R 8 is H.

[0835] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 6 and R 8 is OR;R 1 , R 2 , R 3 , R 4 , R 5 , and R 7 is H.

[0836] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 7 and R 8 is OR;R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 is H.

[0837] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 1 , R 2 , and R 3 is OR;R 4 , R 5 , R 6 , R 7 , and R 8 is H.

[0838] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 1 , R2 , and R 4 is OR;R 3 , R 5 , R 6 , R 7 , and R 8 is H.

[0839] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 1 , R 2 , and R 5 is OR;R 3 , R 4 , R 6 , R 7 , and R 8 is H.

[0840] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 1 , R 2 , and R 6 is OR;R 3 , R 4 , R 5 , R 7 , and R 8 is H.

[0841] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 1 , R 2 , and R 7 is OR;R 3 , R 4 , R 5 , R 6 , and R 8 is H.

[0842] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 1 , R 2 , and R 8 is OR;R 3 , R 4 , R 5 , R 6 , and R 7 is H.

[0843] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 1 , R 3 , and R 4 is OR;R 2 , R 5 , R 6 , R 7 , and R 8 is H.

[0844] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 1 , R 3 , and R 5 is OR;R 2 , R 4 , R 6 , R 7 , and R 8 is H.

[0845] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 1 , R 3 , and R 6 is OR;R 2 , R 4 , R 5 , R 7 , and R 8 is H.

[0846] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 1 , R 3 , and R 7 is OR;R 2 , R 4 , R 5 , R 6 , and R 8 is H.

[0847] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 1 , R 3 , and R 8 is OR;R 2 , R 4 , R 5 , R 6 , and R 7 is H.

[0848] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 1 , R 4 , and R 5 is OR;R 2 , R 3 , R 6 , R 7 , and R 8 is H.

[0849] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a 1 , R 4 , and R 6 is OR;R 2 , R 3 , ...

Claims

[Claim 1] 1. A method for increasing autophagy in a cell, comprising contacting the cell with an effective amount of a urolithin or a pharmaceutically acceptable salt thereof, thereby increasing autophagy in the cell.

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