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Protection of normal cells

A technology of normal cells and living cells, applied in the fields of pharmacology, medicine, and biochemistry, which can solve problems such as limitation and small ROS

Inactive Publication Date: 2011-06-29
CHS PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

They are therefore limited by the relatively small amount of ROS they can scavenge

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0239] Example 1 - Sulindac as a substrate for MsrA enzyme

[0240] It is known that methionine sulfoxide reductase (MsrA) shows specificity to substrates containing methyl sulfoxide group in S configuration. This example provides evidence that sulindac, an antioxidant known to contain a methylsulfoxide moiety, can serve as a substrate for MsrA.

[0241] Materials and methods

[0242] Reductase test. The reduction of sulindac was measured by a modified NADPH oxidation assay using purified Msr enzyme. Prepare a reaction mixture containing 50 mM Tris-Cl buffer, pH 7.4, 15 µg E. coli thioredoxin reductase, 1 µg E. coli thioredoxin reductase, 100 nmol NADPH, 1 µmole sulindac and 100-400 ng MsrA in a final volume of for 500 μl. Incubate at 37°C for various times.

[0243] The amount of the synthesized product (sulindac sulfide) was determined by measuring NADPH oxidation spectrophotometrically at 340 nm. Since sulindac absorbs strongly at this wavelength, the decrease in abso...

Embodiment 2

[0249] Example 2: Sulindac is a substrate for Msr enzymes in bacteria and mammals

[0250] This example demonstrates that sulindac is a substrate of MsrA and membrane-bound Msr in E. coli, and may be a substrate of other Msr enzymes in mammalian tissues.

[0251] Materials and methods

[0252] Compounds, Enzymes and Substrates. Sulindac (S), sulindac sulfide (SS) and all other compounds and E. coli thioredoxin reductase were obtained from Sigma Chemicals (St. Louis, MO) unless otherwise noted. Thioredoxin (isolated from E. coli) was purchased from Promega (Madison, WI). N-acetyl- 3 H-met-R, S-(O), met-R-(O), met-S-(O) DABS-met-R-(O) and DABS-met-S-(O) according to existing methods Preparation (Brot N. et al., Anal.Biochem.122(1982) 291-294; Lavine, F.T.J.Biol.Chem.169(1947) 477-491; Minetti G. et al., Ital.J.Biochem.43(1994) 273 -283).

[0253]bacterial enzymes. Recombinant MsrA and MsrB from Escherichia coli were obtained using existing methods (Grimaud, R. et al., J. ...

Embodiment 3

[0282] Example 3 Synthesis of sulindac-methionine-catalyzed antioxidant

[0283] As mentioned above, sulindac is a substrate of MsrA but not MsrB. Sulindac contains a methylsulfoxide moiety that is recognized by the MsrA enzyme, but does not contain an N-methionine sulfoxide moiety (see figure 2 ). This example illustrates the chemical synthesis route of sulindac derivatives. These sulindac derivatives are modified to contain N-substituted methionine, wherein the methionine amino group is a peptide or amide bond. Such sulindac derivatives have Favorable as a substrate for multiple Msr enzymes.

[0284] see Figure 4A, showing that compound 2a (1(Z)-5-fluoro-2-methyl-1-[4-(methylsulfinyl)phenyl]methylene]-1hydro-indene-3-[1- methylthiomethylenyl-2-aminoacetyl]propanoic acid). Compound 2a contains a methionine group linked via an amino group to the acetyl moiety of sulindac. The compound was synthesized as follows starting from sulindac and methionine sulfoxide methyl est...

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Abstract

The invention provides compositions comprising sulindac, R-epimer sulindac, S-epimer sulindac, derivatives, metabolites, and structural analogs thereof which protect normal cells against damage caused by solar rays, oxidative damage, environmental factors, diseases and organisms.

Description

[0001] Cross References to Related Applications [0002] This application claims priority to U.S. Patent Application 12 / 115,331, filed May 5, 2008, which is a continuation-in-part (granted) of U.S. 11 / 512,616, filed August 29, 2006, U.S. 11 / 512,616 is a divisional application of USSN 10 / 723,809 (now U.S. Patent No. 7,129,374), filed November 26, 2003, which claims priority over provisional application U.S. 60 / 429,269, filed November 26, 2002 rights, all of which are incorporated herein by reference. technical field [0003] The present invention relates to the fields of biochemistry, pharmacology and medicine. More specifically, the present invention relates to methods and compositions for promoting health and extending lifespan by reducing oxidative damage to cells and tissues. Background technique [0004] Oxygen participates extensively in normal metabolic reactions and is essential for all aerobic organisms, including humans. Reactive oxygen species (ROS), such as per...

Claims

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Application Information

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IPC IPC(8): A61K31/255A61K31/165A61P17/18
CPCA61K31/192A61P17/18A61P25/00A61P31/00A61P35/00A61P39/02A61P39/06A61P43/00A61P9/10Y02A50/30
Inventor 赫伯特·魏斯巴赫内森·布洛特
Owner CHS PHARMA
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