Targeted delivery of 1,2,4,5-tetraoxane compounds and uses thereof

Abstract

Disclosed are 1,2,4,5-tetraoxane compounds and derivatives thereof having anti-cancer properties. Disclosed are pharmaceutical compositions and formulations of these compounds in unit dosage form suitable for delivery to a subject in need thereof. The pharmaceutical compositions or formulations may contain one or more active agents, such as one or more additional anti-cancer agents, in addition to the compounds. Also disclosed are methods for treating cancer, reducing cancer, or treating or ameliorating one or more symptoms associated with cancer in a subject. The methods include (i) administering an effective amount of these compounds to a subject in need thereof. These compounds may be administered orally, parenterally, by inhalation, mucosally, or a combination thereof. The compounds may selectively kill cancer cells and / or cancer stem cells over non-cancerous cells by inducing ferroptosis in the cancer cells and / or cancer stem cells.

Description

[Technical field]

[0001] The present invention is generally in the field of 1,2,4,5-tetraoxane compounds and their use as anti-cancer and anti-cancer stem cell agents. [Background technology]

[0002] Triple-negative breast cancer (TNBC) MDA-MB-231 cells are more aggressive and difficult to kill than estrogen, progesterone and HER2 positive breast cancer cells. As there is no known target for TNBC, chemotherapy and radiotherapy are the only options for TNBC. However, patients usually suffer from severe side effects from these treatments. In addition, traditional treatments such as radiotherapy and photodynamic therapy require external light sources to generate therapeutic reactive oxygen species to kill cancer. These two methods suffer from shallow laser penetration and hypoxia caused by tumors, resulting in poor therapeutic efficiency.

[0003] Cancer cells and cancer stem cells (CSCs) can also develop apoptosis resistance to some existing drugs, such as taxol and artesunate. Because chemotherapy and radiotherapy mainly kill cancer cells by inducing apoptosis, these methods may develop resistance to apoptotic cell death and therefore fail to achieve their therapeutic goals. In addition, CSCs are known to be resistant to chemotherapy or radiotherapy. CSCs have the ability of self-renewal. If a drug can treat cancer cells but not CSCs, the patient is more likely to relapse with cancer. Even if a drug can only treat CSCs, the patient will still suffer from the disease due to the presence of cancer cells.

[0004] Ferroptosis is an iron-dependent and reactive oxygen species (ROS)-dependent cell death pathway. It is known that cancer cells have elevated iron levels, which favor ferroptosis, induce harmful lipid peroxidation and irreversible cell death, and bypass anti-apoptotic pathways. However, most ferroptosis inducers lack selectivity for cancer cells compared to non-cancer cells. For example, erastin and RSL3 are more cytotoxic to non-cancer cells than cancer cells, indicating that they do not have selectivity for cancer cells.

[0005] There remains a need to develop anti-cancer compounds that have selectivity for cancer cells and cancer stem cells over non-cancerous cells. Summary of the Invention [Problem to be solved by the invention]

[0006] It is therefore an object of the present invention to provide anti-cancer compounds.

[0007] Another object of the present invention is to provide methods of using the anti-cancer compounds. [Means for solving the problem]

[0008] 1,2,4,5-tetraoxane compounds and derivatives and methods of using the compounds to treat cancer, reduce cancer, or treat or ameliorate one or more symptoms associated with cancer in a subject are described.

[0009] In general, the compounds may have three moieties: a cyclic ring moiety, a 1,2,4,5-tetraoxane moiety, and a targeting moiety. In some forms, the compounds may have the structure of Formula I:

[0010] [ka]

[0011] (a) A' can be a substituted or unsubstituted monocyclic ring, a substituted or unsubstituted polycyclic ring; (b) R1 and R2 can be independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, substituted or unsubstituted aralkyl, substituted or unsubstituted carbonyl, substituted or unsubstituted alkoxy, amido, amino, phosphonium, phosphanyl, phosphonyl, silyl, sulfinyl, thiol, hydroxyl, or R1 and R2 together with the carbon to which they are attached form a substituted or unsubstituted monocyclic ring, or a substituted or unsubstituted polycyclic ring; (c) the substituents may be a substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, substituted or unsubstituted aralkyl, substituted or unsubstituted carbonyl, substituted or unsubstituted alkoxy, halogen, hydroxyl, phenoxy, aroxy, alkylthio, phenylthio, arylthio, cyano, isocyano, nitro, carboxyl, amino, amido, oxo, silyl, sulfinyl, sulfonyl, sulfonic acid, phosphonium, phosphanyl, phosphoryl, phosphonyl, thiol, amino acid, peptide, polypeptide, or sugar group (such as a glucose group or acetylated glucose), or a combination thereof.

[0012] In some forms, the compound may have the structure of formula II:

[0013] [ka]

[0014] (a) A' and B' can independently be a substituted or unsubstituted monocyclic ring, such as those described above for A', or a substituted or unsubstituted polycyclic ring; (b) the substituents can be any of the substituents described above.

[0015] In some forms, the compound may have the structure of formula III:

[0016] [ka]

[0017] (a) A' can be as described above; (b) a can be an integer from 1 to 20; (c) b can be an integer from 0 to 24; (d) each occurrence of R3 can be substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, substituted or unsubstituted aralkyl, halogen, hydroxyl, substituted or unsubstituted alkoxy, aroxy, cyano, isocyano, nitro, substituted or unsubstituted carbonyl, amino, amido, silyl, sulfinyl, substituted or unsubstituted sulfonyl, phosphonium, phosphanyl, phosphoryl, phosphonyl, thiol, or a sugar group (such as a glucose group or an acetylated glucose); the substituents can be any of the substituents described above.

[0018] In some forms, the compound may have the structure of formula IV:

[0019] [ka]

[0020] (a) A' and a can be as described above; (b) Z' and R4 can be independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, substituted or unsubstituted aralkyl, substituted or unsubstituted carbonyl, substituted or unsubstituted alkoxy, amino, amido, silyl, sulfinyl, sulfonyl, phosphonium, phosphanyl, phosphoryl, phosphonyl, thiol, or a sugar group (such as a glucose group or acetylated glucose); the substituents can be any of the substituents described above.

[0021] In some embodiments, the compound may have the structure of Formula V:

[0022] [ka]

[0023] (a) A', a, and Z' can be as described above; (b) X' is

[0024] [ka]

[0025] , O, NR6, or S, and c can be an integer from 0 to 30; (c) W' can be C, PR7, S, or Si; (d) Y' can be NR8 or O; (e) R6 and R7 are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted ... (f) R5 and R8 can be independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted polyheteroaryl, substituted or unsubstituted aralkyl, substituted or unsubstituted carbonyl, substituted or unsubstituted alkoxy, aroxy, amido, amino, phosphonium, phosphanyl, phosphonyl, phosphoryl, phosphate, silyl, sulfinyl, thiol, or hydroxyl; R5 and R8 may be, together with Y' to which they are attached, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted cycloalkenyl, a substituted or unsubstituted cycloalkynyl, a substituted or unsubstituted heterocyclyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted polyaryl, a substituted or unsubstituted polyheteroaryl, a substituted or unsubstituted aralkyl, a substituted or unsubstituted carbonyl, a substituted or unsubstituted alkoxy, an aroxy, an amido, an amino, a phosphonium, a phosphanyl, a phosphonyl, a phosphoryl, a phosphate, a silyl, a sulfinyl, a thiol, or a hydroxyl; or R5 and R8 together with Y' to which they are attached form a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted cycloalkenyl, a substituted or unsubstituted cycloalkynyl, a substituted or unsubstituted heterocyclyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted polyaryl, or a substituted or unsubstituted polyheteroaryl; the substituents may be any of the substituents described above.

[0026] In some forms, the compound may have the structure of formula VI:

[0027] [ka]

[0028] (a) A' and a can be as described above; (b) Z' can be hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, substituted or unsubstituted aralkyl, substituted or unsubstituted carbonyl, substituted or unsubstituted alkoxy, amino, amido, silyl, phosphonium, or a sugar group (such as a glucose group or an acetylated glucose); (c) X' can be

[0029] [ka]

[0030] or O, and c is an integer from 0 to 10; (d) R5 and R8 are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, substituted or unsubstituted aralkyl, substituted or unsubstituted carbonyl, substituted or unsubstituted alkoxy, amido, amino, phosphonium, phosphazene, or R5 and R8, together with the nitrogen to which they are attached, can be substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkynyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heterocycloalkenyl, substituted or unsubstituted heterocycloalkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, or substituted or unsubstituted polyheteroaryl.

[0031] In some forms, the compound may have the structure of formula VII:

[0032] [ka]

[0033] (a) a, X', R5, R8 can be as described above; (b) Z' can be hydrogen or substituted or unsubstituted alkyl; (c) R9 can be hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, substituted or unsubstituted aralkyl, substituted or unsubstituted carbonyl, substituted or unsubstituted alkoxy, amido, amino, phosphonium, phosphanyl, or silyl, and d is an integer from 0 to 9; and the substituents can be any of the substituents described above.

[0034] In some forms, the compound may have the structure of formula VIII:

[0035] [ka]

[0036] (a) a, X', R5, and R8 can be as described above; (b) a' can be an integer from 1 to 20; (c) Z' can be hydrogen or a substituted or unsubstituted alkyl; (d) R 10 can be substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, substituted or unsubstituted aralkyl, substituted or unsubstituted carbonyl, substituted or unsubstituted alkoxy, amido, amino, phosphonium, phosphanyl, or silyl, where e is an integer from 0 to 24; and the substituents can be any of the substituents described above.

[0037] In some forms, the compound may have the structure of formula IX:

[0038] [ka]

[0039] (a) a, a', Z, X', R5, and R8 can be as described above; (b) R 14 can be hydrogen, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbonyl, substituted or unsubstituted alkoxyl, or amido.

[0040] The compound may have the structure of formula X.

[0041] [ka]

[0042] (a) A' and A" can be independently a substituted or unsubstituted monocyclic ring, a substituted or unsubstituted polycyclic ring; (b) L' can be a linker such as oxygen, sulfur, carbon, boron, substituted or unsubstituted alkoxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heteroaryl, phosphoryl, sulfinyl, sulfonyl, ether, polyether, disulfide, and amino; (c) the substituents can be independently substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, It may be a substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, substituted or unsubstituted aralkyl, substituted or unsubstituted carbonyl, substituted or unsubstituted alkoxy, halogen, hydroxyl, phenoxy, aroxy, alkylthio, phenylthio, arylthio, cyano, isocyano, nitro, carboxyl, amino, amido, oxo, silyl, sulfinyl, sulfonyl, sulfonic acid, phosphonium, phosphanyl, phosphoryl, phosphonyl, thiol, amino acid, peptide, polypeptide, or sugar group (such as a glucose group or acetylated glucose), or a combination thereof.

[0043] In some forms, the compound may have the structure of formula XI:

[0044] [ka]

[0045] (a) A', A", and L' can be as described above; (b) a and a" can independently be an integer from 1 to 20, 1 to 15, 1 to 10, 1 to 5, 1 to 3, or 1 or 2; (c) Z', Z", R 21 , and R' 21may be independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, substituted or unsubstituted aralkyl, substituted or unsubstituted carbonyl, substituted or unsubstituted alkoxy, amino, amido, silyl, sulfinyl, sulfonyl, phosphonium, phosphanyl, phosphoryl, phosphonyl, thiol, or a sugar group (such as a glucose group or acetylated glucose); the substituents may be any of the substituents described above.

[0046] In some forms, the compound may have the structure of formula XII:

[0047] [ka]

[0048] (a) A', A", L', a, a", Z', and Z" can be as described above; (b) X' and X" are independently

[0049] [ka]

[0050] , O, NR6, or S, where c can be an integer from 0 to 30, 0 to 25, 0 to 20, 0 to 15, 0 to 10, 0 to 5, 0 to 3, or 0, 1, or 2; (c) W' and W" can independently be C, PR7, S, or Si; (d) Y' and Y" can independently be a bond or can be NR8 or O; (e) R 22 and R' 22 is, independently,

[0051] [ka]

[0052] (f) R6, R7, and R8 can be independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, substituted or unsubstituted aralkyl, substituted or unsubstituted carbonyl, substituted or unsubstituted alkoxy, aroxy, amido, amino, phosphonium, phosphanyl, phosphonyl, phosphoryl, phosphate, silyl, sulfinyl, thiol, or hydroxyl; the substituents can be any of the above-mentioned substituents.

[0053] Disclosed are pharmaceutical compositions and pharmaceutical formulations in unit dosage form suitable for delivery of the compounds of the present invention, and their preparation.Generally, the pharmaceutical compositions or pharmaceutical formulations contain the compounds of the present invention and pharma- ceutical acceptable excipients.The compound in the pharmaceutical compositions or pharmaceutical formulations is in an amount effective for treating cancer, reducing cancer, or treating or improving one or more symptoms associated with cancer in a subject.In some forms, the pharmaceutical compositions or pharmaceutical formulations may further contain one or more active agents, such as one or more additional anti-cancer agents, in addition to the compounds.

[0054] The method of using the compounds of the present invention includes the step of (i) administering to the subject an amount of the compound effective to treat, reduce, or treat or ameliorate one or more symptoms associated with cancer in the subject. The subject is typically a mammal, such as a human. In some forms, the cancer to be treated or reduced can be colon cancer, breast cancer, ovarian cancer, cervical cancer, lung cancer, rectal cancer, kidney cancer, liver cancer, brain cancer, or leukemia, or a combination thereof. The compound can be administered orally, parenterally, by inhalation, mucosally, topically, or a combination thereof. In some forms, the method of the present invention can further include administering to the subject one or more second active agents, such as additional anti-cancer agents, before, during, and / or after step (i).

[0055] Also disclosed is a method for treating cancer cells and / or cancer stem cells in a subject in need thereof. The method comprises administering to the subject an effective amount of a compound of the present invention, wherein the compound exerts an IC 50 Values ​​are IC 50 and / or the compound has an IC 50 Values ​​are the IC of a known compound (e.g., OZ277, OZ439, RKA182, OZ277, OZ439, RKA182, FINO2, or a cholic acid / deoxycholic acid / steroid derivative of 1,2,4,5-tetraoxane) against the same cancer cells or cancer stem cells tested under the same conditions. 50 The pH is lower than the value. In some forms, the cancer cells being treated can be MDA-MB-231 cells, MCF7 cells, Hela cells, T47D cells, Huh7 cells, PLC cells, U2OS cells, HEK293 cells, HepG2 cells, Jurkat cells, HCT116 cells, HEYA8 cells, or HL-60 cells, or a combination thereof; and / or the non-cancerous cells can be NIH3T3 cells, MDCK cells, or bEnd.3 cells, or a combination thereof. In some forms, the compound induces ferroptosis in the cancer cells and / or cancer stem cells, and optionally, the intracellular pH of the cancer cells and / or cancer stem cells is within the range of 6-7.5. [Brief description of the drawings]

[0056] [Figure 1] FIG. 1 is a schematic representation of the biological characteristics of exemplary compounds. [Diagram 2] FIG. 1 is a schematic diagram of the in vivo experimental procedure. [Figure 3A] FIG. 13 is a graph showing the results of three independent experiments regarding dose-dependent survival curves of HeyA8, HeyA8 CSCs, and NIH3T3 in response to 48-hour treatment with Compound 37b (mean±SD, n=3). [Figure 3B]This is a graph showing the results of three independent experiments regarding dose-dependent viability curves of HeyA8, HeyA8 CSCs, and NIH3T3 in response to 48-hour treatment with Compound 48 (mean±SD, n=3). [Figure 3C] Figure 1 is a bar graph showing that compounds 37b and 48 could reduce cell viability of both ovarian cancer cells and ovarian cancer stem cells (CSCs). *P≦0.05 vs. drug-treated controls. Data are plotted as mean±SD, n=3 biologically independent samples. All P values ​​were determined using two-tailed Student's t-test. [Figure 4] 1 is a bar graph showing the protective effect of DFO and Fer-1 on HeyA8 cancer cells after 24 hours of treatment with compound 48. *P≦0.01, ***P≦0.001 vs. no pretreatment group. Data are plotted as mean±SD, n=3 biologically independent samples. All P values ​​were determined using two-tailed Student's t-test. [Figure 5A] 1 is a bar graph showing the protective effect of Q-VD-OPh, deferasirox (DFX) and ferrostatin-1 (Fer-1) on HeyA8 cancer stem cells after 24 hours of treatment with compound 48 and compound 37b. *P≦0.05, **P≦0.01 vs. no pretreatment group. Data are plotted as mean±SD, n=3 biologically independent samples. NS, no statistically significant change. All P values ​​were determined using two-tailed Student's t-test. [Figure 5B] 1 is a bar graph showing the protective effects of Q-VD-OPh, deferasirox (DFX) and ferrostatin-1 (Fer-1) on HeyA8 cells after 24 hours of treatment with compound 48 and compound 37b. *P≦0.05, **P≦0.01 vs. no pretreatment group. Data are plotted as mean±SD, n=3 biologically independent samples. NS, no statistically significant change. All P values ​​were determined using two-tailed Student's t-test. [Figure 6]1 is a bar graph showing the effect of erastin, RSL3, and artesunate on cell viability of both ovarian cancer cells and ovarian cancer stem cells (CSCs). *P≦0.05 and **P≦0.01 vs. DMSO control. Data are plotted as mean±SD, n=3 biologically independent samples. All P values ​​were determined using two-tailed Student's t-test. [Figure 7A] 1 is a graph showing tumor volume of xenograft tumors versus time after subcutaneous injection of DMSO, PTX, compound 37b, or compound 48. Nude mice were subcutaneously injected with HEYA8 CSC cells (106) and randomly assigned to one of six treatment groups (n=4): (i) DMSO, (ii) paclitaxel (PTX), 5 mg / kg, (iii) compound 37b, 5 mg / kg, (iv) compound 37b, 10 mg / kg, (v) compound 48, 5 mg / kg, or (vi) compound 48, 10 mg / kg. When tumor ulceration began to appear in control animals (DMSO) (day 25), all animals in the experiment were sacrificed and photographed. [Figure 7B] Photographs of tumors from sacrificed animals of the different treatment groups after 25 days. [Figure 7C] 1 is a graph showing tumor weight of xenograft tumors versus time after subcutaneous injection of DMSO, PTX, Compound 37b, or Compound 48. Data are presented as mean±SEM. *P≦0.05 vs. DMSO group. [Figure 8A] 1 is a bar graph showing the effect of Fer-1 (50 μM) on MDA-MB-231 cells treated for 24 hours with compounds 37b, 37a, and 30b, respectively, at the concentrations shown. *P≦0.5, **P≦0.01, ***P≦0.001 vs. cells without pretreatment; NS, no statistically significant change. Data are plotted as mean±SD, n=3 biologically independent samples. All P values ​​were determined using two-tailed Student's t-test. [Figure 8B]1 is a bar graph showing the effect of Fer-1 (50 μM) on MDA-MB-231 cells treated for 24 hours with compounds 6b, 48, 30a, and 37f, respectively, at the concentrations shown. *P≦0.01, **P≦0.002, ***P≦0.001 vs. cells without pretreatment. Data are plotted as mean±SD, n=3 biologically independent samples. [Figure 8C] 1 is a bar graph showing the effect of Fer-1 and DFO on MDA-MB-231 cells treated for 24 hours with compounds 56 and 53, respectively, at the concentrations shown. *P≦0.01, **P≦0.002, ***P≦0.001 versus cells without pretreatment. All P values ​​were determined using two-tailed Student's t-test. [Figure 9] 1 is a bar graph showing the effect of liproxstatin (30 μM) on MDA-MB-231 cells treated for 24 hours with compounds 48 and 37b, respectively, at the concentrations shown. **P≦0.01 vs. cells without pretreatment. Data are plotted as mean±SD, n=3 biologically independent samples. All P values ​​were determined using a two-tailed Student's t-test. [Figure 10] Figure 1 is a bar graph showing the relative mean fluorescence intensity of cells with HKOH-1r measured from confocal images of MDA-MB-231 cells after treatment with compounds 48 and 37b, respectively. Scale bar represents 50 μm. Data are mean ± sem, n = 20 cells for HKOH-1. Statistical significance was determined by Student's t-test as ***P ≦ 0.01. [Figure 11] 1 is a bar graph showing detection of lipid ROS by compound 48 (5 μM), compound 37b (1 μM), or RSL3 (0.5 μM) by BODIPY 581 / 591 C11 after 6 hours of incubation in MDA-MB-231 cells. **P≦0.01 vs. DMSO group. Data are plotted as mean±SD, n=3 biologically independent samples. All P values ​​were determined using two-tailed Student's t-test. [Figure 12A]Figure 1 shows the tumor volume of xenograft tumors versus time after subcutaneous injection of DMSO, PTX, Compound 37b, or Compound 48. Nude mice were injected subcutaneously with MDA-MB-231 cells (106) and randomly assigned to one of six treatment groups (n=5): (i) DMSO, (ii) paclitaxel (PTX), 5 mg / kg, (iii) Compound 37b, 5 mg / kg, (iv) Compound 37b, 10 mg / kg, (v) Compound 48, 5 mg / kg, or (vi) Compound 48, 10 mg / kg. When tumor ulceration began to appear in control animals (DMSO) (day 25), all animals in the experiment were sacrificed and photographed. [Figure 12B] Photographs of tumors from sacrificed animals of the different treatment groups after 25 days. [Figure 12C] 1 is a graph showing tumor weight of xenograft tumors versus time after subcutaneous injection of DMSO, PTX, Compound 37b, or Compound 48. Data are presented as mean±SEM. *P≦0.05 vs. DMSO group. [Figure 12D] Photographs (200x) showing morphological observations by HE staining of heart, liver, kidney, lung, and spleen tissues of mice treated with DMSO, paclitaxel, compound 37b, or compound 48. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0057] I. Definition It is to be understood that the disclosed compounds, compositions, and methods are not limited to particular synthetic methods, particular analytical techniques, or particular reagents, unless otherwise specified, which may vary, and the terminology used herein is for the purpose of describing particular forms and embodiments only, and is not intended to be limiting.

[0058] As used herein, "substituted" refers to all permissible substituents of compounds or functional groups described herein. In the broadest sense, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. Representative substituents include substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted phenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, substituted or unsubstituted aralkyl, halogen, hydroxyl, alkoxy, phenoxy, aroxy, silyl, thiol, alkylthio, substituted alkylthio, phenylthio, arylthio, cyano, isocyano, nitro, substituted or unsubstituted carbonyl, carboxyl, amino, amido, oxo, sulfinyl, sulfonyl, sulfonic acid, phosphonium, phosphanyl, phosphoryl, phosphonyl, amino acid, lactic acid-glycolic acid copolymer, peptide, polypeptide group, and sugar group (glucose group, acetylated glucose, fructose, acetylated fructose, etc.). Such substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted phenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, substituted or unsubstituted aralkyl, halogen, hydroxyl, alkoxy, phenoxy, aroxy, silyl, thiol, alkylthio, substituted alkylthio, phenylthio, arylthio, cyano, isocyano, nitro, substituted or unsubstituted carbonyl, carboxyl, amino, amido, oxo, sulfinyl, sulfonyl, sulfonic acid, phosphonium, phosphanyl, phosphoryl, phosphonyl, amino acid, lactic-glycolic acid copolymer, peptide, polypeptide groups, and sugar groups may be further substituted.

[0059] As used herein, "alkyl" refers to the radical of a saturated aliphatic group, including straight chain alkyl groups, branched chain alkyl groups, and cycloalkyl (alicyclic). In some embodiments, a straight chain or branched chain alkyl group has 30 or fewer carbon atoms in its backbone (e.g., C1-C for straight chain). 30 , C3~C for branched chain 30 ), 20 or fewer, 15 or fewer, or 10 or fewer carbon atoms. Alkyl includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, pentyl, hexyl, heptyl, octyl, decyl, tetradecyl, hexadecyl, eicosyl, tetracosyl, and the like. Similarly, cycloalkyl is a non-aromatic carbon-based ring made up of at least three carbon atoms, e.g., a non-aromatic monocyclic or non-aromatic polycyclic ring containing 3-30 carbon atoms, 3-20 carbon atoms, or 3-10 carbon atoms in its ring structure and having 5, 6, or 7 carbons in the ring structure. Cycloalkyls containing polycyclic ring systems can have two or more non-aromatic rings in which two or more carbons are common to two adjacent rings (i.e., "fused cycloalkyl rings"). Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctanyl, and the like.

[0060] The term "alkyl," as used throughout the specification, examples, and claims, is intended to include both "unsubstituted alkyls" and "substituted alkyls," the latter of which refers to alkyl moieties having one or more substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone. Such substituents include any of the substituents described above, for example, halogen (such as fluorine, chlorine, bromine, or iodine), hydroxyl, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl), thiocarbonyl (such as thioester, thioacetate, or thioformate), aryl, alkoxyl, aralkyl, phosphonium, phosphanyl, phosphonyl, phosphoryl, phosphate, phosphonate, phosphinate, amino, amido, amidine, imine, cyano, nitro, azido, oxo, sulfhydryl, thiol, alkylthio, silyl, sulfinyl, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, aromatic or heteroaromatic moieties; -NRR', where R and R' are independently hydrogen, alkyl, or aryl, and the nitrogen atom is optionally quaternized; -SR, where R is phosphonyl, sulfinyl, silyl hydrogen, alkyl, or aryl. ]; -CN; -NO2; -COOH; carboxylate; -COR, -COOR, or -CON(R)2, where R is hydrogen, alkyl, or aryl; imino, silyl, ether, haloalkyl (-CF3, -CH2-CF3, -CCl3, etc.); -CN; -NCOCOCH2CH2; -NCOCOCHCH; and -NCS; and combinations thereof. The term "alkyl" also includes "heteroalkyl."

[0061] Unless the number of carbon atoms is otherwise specified, as used herein, "lower alkyl" refers to an alkyl group as defined above having 1 to 10 carbons in its backbone structure, more preferably 1 to 6 carbons. Similarly, "lower alkenyl" and "lower alkynyl" have similar chain lengths.

[0062] As used herein, "heteroalkyl" refers to a linear or branched or cyclic carbon-containing alkyl radical, or a combination thereof, containing at least one heteroatom. Suitable heteroatoms include, but are not limited to, O, N, Si, P, and S, with nitrogen, phosphorus, and sulfur atoms being optionally oxidized, and nitrogen heteroatoms being optionally quaternized. For example, the term "heterocycloalkyl group" refers to a cycloalkyl group as defined above, in which at least one of the ring carbon atoms is replaced by a heteroatom, such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus.

[0063] The term "alkenyl" as used herein is a hydrocarbon group having 2-24 carbon atoms and whose structural formula contains at least one carbon-carbon double bond. Alkenyl groups include linear alkenyl groups, branched alkenyls, and cycloalkenyls. Cycloalkenyls are non-aromatic carbon-based rings composed of at least three carbon atoms and at least one carbon-carbon double bond, such as non-aromatic monocyclic or polycyclic rings containing 3-30 carbon atoms and at least one carbon-carbon double bond, 3-20 carbon atoms and at least one carbon-carbon double bond, or 3-10 carbon atoms and at least one carbon-carbon double bond in their ring structure, and 5, 6, or 7 carbons and at least one carbon-carbon double bond in the ring structure. Cycloalkenyls containing polycyclic ring systems may have two or more non-aromatic rings in which two or more carbons are common to two adjacent rings (i.e., "fused cycloalkenyl rings") and contain at least one carbon-carbon double bond. Asymmetric structures such as (AB)C=C(C'D) are intended to include both E and Z isomers. This may be assumed in structural formulas herein where an asymmetric alkene is present, or may be explicitly indicated by the bond symbol C. The term "alkenyl" as used throughout this specification, examples, and claims is intended to include both "unsubstituted alkenyl" and "substituted alkenyl," the latter of which refers to an alkenyl moiety having one or more substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone. The term "alkenyl" also includes "heteroalkenyl."

[0064] The term "substituted alkenyl" refers to an alkenyl moiety having one or more substituents replacing one or more hydrogen atoms on one or more carbons of the hydrocarbon backbone. Such substituents may be any of the substituents described above.

[0065] As used herein, "heteroalkenyl" refers to a linear or branched or cyclic carbon-containing alkenyl radical, or combination thereof, containing at least one heteroatom. Suitable heteroatoms include, but are not limited to, O, N, Si, P, and S, with nitrogen, phosphorus, and sulfur atoms being optionally oxidized, and nitrogen heteroatoms being optionally quaternized. For example, the term "heterocycloalkenyl group" refers to a cycloalkenyl group in which at least one of the ring carbon atoms is replaced by a heteroatom, such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus.

[0066] The term "alkynyl" as used herein refers to a hydrocarbon group having 2-24 carbon atoms and whose structural formula contains at least one carbon-carbon triple bond. Alkynyl groups include straight chain alkynyl groups, branched chain alkynyl groups, and cycloalkynyl groups. Cycloalkynyl groups are non-aromatic carbon-based rings composed of at least three carbon atoms and at least one carbon-carbon triple bond, such as non-aromatic monocyclic or polycyclic rings containing 3-30 carbon atoms and at least one carbon-carbon triple bond, 3-20 carbon atoms and at least one carbon-carbon triple bond, or 3-10 carbon atoms and at least one carbon-carbon triple bond in their ring structure, with 5, 6, or 7 carbons and at least one carbon-carbon triple bond in the ring structure. Cycloalkynyls containing polycyclic ring systems have two or more non-aromatic rings in which two or more carbons are common to two adjacent rings (i.e., "fused cycloalkynyl rings") and may contain at least one carbon-carbon triple bond. The term "alkynyl" used throughout the specification, examples, and claims is intended to include both "unsubstituted alkynyl" and "substituted alkynyl", the latter referring to an alkynyl moiety having one or more substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone. The term "alkynyl" also includes "heteroalkynyl".

[0067] The term "substituted alkynyl" refers to an alkynyl moiety having one or more substituents replacing one or more hydrogen atoms on one or more carbons of the hydrocarbon backbone. Such substituents may be any of the substituents described above.

[0068] As used herein, "heteroalkynyl" refers to a linear or branched or cyclic carbon-containing alkynyl radical, or combination thereof, containing at least one heteroatom. Suitable heteroatoms include, but are not limited to, O, N, Si, P, and S, with nitrogen, phosphorus, and sulfur atoms being optionally oxidized, and nitrogen heteroatoms being optionally quaternized. For example, the term "heterocycloalkynyl group" refers to a cycloalkynyl group in which at least one of the ring carbon atoms is replaced by a heteroatom, such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus.

[0069] As used herein, the term "aryl" refers to any C5-C 26 It is a carbon-based aromatic group, a heteroaromatic group, a fused aromatic group, or a fused heteroaromatic group. For example, as used herein, "aryl" can include 5-, 6-, 7-, 8-, 9-, 10-, 14-, 18-, and 24-membered monocyclic aromatic groups, including, but not limited to, benzene, naphthalene, anthracene, phenanthrene, chrysene, pyrene, corannulene, coronene, and the like. "Aryl" also includes polycyclic ring systems having two or more cyclic rings (i.e., "fused aromatic rings") in which two or more carbons are common to two adjacent rings, at least one of the rings is aromatic, and the other cyclic rings can be, for example, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, and / or heterocyclic. The aryl group can be substituted with one or more groups, including, for example, but not limited to, alkyl, alkynyl, alkenyl, aryl, halide, nitro, amino, ester, ketone, aldehyde, hydroxy, carboxylic acid, or alkoxy.

[0070] The term "substituted aryl" refers to an aryl group in which one or more hydrogen atoms on one or more aromatic rings are replaced with one or more substituents. Such substituents may be any of the substituents described above.

[0071] "Heterocycle" and "heterocyclyl" are used interchangeably and refer to a cyclic radical bonded through a ring carbon or nitrogen atom of a non-aromatic monocyclic or polycyclic ring containing 3 to 30 ring atoms, 3 to 20 ring atoms, 3 to 10 ring atoms, or 5 to 6 ring atoms, each ring consisting of carbon and each of non-peroxide oxygen, sulfur, and N(Y), where Y is absent or is H, O, C1-C 10 alkyl, phenyl or benzyl.] and optionally containing 1 to 4 heteroatoms selected from the group consisting of , optionally containing 1 to 3 double bonds and optionally substituted by one or more substituents. Heterocyclyl is by definition distinct from heteroaryl. Heterocycles can be heterocycloalkyl, heterocycloalkenyl, heterocycloalkynyl, etc., such as piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, dihydrofuro[2,3-b]tetrahydrofuran, morpholinyl, piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pyranyl, 2H-pyrrolyl, 4H-quinolizinyl, quinuclidinyl, tetrahydrofuranyl, 6H-1,2,5-thiadiazinyl, etc. Heterocycle groups can be optionally substituted by one or more substituents as defined above for alkyl and aryl.

[0072] The term "heteroaryl" refers to a C5-C aryl group in which one or more carbon atoms in one or more aromatic ring structures are replaced by heteroatoms. 30Heteroaryl refers to a 1-membered aromatic ring system, a fused aromatic ring system, a biaromatic ring system, or a combination thereof. Suitable heteroatoms include, but are not limited to, oxygen, sulfur, and nitrogen. The term "heteroaryl" as used herein is broadly defined to include 5-, 6-, 7-, 8-, 9-, 10-, 14-, 18-, and 24-membered monocyclic aromatic groups that may contain 1 to 4 heteroatoms, such as pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, tetrazole, pyrazole, pyridine, pyrazine, pyridazine, pyrimidine, and the like. Heteroaryl groups may also be referred to as "aryl heterocycles" or "heteroaromatics." "Heteroaryl" also includes polycyclic ring systems having two or more rings in which two or more carbons are common to two adjacent rings (i.e., "fused rings"), where at least one of the rings is heteroaromatic, e.g., the other cyclic rings can be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocyclic, or combinations thereof.Examples of heteroaryl rings include, but are not limited to, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-diphenyl aryl, and the like. Thiazinyl, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isatinoyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, naphthyridinyl, octahydroisoquinolinyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxindolyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyrid These include lysinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienoxazolyl, thienoimidazolyl, thiophenyl, and xanthenyl. One or more of these rings may be substituted as defined below for "substituted heteroaryl."

[0073] The term "substituted heteroaryl" refers to a heteroaryl group in which one or more hydrogen atoms on one or more of the heteroaromatic rings are replaced with one or more substituents. Such substituents may be any of the substituents described above.

[0074] The term "polyaryl" refers to a chemical moiety that includes two or more aryls, heteroaryls, and combinations thereof. These aryls, heteroaryls, and combinations thereof are fused or bonded via single bonds, ethers, esters, carbonyls, amides, sulfonyls, sulfonamides, alkyls, azos, and combinations thereof. For example, a "polyaryl" can be a polycyclic ring system having two or more cyclic rings in which two or more carbons are common to two adjacent rings (i.e., "fused aromatic rings"), where two or more of the rings are aromatic. When two or more heteroaryls are involved, the chemical moiety can be referred to as a "polyheteroaryl."

[0075] The term "substituted polyaryl" refers to a polyaryl in which one or more of the aryl, heteroaryl are substituted with one or more substituents. Such substituents may be any of the substituents described above. When more than one heteroaryl is involved, the chemical moiety may be referred to as a "substituted polyheteroaryl."

[0076] The term "cyclic ring" refers to a substituted or unsubstituted monocyclic ring or a substituted or unsubstituted polycyclic ring (such as those formed from a monocyclic or fused ring system) including, for example, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkynyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted polyaryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted polyheteroaryl, having 3 to 30 carbon atoms, where geometric constraints permit. The substituted cycloalkyl, substituted cycloalkenyl, substituted cycloalkynyl, and substituted heterocyclyl are each substituted as defined above for alkyl, alkenyl, alkynyl, heterocyclyl, aryl, heteroaryl, polyaryl, and polyheteroaryl, respectively.

[0077] The term "aralkyl" as used herein refers to an aryl or heteroaryl group having an alkyl, alkynyl, or alkenyl group as defined above attached to an aromatic group, such as an aryl, heteroaryl, polyaryl, or polyheteroaryl. An example of an aralkyl group is the benzyl group.

[0078] The terms "alkoxyl" or "alkoxy", "aroxy" or "aryloxy" generally refer to a group of the formula -OR v In the formula, R vExamples include, but are not limited to, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted alkylaryl, substituted or unsubstituted alkylheteroaryl, substituted or unsubstituted aralkyl, substituted or unsubstituted carbonyl, sugar group, phosphonium, phosphanyl, phosphonyl, sulfinyl, silyl, thiol, amido, and amino. Exemplary alkoxyl groups include methoxy, ethoxy, propyloxy, tert-butoxy, and the like. A "lower alkoxy" group is an alkoxy group containing 1 to 6 carbon atoms. An "ether" is two functional groups covalently linked by an oxygen, as defined below. Thus, the substituent of an alkyl that makes it an ether is or resembles an alkoxyl and can be represented, for example, by one of -O-alkyl, -O-alkenyl, -O-alkynyl, -O-aryl, -O-heteroaryl, -O-polyaryl, -O-polyheteroaryl, -O-heterocyclyl, and the like.

[0079] The term "substituted alkoxy" refers to an alkoxy group having one or more substituents replacing one or more hydrogen atoms on one or more carbons of the alkoxy backbone. Such substituents may be any of the substituents described above.

[0080] As used herein, the term "ether" refers to a compound of formula A 2 Office Automation 1 In the formula, A 2 and A 1may independently be a sugar group, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, phosphonium, phosphanyl, phosphonyl, sulfinyl, silyl, thiol, substituted or unsubstituted carbonyl, alkoxy, amido, or amino as described above.

[0081] The term "polyether" as used herein is represented by the formula:

[0082] [ka]

[0083] In the formula, A 3 can be the above-mentioned sugar group, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, phosphonium, phosphanyl, substituted or unsubstituted carbonyl, alkoxy, amido, or amino; and g can be a positive integer from 1 to 30.

[0084] The term "phenoxy" is art recognized and has the formula -OR v [In the formula, R v (i.e., -O-C6H5). Those skilled in the art will recognize that phenoxy is a member of the alloxy genus.

[0085] The term "substituted phenoxy" refers to a phenoxy group, as defined above, having one or more substituents replacing one or more hydrogen atoms on one or more carbons of the phenyl ring.

[0086] The terms "aroxy" and "aryloxy" as used interchangeably herein refer to -O-aryl or -O-heteroaryl, where aryl and heteroaryl are as defined herein.

[0087] The terms "substituted aroxy" and "substituted aryloxy," as used interchangeably herein, refer to -O-aryl or -O-heteroaryl bearing one or more substituents replacing one or more hydrogen atoms on one or more ring atoms of the aryl and heteroaryl as defined herein. Such substituents may be any of the substituents described above.

[0088] As used herein, the term "amino" includes the following groups:

[0089] [ka]

[0090] wherein E is absent or E is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, substituted or unsubstituted heterocyclyl, and wherein, independently of E, R x , R xi and R xiiare each independently substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbonyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl (e.g., substituted or unsubstituted alkylaryl, substituted or unsubstituted arylalkyl), substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, substituted or unsubstituted heterocyclyl, hydroxyl, alkoxy, phosphonium, phosphanyl, phosphonyl, sulfinyl, silyl, thiol, amido, amino, or -(CH) m -R''', where R''' represents a hydroxyl group, a substituted or unsubstituted carbonyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted cycloalkenyl group, a substituted or unsubstituted heterocyclyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted polyaryl group, a substituted or unsubstituted polyheteroaryl group, an alkoxy group, a phosphonium group, a phosphanyl group, an amido group, or an amino group; and m is 0 or an integer ranging from 1 to 8. The term "quaternary amino" refers to any group selected from the group consisting of nitrogen, R x , R xi , and R xii However, the N to which they are bonded + Also included are groups completing heterocyclyl or heteroaryl ring structures having 3 to 14 atoms.

[0091] The terms "amide" or "amido" are used interchangeably and refer to both unsubstituted amides and substituted amides and are represented by the general formula:

[0092] [ka]

[0093] wherein E is as defined above for "amino" and, independently of E, R and R' are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbonyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl (e.g., substituted or unsubstituted alkylaryl, substituted or unsubstituted arylalkyl), substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, substituted or unsubstituted heterocyclyl, hydroxyl, alkoxy, phosphonium, phosphanyl, phosphonyl, sulfinyl, silyl, thiol, amido, amino, or -(CH) m represents -R''', or R and R', together with the N atom to which they are attached, complete a heterocyclyl having 3 to 14 atoms in the ring structure; R''' and m are as defined above for "amino". In some embodiments, when E is oxygen, a carbamate is formed.

[0094] The term "carbonyl," as used herein, is art-recognized and includes moieties that may be represented by the general formula:

[0095] [ka]

[0096] wherein X is a bond or represents oxygen or sulfur; R is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbonyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl (e.g., substituted or unsubstituted alkylaryl, substituted or unsubstituted arylalkyl), substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, substituted or unsubstituted heterocyclyl, hydroxyl, alkoxy, phosphonium, phosphanyl, amido, amino, or -(CH) m E" is absent or E" is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, substituted or unsubstituted heterocyclyl; R' is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbonyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl (e.g., substituted or unsubstituted alkylaryl, substituted or unsubstituted arylalkyl), substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, substituted or unsubstituted heterocyclyl, hydroxyl, alkoxy, phosphonium, phosphanyl, amido, amino, or -(CH) mR" represents hydroxyl, substituted or unsubstituted carbonyl, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, alkoxy, phosphonium, phosphanyl, amido, or amino; and m is 0 or an integer ranging from 1 to 8. When X is oxygen and R is as defined above, the moiety is also referred to as a carboxyl group. When X is oxygen and R is hydrogen, the formula represents a "carboxylic acid". When X is oxygen and R' is hydrogen, the formula represents a "formate". When X is oxygen and R or R' is not hydrogen, the formula represents an "ester". In general, when the oxygen atom of the above formula is replaced by a sulfur atom, the formula represents a "thiocarbonyl" group. Where X is a sulfur and R or R' is not hydrogen, the formula represents a "thioester." Where X is a sulfur and R is hydrogen, the formula represents a "thiocarboxylic acid." Where X is a sulfur and R' is hydrogen, the formula represents a "thioformate." Where X is a bond and R is not hydrogen, the formula represents a "ketone." Where X is a bond and R is hydrogen, the formula represents an "aldehyde."

[0097] The term "substituted carbonyl" refers to a carbonyl as defined above in which one or more hydrogen atoms on the R, R', or group to which the moiety is attached are independently replaced.

[0098] [ka] ,

[0099] Such substituents may be any of the substituents described above.

[0100] The term "carboxyl" is as defined above for carbonyl and more specifically refers to a group of the formula -R iv COOH, where R ivis substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted alkylaryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, or substituted or unsubstituted heteroaryl.

[0101] The term "substituted carboxyl" refers to a carboxyl as defined above, where R iv In the formula (I), one or more hydrogen atoms are replaced. Such a substitutent may be any of the substitutents described above.

[0102] The term "phosphanyl" is represented by the formula:

[0103] [ka]

[0104] wherein E is absent or E is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aralkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, substituted or unsubstituted heterocyclyl, and wherein, independently of E, R vi and R viiare each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbonyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl (e.g., substituted or unsubstituted alkylaryl, substituted or unsubstituted arylalkyl, etc.), substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, substituted or unsubstituted heterocyclyl, hydroxyl, alkoxy, phosphonium, phosphanyl, phosphonyl, sulfinyl, silyl, thiol, amido, amino, or -(CH) m -R''' or R vi and R vii together with the P atom to which they are attached complete a heterocycle having 3 to 14 atoms in the ring structure; R''' and m are as defined above for "amino."

[0105] The term "phosphonium" is represented by the formula:

[0106] [ka]

[0107] wherein E is as defined above for "phosphanyl" and independently represents R vi , R vii , and R viiiare each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbonyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl (e.g., substituted or unsubstituted alkylaryl, substituted or unsubstituted arylalkyl, etc.), substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, substituted or unsubstituted heterocyclyl, hydroxyl, alkoxy, phosphonium, phosphanyl, phosphonyl, sulfinyl, silyl, thiol, amido, amino, or -(CH) m -R''' or R vi , R vii , and R viii are the P to which they are bonded + Together with the atoms, complete a heterocycle having 3 to 14 atoms in the ring structure; R''' and m are as defined above for "amino".

[0108] The term "phosphonyl" is represented by the formula:

[0109] [ka]

[0110] wherein E is absent or E is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aralkyl (e.g., substituted or unsubstituted alkylaryl, substituted or unsubstituted arylalkyl, etc.), substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, substituted or unsubstituted heterocyclyl, wherein, independently of E, R vi and R viiare independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbonyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl (e.g., substituted or unsubstituted alkylaryl, substituted or unsubstituted arylalkyl, etc.), substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, substituted or unsubstituted heterocyclyl, hydroxyl, alkoxy, phosphonium, phosphanyl, phosphonyl, sulfinyl, silyl, thiol, amido, amino, or -(CH) m -R''', or R vi and R vii together with the P atom to which they are attached complete a heterocycle having 3 to 14 atoms in the ring structure; R''' and m are as defined above for "amino."

[0111] The term "substituted phosphonyl" refers to any of E, R vi and R vii represents an independently substituted phosphonyl, such substituents may be any of the substituents described above.

[0112] The term "phosphoryl" refers to phosphonyl, where E is absent, oxygen, alkoxy, aroxy, substituted alkoxy or substituted aroxy as defined above, and independently of E, R vi and R vii are independently hydroxyl, alkoxy, aroxy, substituted alkoxy or substituted aroxy as defined above. As will be understood by those of skill in the art, when E is oxygen, phosphoryl cannot be bonded to another species, for example, to form an oxygen-oxygen bond or other labile bond.

[0113] The term "sulfinyl" is represented by the formula:

[0114] [ka]

[0115] wherein E is as defined above for "phosphonyl" and, independently of E, R is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbonyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl (e.g., substituted or unsubstituted alkylaryl, substituted or unsubstituted arylalkyl), substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, substituted or unsubstituted heterocyclyl, hydroxyl, alkoxy, phosphonium, phosphanyl, phosphonyl, silyl, thiol, amido, amino, or -(CH) m represents -R''', or E and R, together with the S atom to which they are attached, complete a heterocycle having 3 to 14 atoms in the ring structure; R''' and m are as defined above for "amino".

[0116] The term "sulfonyl" is represented by the formula:

[0117] [ka]

[0118] wherein E is as defined above for "phosphonyl" and, independently of E, R is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbonyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl (e.g., substituted or unsubstituted alkylaryl, substituted or unsubstituted arylalkyl), substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, substituted or unsubstituted heterocyclyl, hydroxyl, alkoxy, phosphonium, phosphanyl, amido, amino, or -(CH)m represents -R''', or E and R, together with the S atom to which they are attached, complete a heterocycle having 3 to 14 atoms in the ring structure; R''' and m are as defined above for "amino".

[0119] The term "substituted sulfonyl" refers to sulfonyl in which E, R, or both, are independently substituted. Such substituents may be any of the substituents described above.

[0120] The term "sulfonic acid" refers to sulfonyl, as defined above, where R is hydroxyl and E is absent or E is substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted alkylaryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, or substituted or unsubstituted heteroaryl.

[0121] The term "sulfate" refers to a sulfonyl, as defined above, where E is absent, or is oxygen, alkoxy, aroxy, substituted alkoxy, or substituted aroxy, as defined above, and R is independently hydroxyl, alkoxy, aroxy, substituted alkoxy, or substituted aroxy, as defined above. As will be understood by one of skill in the art, when E is oxygen, the sulfate cannot be attached to another chemical species, for example, to form an oxygen-oxygen bond or another labile bond.

[0122] The term "sulfonate" refers to sulfonyl, as defined above, where E is oxygen, alkoxy, aroxy, substituted alkoxy or substituted aroxy as defined above, and R is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted amino, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, substituted or unsubstituted alkylaryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, -(CH) m -R''', where R''' represents a hydroxy group, a substituted or unsubstituted carbonyl group, an aryl, a cycloalkyl ring, a cycloalkenyl ring, a heterocycle, an amide, an amino, or a polycycle; and m is 0 or an integer ranging from 1 to 8. As will be understood by one of ordinary skill in the art, when E is oxygen, the sulfonate cannot be bonded to another chemical species, for example, to form an oxygen-oxygen bond or another labile bond.

[0123] The term "sulfamoyl" refers to a sulfonamide or a sulfonamide of the formula:

[0124] [ka]

[0125] wherein E is absent or E is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aralkyl (e.g., substituted or unsubstituted alkylaryl, substituted or unsubstituted cycloalkyl, etc.), substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, substituted or unsubstituted heterocyclyl, wherein, independently of E, R and R' are each independently hydrogen, substituted or unsubstituted alkyl, , substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbonyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl (e.g., substituted or unsubstituted alkylaryl, substituted or unsubstituted arylalkyl, etc.), substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, substituted or unsubstituted heterocyclyl, hydroxyl, alkoxy, phosphonium, phosphanyl, amido, amino, or -(CH) m represents -R''', or R and R', together with the N atom to which they are attached, complete a heterocycle having 3 to 14 atoms in the ring structure; R''' and m are as defined above for "amino".

[0126] The term "silyl group," as used herein, is represented by the formula -SiRR'R", where R, R', and R" can be independently hydrogen, a saccharide group, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl (e.g., substituted or unsubstituted alkylaryl, substituted or unsubstituted arylalkyl, etc.), substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, substituted or unsubstituted carbonyl, phosphonium, phosphanyl, phosphonyl, sulfinyl, thiol, amido, amino, alkoxy, or oxo, as described above.

[0127] The term "thiol" is used interchangeably and is represented by -SR, where R can be hydrogen, a sugar group, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl (e.g., substituted or unsubstituted alkylaryl, substituted or unsubstituted arylalkyl, etc.), substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, substituted or unsubstituted carbonyl, phosphonium, phosphanyl, amido, amino, alkoxy, oxo, phosphonyl, sulfinyl, or silyl as described above.

[0128] The term "alkylthio" refers to an alkyl group, as defined above, having a sulfur radical attached thereto. The "alkylthio" moiety is represented by -S-alkyl. Representative alkylthio groups include methylthio, ethylthio, and the like. The term "alkylthio" also encompasses cycloalkyl groups having a sulfur radical attached thereto.

[0129] The term "substituted alkylthio" refers to an alkylthio group having one or more substituents replacing one or more hydrogen atoms on one or more carbons of the alkylthio backbone.

[0130] The term "phenylthio" is art-recognized and refers to --S--C.sub.6H.sub.5, i.e., a phenyl group attached to a sulfur atom.

[0131] The term "substituted phenylthio" refers to a phenylthio group, as defined above, having one or more substituents replacing a hydrogen on one or more carbons of the phenyl ring.

[0132] The term "arylthio" refers to the group --S-aryl or --S-heteroaryl, where aryl and heteroaryl are as defined herein.

[0133] The term "substituted arylthio" refers to -S-aryl or -S-heteroaryl having one or more substituents replacing a hydrogen atom on one or more ring atoms of the aryl and heteroaryl rings as defined herein.

[0134] The terms "hydroxyl" and "hydroxy" are used interchangeably and are represented as --OH.

[0135] The term "oxo" refers to =O attached to a carbon atom.

[0136] The terms "cyano" and "nitrile" are used interchangeably and refer to --CN.

[0137] The term "nitro" refers to --NO.

[0138] The term "phosphate" refers to -O-PO3.

[0139] The terms "azide" or "azido" are used interchangeably and refer to --N3.

[0140] The disclosed compounds and substituents may independently carry two or more of the groups listed above. For example, if the compound or substituent is a linear alkyl group, one of the hydrogen atoms of the alkyl group may be replaced by a hydroxyl group, an alkoxy group, etc. Depending on the group selected, the first group may be incorporated into the second group, or the first group may be pendant (i.e., attached) to the second group. For example, the expression "an alkyl group containing an ester group" may allow the ester group to be incorporated into the backbone of the alkyl group. Alternatively, the ester may be attached to the backbone of the alkyl group. The nature of the group selected will determine whether the first group is embedded or attached to the second group.

[0141] Compounds and substituents may be independently substituted with the substituents described above in the definition of "substituted."

[0142] II. Composition 1,2,4,5-tetraoxane compounds and derivatives thereof (collectively also referred to herein as "compounds") have been developed that have anti-cancer properties against cancer cells and / or cancer stem cells, and that have broad anti-cancer properties and should be suitable for use in treating and / or ameliorating the symptoms of multiple types of cancer.

[0143] In general, the compounds contain three moieties:

[0144] [ka]

[0145] Without being bound by theory, the cyclic ring portion of the compound may provide lipid solubility for cell permeability and maintain the lethality of the compound to cancer cells and / or cancer stem cells; and the targeting portion may provide water solubility, cytotoxicity, and selectivity for cancer cells and / or cancer stem cells over non-cancer cells. For example, the targeting portion may localize the compound to a specific location in cancer cells and / or cancer stem cells, enhancing efficacy and minimizing off-target effects, i.e., binding to non-cancer cells.

[0146] The overall structure of these compounds makes them useful for inducing ferroptosis to kill cancer cells and / or cancer stem cells. The term "cancer cells" refers to cells with abnormal growth and division with invasive potential. Tumors contain cancer cells that have uncontrolled growth and promote the construction of blood vessels. The term "cancer stem cells" refers to tumor-initiating cells that are characterized by the ability of self-renewal, differentiation, and chemotherapy resistance. Without being bound by theory, cancer cells differ from cancer stem cells in at least the following aspects. For example, wnt / β-catenin, Notch, or hedgehog signaling pathways may play a role in controlling the growth and development of cancer stem cells rather than cancer cells. Cancer stem cells may be positive for stem cell surface markers such as CD133, CD117, Bmi-1, Nanog, Sox4, CD44, etc. Compared to cancer cells, cancer stem cells may overexpress ABC drug transporters to excrete chemotherapy drugs such as paclitaxel and doxorubicin. Cancer stem cells may belong to the side population cells that exclude DNA-specific dye by Hoechst33342. Ferroptosis is an iron-dependent and reactive oxygen species (ROS)-dependent cell death pathway. It is well known that cancer cells have elevated iron levels, which favor ferroptosis and induce harmful lipid peroxides and irreversible cell death. The compound may selectively induce ferroptosis in cancer cells and cancer stem cells compared to non-cancer cells. In addition, the compound may generate reactive oxygen species in cancer cells and cancer stem cells independent of pH (e.g., generate hydroxyl radicals and lipid peroxides under neutral pH), thereby eliminating the need for an acidic intracellular environment in complex formulations containing multiple components (e.g., enzymes that catalyze hydrogen peroxide production, iron oxide, etc.) and chemodynamic therapy, i.e., ferroptosis.

[0147] Pharmaceutical compositions and formulations containing the compounds are also disclosed.

[0148] A. Compound 1. 1,2,4,5-Tetraoxane and its derivatives The compound may have the structure of Formula I.

[0149] [ka]

[0150] (a) A' can be a substituted or unsubstituted monocyclic ring, a substituted or unsubstituted polycyclic ring; (b) R1 and R2 can be independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, substituted or unsubstituted aralkyl, substituted or unsubstituted carbonyl, substituted or unsubstituted alkoxy, amido, amino, phosphonium, phosphanyl, phosphonyl, silyl, sulfinyl, thiol, hydroxyl, or R1 and R2 together with the carbon to which they are attached form a substituted or unsubstituted monocyclic ring, or a substituted or unsubstituted polycyclic ring. E.

[0151] Exemplary substituents can be substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, substituted or unsubstituted aralkyl, substituted or unsubstituted carbonyl, substituted or unsubstituted alkoxy, halogen, hydroxyl, phenoxy, aroxy, alkylthio, phenylthio, arylthio, cyano, isocyano, nitro, carboxyl, amino, amido, oxo, silyl, sulfinyl, sulfonyl, sulfonic acid, phosphonium, phosphanyl, phosphoryl, phosphonyl, thiol, amino acid, peptide, polypeptide, or sugar group (such as a glucose group or acetylated glucose), or combinations thereof.

[0152] In some embodiments, A' can be substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkynyl, substituted or unsubstituted heterocyclyl (such as substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heterocycloalkenyl, substituted or unsubstituted heterocycloalkynyl), substituted or unsubstituted aryl, substituted or unsubstituted polyaryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted polyheteroaryl, having from 3 to 30 carbon atoms, where geometric constraints permit.

[0153] The alkyl can be a linear alkyl, a branched alkyl, or a cyclic (monocyclic or polycyclic) alkyl. Exemplary alkyls include linear C1-C 30 Alkyl, branched C4-C 30 Alkyl, cyclic C3-C 30 Alkyl, linear C1-C 20 Alkyl, branched C4-C 20 Alkyl, cyclic C3-C 20 Alkyl, linear C1-C 10 Alkyl, branched C4-C 10 Alkyl, cyclic C3-C 10 Alkyl, linear C1-C6 alkyl, branched C4-C6 alkyl, cyclic C3-C6 alkyl, linear C1-C4 alkyl, cyclic C3-C4 alkyl, e.g. linear C1-C 10 , C1 to C9, C1 to C8, C1 to C7, C1 to C6, C1 to C5, C1 to C4, C1 to C3, C1 to C2 alkyl groups, branched C3 to C9, C3 to C9, C3 to C8, C3 to C7, C3 to C6, C3 to C5, C3 to C4 alkyl groups, and cyclic C3 to C9, C3 to C9, C3 to C8, C3 to C7, C3 to C6, C3 to C5, C3 to C4 alkyl groups.

[0154] The alkenyl may be a straight-chain alkenyl, a branched alkenyl, or a cyclic (monocyclic or polycyclic) alkenyl. Exemplary alkenyls include straight-chain C1-C 30 Alkenyl, branched C4-C 30 Alkenyl, cyclic C3-C 30Alkenyl, linear C1-C 20 Alkenyl, branched C4-C 20 Alkenyl, cyclic C3-C 20 Alkenyl, linear C1-C 10 Alkenyl, branched C4-C 10 Alkenyl, cyclic C3-C 10 Alkenyl, linear C1-C6 alkenyl, branched C4-C6 alkenyl, cyclic C3-C6 alkenyl, linear C1-C4 alkenyl, cyclic C3-C4 alkenyl, e.g. linear C1-C 10 , C1 to C9, C1 to C8, C1 to C7, C1 to C6, C1 to C5, C1 to C4, C1 to C3, C1 to C2 alkenyl groups, branched C3 to C9, C3 to C9, C3 to C8, C3 to C7, C3 to C6, C3 to C5, C3 to C4 alkenyl groups, and cyclic C3 to C9, C3 to C9, C3 to C8, C3 to C7, C3 to C6, C3 to C5, C3 to C4 alkenyl groups.

[0155] The alkynyl may be a straight-chain alkynyl, a branched alkynyl, or a cyclic (monocyclic or polycyclic) alkynyl. Exemplary alkynyls include straight-chain C1-C 30 Alkynyl, branched C4-C 30 Alkynyl, cyclic C3-C 30 Alkynyl, linear C1-C 20 Alkynyl, branched C4-C 20 Alkynyl, cyclic C3-C 20 Alkynyl, linear C1-C 10 Alkynyl, branched C4-C 10 Alkynyl, cyclic C3-C 10 Alkynyl, linear C1-C6 alkynyl, branched C4-C6 alkynyl, cyclic C3-C6 alkynyl, linear C1-C4 alkynyl, cyclic C3-C4 alkynyl, e.g. linear C1-C 10, C1 to C9, C1 to C8, C1 to C7, C1 to C6, C1 to C5, C1 to C4, C1 to C3, C1 to C2 alkynyl groups, branched C3 to C9, C3 to C9, C3 to C8, C3 to C7, C3 to C6, C3 to C5, C3 to C4 alkynyl groups, and cyclic C3 to C9, C3 to C9, C3 to C8, C3 to C7, C3 to C6, C3 to C5, C3 to C4 alkynyl groups.

[0156] It is understood that the exemplary alkyl, alkenyl, and alkynyl groups can all be heteroalkyl, heteroalkenyl, and heteroalkynyl, respectively. For example, alkyl can be a linear C-C 30 Heteroalkyl, branched C4-C 30 Heteroalkyl, cyclic C3-C 30 Heteroalkyl (i.e., heterocycloalkyl), linear C1-C 20 Heteroalkyl, branched C4-C 20 Heteroalkyl, cyclic C3-C 20 Heteroalkyl, linear C1-C 10 Heteroalkyl, branched C4-C 10 Heteroalkyl, cyclic C3-C 10 Heteroalkyl, linear C1-C6 heteroalkyl, branched C4-C6 heteroalkyl, cyclic C3-C6 heteroalkyl, linear C1-C4 heteroalkyl, cyclic C3-C4 heteroalkyl, e.g. linear C1-C 10 , a C1-C9, C1-C8, C1-C7, C1-C6, C1-C5, C1-C4, C1-C3, C1-C2 heteroalkyl group, a branched C3-C9, C3-C9, C3-C8, C3-C7, C3-C6, C3-C5, C3-C4 heteroalkyl group, or a cyclic C3-C9, C3-C9, C3-C8, C3-C7, C3-C6, C3-C5, C3-C4 heteroalkyl group.

[0157] Alkenyl is a straight-chain C2-C 30 Heteroalkenyl, branched C4-C 30 Heteroalkenyl, cyclic C3-C 30 Heteroalkenyl (i.e., heterocycloalkenyl), linear C1-C 20Heteroalkenyl, branched C4-C 20 Heteroalkenyl, cyclic C3-C 20 Heteroalkenyl, linear C1-C 10 Heteroalkenyl, branched C4-C 10 Heteroalkenyl, cyclic C3-C 10 Heteroalkenyl, linear C1-C6 heteroalkenyl, branched C4-C6 heteroalkenyl, cyclic C3-C6 heteroalkenyl, linear C1-C4 heteroalkenyl, cyclic C3-C4 heteroalkenyl, e.g. linear C1-C 10 , a C1-C9, C1-C8, C1-C7, C1-C6, C1-C5, C1-C4, C1-C3, or C1-C2 heteroalkenyl group, a branched C3-C9, C3-C9, C3-C8, C3-C7, C3-C6, C3-C5, or C3-C4 heteroalkenyl group, or a cyclic C3-C9, C3-C9, C3-C8, C3-C7, C3-C6, C3-C5, or C3-C4 heteroalkenyl group.

[0158] Alkynyl is a straight-chain C2-C 30 Heteroalkynyl, branched C4-C 30 Heteroalkynyl, cyclic C3-C 30 Heteroalkynyl (i.e., heterocycloalkynyl), linear C1-C 20 Heteroalkynyl, branched C4-C 20 Heteroalkynyl, cyclic C3-C 20 Heteroalkynyl, linear C1-C 10 Heteroalkynyl, branched C4-C 10 Heteroalkynyl, cyclic C3-C 10 Heteroalkynyl, linear C1-C6 heteroalkynyl, branched C4-C6 heteroalkynyl, cyclic C3-C6 heteroalkynyl, linear C1-C4 heteroalkynyl, cyclic C3-C4 heteroalkynyl, for example, linear C1-C 10, a C1-C9, C1-C8, C1-C7, C1-C6, C1-C5, C1-C4, C1-C3, or C1-C2 heteroalkynyl group, a branched C3-C9, C3-C9, C3-C8, C3-C7, C3-C6, C3-C5, or C3-C4 heteroalkynyl group, or a cyclic C3-C9, C3-C9, C3-C8, C3-C7, C3-C6, C3-C5, or C3-C4 heteroalkynyl group.

[0159] The aryl group is C5-C 30 Aryl, C5-C 20 Aryl, C5-C 12 Aryl, C5-C 11 Aryl, C5-C9 Aryl, C6-C 20 Aryl, C6-C 12 Aryl, C6-C 11 The aryl may be a heteroaryl, e.g., a C5-C 30 Heteroaryl, C5-C 20 Heteroaryl, C5-C 12 Heteroaryl, C5-C 11 Heteroaryl, C5-C9 heteroaryl, C6-C 30 Heteroaryl, C6-C 20 Heteroaryl, C6-C 12 Heteroaryl, C6-C 11 It is understood that the polyaryl group can be a C heteroaryl, or a C6-C9 heteroaryl. 10 ~C 30 Polyaryl, C 10 ~C 20 Polyaryl, C 10 ~C 12 Polyaryl, C 10 ~C 11 Polyaryl, or C 12 ~C 20 The aryl may be a polyaryl. The aryl may be a polyheteroaryl, e.g., C 10 ~C 30 Polyheteroaryl, C 10 ~C 20 Polyheteroaryl, C 10 ~C 12 Polyheteroaryl, C 10~C 11 Polyheteroaryl, or C 12 ~C 20 It is understood that it may be polyheteroaryl.

[0160] In some forms, the compound may have the structure of Formula II:

[0161] [ka]

[0162] (a) A' and B' can independently be a substituted or unsubstituted monocyclic ring, such as those described above for A', or a substituted or unsubstituted polycyclic ring; (b) the substituents can be any of the substituents described above.

[0163] In some forms, the compound may have the structure of formula III:

[0164] [ka]

[0165] (a) A' can be as described above; (b) a can be an integer from 1 to 20; (c) b can be an integer from 0 to 24; (d) each occurrence of R3 can be substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, substituted or unsubstituted aralkyl, halogen, hydroxyl, substituted or unsubstituted alkoxy, aroxy, cyano, isocyano, nitro, substituted or unsubstituted carbonyl, amino, amido, silyl, sulfinyl, substituted or unsubstituted sulfonyl, phosphonium, phosphanyl, phosphoryl, phosphonyl, thiol, or a sugar group (such as a glucose group or an acetylated glucose); the substituents can be any of the substituents described above.

[0166] In some forms of Formula III, a can be an integer from 1 to 15, 1 to 12, 1 to 10, 1 to 8, 1 to 5, or 1 to 3, e.g., 1 or 2; and b is an integer from 1 to 10, 1 to 8, 1 to 5, or 1 to 3, e.g., 1 or 2.

[0167] In some forms, the compound may have the structure of formula IV:

[0168] [ka]

[0169] (a) A' and a can be as described above; (b) Z' and R4 can be independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, substituted or unsubstituted aralkyl, substituted or unsubstituted carbonyl, substituted or unsubstituted alkoxy, amino, amido, silyl, sulfinyl, sulfonyl, phosphonium, phosphanyl, phosphoryl, phosphonyl, thiol, or a sugar group (such as a glucose group or acetylated glucose); the substituents can be any of the substituents described above.

[0170] In some forms of formula IV, a can be an integer between 1 and 15, between 1 and 12, between 1 and 10, between 1 and 8, between 1 and 5, or between 1 and 3, for example, 1 or 2. In some forms of formula IV, Z' can be hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl. In some forms of formula IV, R4 can be substituted or unsubstituted alkyl, substituted or unsubstituted carbonyl, substituted or unsubstituted alkoxy, amido, amino, or sulfinyl, sulfonyl, phosphonium, phosphanyl, phosphoryl, phosphonyl, thiol, or sugar group (such as glucose group or acetylated glucose). In some forms of formula IV, R4 can contain at least one oxygen and can be bonded to the carbon through the oxygen.

[0171] In some forms of formula IV, a can be an integer from 1 to 5, 1 to 3, e.g., 1 or 2; Z' can be hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl; R4 can be substituted or unsubstituted alkyl, substituted or unsubstituted carbonyl, substituted or unsubstituted alkoxy, amido, amino, or sulfinyl, sulfonyl, phosphonium, phosphanyl, phosphoryl, phosphonyl, thiol, or a sugar group (such as a glucose group or acetylated glucose).

[0172] In some embodiments, the compound may have the structure of Formula V:

[0173] [ka]

[0174] (a) A', a, and Z' can be as described above; (b) X' can be

[0175] [ka]

[0176] , O, NR6, or S, and c can be an integer from 0 to 30; (c) W' can be C, PR7, S, or Si; (d) Y' can be NR8 or O; (e) R6 and R7 are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted ... (f) R5 and R8 can be independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted polyheteroaryl, substituted or unsubstituted aralkyl, substituted or unsubstituted carbonyl, substituted or unsubstituted alkoxy, aroxy, amido, amino, phosphonium, phosphanyl, phosphonyl, phosphoryl, phosphate, silyl, sulfinyl, thiol, or hydroxyl; R5 and R8 may be, together with Y' to which they are attached, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted cycloalkenyl, a substituted or unsubstituted cycloalkynyl, a substituted or unsubstituted heterocyclyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted polyaryl, a substituted or unsubstituted polyheteroaryl, a substituted or unsubstituted aralkyl, a substituted or unsubstituted carbonyl, a substituted or unsubstituted alkoxy, an aroxy, an amido, an amino, a phosphonium, a phosphanyl, a phosphonyl, a phosphoryl, a phosphate, a silyl, a sulfinyl, a thiol, or a hydroxyl; or R5 and R8 together with Y' to which they are attached form a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted cycloalkenyl, a substituted or unsubstituted cycloalkynyl, a substituted or unsubstituted heterocyclyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted polyaryl, or a substituted or unsubstituted polyheteroaryl; the substituents may be any of the substituents described above.

[0177] In some forms of Formula V, a can be an integer from 1 to 15, 1 to 12, 1 to 10, 1 to 8, 1 to 5, or 1 to 3, e.g., 1 or 2. In some forms of Formula V, Z' can be hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl. In some forms of Formula V, X' can be

[0178] [ka]

[0179] or O, where c can be 0 or an integer from 1 to 10, 1 to 8, 1 to 5, or 1 to 3, e.g., 1 or 2. In some forms of Formula V, X' can be O. In some forms of Formula V, W' can be C, PR7, or S, where R7 can be hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, amino, thiol, or substituted or unsubstituted alkoxy.

[0180] In some forms of formula V, a can be an integer from 1 to 5, 1 to 3, for example, 1 or 2; Z' can be hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl; X' can be

[0181] [ka]

[0182] or O, where c can be 0 or an integer from 1 to 10, 1 to 8, 1 to 5, or 1 to 3; W' can be C, PR7, or S, where R7 can be hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, amino, thiol, or substituted or unsubstituted alkoxy; Y' can be NR8 or O; R5 and R8 are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl (e.g., substituted or unsubstituted alkylaryl, substituted or unsubstituted ... or unsubstituted arylalkyl, substituted or unsubstituted alkylheteroaryl, substituted or unsubstituted heteroarylalkyl, etc., substituted or unsubstituted carbonyl, substituted or unsubstituted alkoxy, amido, amino, or sulfinyl, sulfonyl, phosphonium, phosphanyl, phosphoryl, phosphonyl, thiol, silyl, or a sugar group (such as a glucose group or an acetylated glucose); or R5 and R8 together with Y' to which they are attached form a substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heterocycloalkenyl, or substituted or unsubstituted heterocycloalkynyl.

[0183] In some embodiments, the compound may have the structure of formula VI:

[0184] [ka]

[0185] (a) A' and a can be as described above; (b) Z' can be hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, substituted or unsubstituted aralkyl, substituted or unsubstituted carbonyl, substituted or unsubstituted alkoxy, amino, amido, silyl, phosphonium, or a sugar group (such as a glucose group or an acetylated glucose); (c) X' can be

[0186] [ka]

[0187] or O, and c is an integer from 0 to 10; (d) R5 and R8 are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, substituted or unsubstituted aralkyl, substituted or unsubstituted carbonyl, substituted or unsubstituted alkoxy, amido, amino, phosphonium, phosphazene, or R5 and R8, together with the nitrogen to which they are attached, can be substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkynyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heterocycloalkenyl, substituted or unsubstituted heterocycloalkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, or substituted or unsubstituted polyheteroaryl.

[0188] In some forms of Formula VI, X' can be O. In some forms of Formula VI, X' can be

[0189] [ka]

[0190] and c can be 0 or an integer from 1 to 10, 1 to 8, 1 to 5, or 1 to 3, such as 1 or 2. In some forms of Formula VI, a can be an integer from 1 to 15, 1 to 12, 1 to 10, 1 to 8, 1 to 5, or 1 to 3, such as 1 or 2. In some forms of Formula VI, Z' can be hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl.

[0191] In some forms of Formula VI, a can be an integer from 1 to 5, or 1 to 3, e.g., 1 or 2; Z' can be hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl; X' can be O; R5 and R8 are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl (e.g., substituted or unsubstituted alkylaryl, substituted or unsubstituted arylalkyl ... R5 and R8, together with the nitrogen to which they are attached, can be a substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heterocycloalkenyl, or substituted or unsubstituted heterocycloalkynyl.

[0192] In some forms of Formulas I-VI, A' can be substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkynyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heterocycloalkenyl, substituted or unsubstituted heterocycloalkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl. In some forms of Formulas I-VI, A' can be substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkynyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heterocycloalkenyl, substituted or unsubstituted heterocycloalkynyl.

[0193] In some embodiments of Formulas I-VI, A' is a substituted or unsubstituted cycloalkyl or a substituted or unsubstituted heterocycloalkyl, such as a substituted or unsubstituted C-C 30 Cycloalkyl, substituted or unsubstituted C3-C 30 Heterocycloalkyl, substituted or unsubstituted C3-C 25 Cycloalkyl, substituted or unsubstituted C3-C 25 Heterocycloalkyl, substituted or unsubstituted C3-C 20 Cycloalkyl, substituted or unsubstituted C3-C 20 Heterocycloalkyl, substituted or unsubstituted C3-C 15 Cycloalkyl, substituted or unsubstituted C3-C 15 Heterocycloalkyl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C3-C 10 Heterocycloalkyl, substituted or unsubstituted C5-C 30 Cycloalkyl, substituted or unsubstituted C5-C 30 Heterocycloalkyl, substituted or unsubstituted C5-C 25 Cycloalkyl, substituted or unsubstituted C5-C 25 Heterocycloalkyl, substituted or unsubstituted C5-C 20Cycloalkyl, substituted or unsubstituted C5-C 20 Heterocycloalkyl, substituted or unsubstituted C5-C 15 Cycloalkyl, substituted or unsubstituted C5-C 15 Heterocycloalkyl, substituted or unsubstituted C5-C 10 Cycloalkyl, substituted or unsubstituted C5-C 10 It may be a heterocycloalkyl.

[0194] In some embodiments of Formulas I-VI, A' is a substituted or unsubstituted C-C 30 Polycycloalkyl, substituted or unsubstituted C6-C 30 Polyheterocycloalkyl, substituted or unsubstituted C6-C 25 Polycycloalkyl, substituted or unsubstituted C6-C 25 Polyheterocycloalkyl, substituted or unsubstituted C6-C 20 Polycycloalkyl, substituted or unsubstituted C6-C 20 Polyheterocycloalkyl, substituted or unsubstituted C6-C 15 Polycycloalkyl, substituted or unsubstituted C6-C 15 Polyheterocycloalkyl, substituted or unsubstituted C6-C 10 Polycycloalkyl, substituted or unsubstituted C6-C 10 Polyheterocycloalkyl, substituted or unsubstituted C 10 ~C 30 Polycycloalkyl, substituted or unsubstituted C 10 ~C 30 Polyheterocycloalkyl, substituted or unsubstituted C 10 ~C 25 Polycycloalkyl, substituted or unsubstituted C 10 ~C 25 Polyheterocycloalkyl, substituted or unsubstituted C 10 ~C 20 Polycycloalkyl, substituted or unsubstituted C 10 ~C 20 Polyheterocycloalkyl, substituted or unsubstituted C 10 ~C 15Polycycloalkyl, substituted or unsubstituted C 10 ~C 15 Polyheterocycloalkyl, for example, substituted or unsubstituted C 10 Polycycloalkyl or substituted or unsubstituted C 10 It may be a polyheterocycloalkyl.

[0195] In some embodiments of Formulas I-VI, A' is a substituted or unsubstituted C3-C 10 Monocycloalkyl, substituted or unsubstituted C3-C 10 It may be monoheterocycloalkyl, substituted or unsubstituted C3-C8 monocycloalkyl, substituted or unsubstituted C3-C8 monoheterocycloalkyl, substituted or unsubstituted C3-C6 monocycloalkyl, substituted or unsubstituted C3-C6 monoheterocycloalkyl, substituted or unsubstituted C3-C5 monocycloalkyl, substituted or unsubstituted C3-C5 monoheterocycloalkyl, such as cyclohexyl.

[0196] In some forms of formulas I-VI, A' can be a substituted adamantylidine or a substituted or unsubstituted cyclohexyl. In some forms of formulas I-VI, A' can be a substituted adamantylidine. In some forms of formulas I-VI, A' can be a substituted or unsubstituted cyclohexyl.

[0197] In some forms, the compound may have the structure of formula VII:

[0198] [ka]

[0199] (a) a, X', R5, R8 can be as described above; (b) Z' can be hydrogen or substituted or unsubstituted alkyl; (c) R9 can be substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, substituted or unsubstituted aralkyl, substituted or unsubstituted carbonyl, substituted or unsubstituted alkoxy, amido, amino, phosphonium, phosphanyl, or silyl, and d can be an integer from 0 to 9; the substituents can be any of the substituents described above.

[0200] In some forms of Formula VII, a can be an integer from 1 to 5, from 1 to 3, for example, 1 or 2. In some forms of Formula VII, X' is

[0201] [ka]

[0202] or O, and c can be 0 or an integer from 1 to 10, 1 to 8, 1 to 5, or 1 to 3. In some forms of Formula VII, X' can be O. In some forms of Formula VII, d can be 0. In some forms of Formula VII, d can be an integer from 1 to 5, 1 to 3, or 1 or 2, and R9 can be hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aralkyl, substituted or unsubstituted carbonyl, substituted or unsubstituted alkoxy, or amido.

[0203] In some forms of Formula VII, a can be an integer from 1 to 5, 1 to 3, or 1 or 2; X' can be O; R5 and R8 can be independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, substituted or unsubstituted carbonyl, substituted or unsubstituted alkoxy, amido, amino, phosphonium, phosphanyl, or silyl, or R5 and R8 together with the nitrogen to which they are attached form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkynyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heterocycloalkenyl, or substituted or unsubstituted heterocycloalkynyl; R9 can be substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbonyl, or substituted or unsubstituted alkoxy.

[0204] In some forms, the compound may have the structure of formula VIII:

[0205] [ka]

[0206] (a) a, X', R5, and R8 can be as described above; (b) a' can be an integer from 1 to 20; (c) Z' can be hydrogen or substituted or unsubstituted alkyl; (d) R 10 can be substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, substituted or unsubstituted aralkyl, substituted or unsubstituted carbonyl, substituted or unsubstituted alkoxy, amido, amino, phosphonium, phosphanyl, or silyl, and e can be an integer from 0 to 24; and the substituents can be any of the substituents described above.

[0207] In some forms of Formula VIII, a and a' can each be an integer from 1 to 5, 1 to 3, for example, 1 or 2. In some forms of Formula VIII, X' is

[0208] [ka]

[0209] or O, where c can be 0 or an integer from 1 to 10, 1 to 8, 1 to 5, or 1 to 3. In some forms of Formula VIII, X′ can be O.

[0210] In some forms of Formula VIII, e can be 0. In some forms of Formula VIII, e can be an integer from 1 to 5, 1 to 4, or 1 or 2, and R 10 In some embodiments of Formula VIII, e can be an integer from 1 to 5, 1 to 4, or 1 or 2, and R 10 is a substituted or unsubstituted branched C1-C 20 Alkyl groups, substituted or unsubstituted branched C1-C 15 Alkyl groups, substituted or unsubstituted branched C1-C 10 In some forms of Formula VIII, e can be an integer from 1 to 5, 1 to 4, or 1 or 2; R 10 teeth,

[0211] [ka]

[0212] and G' can be

[0213] [ka]

[0214] where p is an integer from 0 to 10, 0 to 8, 0 to 6, 0 to 4, 0 to 3, or 0 to 2; R 11 is hydrogen or

[0215] [ka]

[0216] It can be that R 12 and R 13 may be independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl. In some forms of Formula VIII, e may be an integer from 1 to 5, 1 to 4, or 1 or 2, and R 10 can be substituted or unsubstituted tert-butyl, and the substituent can be any of the substituents described above, for example, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbonyl, substituted or unsubstituted alkoxyl, or amide.

[0217] In some forms, the compound may have the structure of formula IX:

[0218] [ka]

[0219] (a) a, a', Z, X', R5, and R8 can be as described above; (b) R 14 can be hydrogen, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbonyl, substituted or unsubstituted alkoxyl, or amido.

[0220] In some forms of Formula IX, a and a' can each be an integer from 1 to 5, 1 to 3, for example, 1 or 2. In some forms of Formula IX, X' is

[0221] [ka]

[0222] or O, where c can be 0 or an integer from 1 to 10, 1 to 8, 1 to 5, or 1 to 3. In some forms of Formula IX, X' can be O. In some forms of Formula IX, R 14 is hydrogen or

[0223] [ka]

[0224] It can be that R 12 and R 13 may be independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl.

[0225] In some forms of formulas V-IX, R5 and R8 can be independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl (e.g., substituted or unsubstituted alkylaryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted alkylheteroaryl, substituted or unsubstituted heteroarylalkyl, etc.), substituted or unsubstituted carbonyl, substituted or unsubstituted alkoxy, amido, amino, or sulfinyl, sulfonyl, phosphonium, phosphanyl, phosphoryl, phosphonyl, thiol, silyl, or sugar group (e.g., glucose group or acetylated glucose), or R5 and R8 together with the nitrogen to which they are attached form a substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heterocycloalkenyl, or substituted or unsubstituted heterocycloalkynyl. In some forms of formulas V-IX, R5 and R8 can be phosphonium, amino, or silyl.

[0226] In some forms of Formula IX, R5 and R8 are independently

[0227] [ka]

[0228] h and i can be independently an integer from 0 to 10, 0 to 8, 0 to 6, or 0 to 3; R 15 ~R 20 may be independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, substituted or unsubstituted alkylaryl, or substituted or unsubstituted arylalkyl, such as methyl, ethyl, propanyl, butyl, pentyl, hexyl, phenyl, or benzyl.

[0229] In some forms of Formulas I-IX, the substituents on the substituted functional groups can be substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, substituted or unsubstituted aralkyl, substituted or unsubstituted carbonyl, substituted or unsubstituted alkoxy, amino, amido, phosphonium, phosphanyl, phosphoryl, phosphonyl, or a sugar group (such as a glucose group or an acetylated glucose), or a combination thereof.

[0230] In some forms of Formulas I-IX, the substituents on the substituted functional groups can be unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted heterocyclyl, unsubstituted aryl, unsubstituted heteroaryl, unsubstituted aralkyl, unsubstituted carbonyl, unsubstituted alkoxy, amino, amido, phosphonium, or sugar groups (such as glucose groups or acetylated glucose), or combinations thereof.

[0231] The compound may have the structure of formula X.

[0232] [ka]

[0233] (a) A' and A" can be independently a substituted or unsubstituted monocyclic ring, a substituted or unsubstituted polycyclic ring; (b) L' can be a linker such as oxygen, sulfur, carbon, boron, substituted or unsubstituted alkoxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heteroaryl, phosphoryl, sulfinyl, sulfonyl, ether, polyether, disulfide, and amino; (c) the substituents can be independently substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, It may be a substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, substituted or unsubstituted aralkyl, substituted or unsubstituted carbonyl, substituted or unsubstituted alkoxy, halogen, hydroxyl, phenoxy, aroxy, alkylthio, phenylthio, arylthio, cyano, isocyano, nitro, carboxyl, amino, amido, oxo, silyl, sulfinyl, sulfonyl, sulfonic acid, phosphonium, phosphanyl, phosphoryl, phosphonyl, thiol, amino acid, peptide, polypeptide, or sugar group (such as a glucose group or acetylated glucose), or a combination thereof.

[0234] In some embodiments, A' and A" can be the same. In some embodiments, A' and A" can be different. In some embodiments, B' and B" can be the same. In some embodiments, B' and B" can be different. In some embodiments, A' and A" can be the same and B' and B" can be different. In some embodiments, A' and A" can be different and B' and B" can be the same. In some embodiments, A' and A" can be different and B' and B" can be different. In some embodiments, A' and A" can be the same and B' and B" can be the same. When A' and A" are the same and B' and B" are the same, the compound of formula X is a dimer.

[0235] In some forms, the compound may have the structure of formula XI:

[0236] [ka]

[0237] (a) A', A", and L' can be as described above; (b) a and a" can independently be an integer from 1 to 20, 1 to 15, 1 to 10, 1 to 5, 1 to 3, or 1 or 2; (c) Z', Z", R 21 , and R' 21 may be independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, substituted or unsubstituted aralkyl, substituted or unsubstituted carbonyl, substituted or unsubstituted alkoxy, amino, amido, silyl, sulfinyl, sulfonyl, phosphonium, phosphanyl, phosphoryl, phosphonyl, thiol, or a sugar group (such as a glucose group or acetylated glucose); the substituents may be any of the substituents described above.

[0238] In some embodiments, the compound of formula XI has A′ and A″ the same, Z and Z′ the same, and R 21 and R' 21 may be a dimer in which

[0239] In some forms, the compound may have the structure of formula XII:

[0240] [ka]

[0241] (a) A', A", L', a, a", Z', and Z" can be as described above; (b) X' and X" are independently

[0242] [ka]

[0243] , O, NR6, or S, where c can be an integer from 0 to 30, 0 to 25, 0 to 20, 0 to 15, 0 to 10, 0 to 5, 0 to 3, or 0, 1, or 2; (c) W' and W" can independently be C, PR7, S, or Si; (d) Y' and Y" can independently be a bond or can be NR8 or O; (e) R 22 and R' 22 is, independently,

[0244] [ka]

[0245] (f) R6, R7, and R8 can be independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, substituted or unsubstituted aralkyl, substituted or unsubstituted carbonyl, substituted or unsubstituted alkoxy, aroxy, amido, amino, phosphonium, phosphanyl, phosphonyl, phosphoryl, phosphate, silyl, sulfinyl, thiol, or hydroxyl; the substituents can be any of the above-mentioned substituents.

[0246] In some forms of Formula XI and XII, Z′ and Z″ can be independently hydrogen or substituted or unsubstituted alkyl. In some forms of Formula XII, X′ and X″ can be independently

[0247] [ka]

[0248] or O, and c can be an integer from 0 to 10, 0 to 5, 0 to 3, or 0, 1, or 2. In some forms of formula XII, W' and W" can be independently C, PR7, or S, and R7 can be hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, amino, thiol, or substituted or unsubstituted alkoxy. In some forms, the compound of formula XII has A' and A" the same, Z' and Z" the same, X' and X" the same, Y' and Y" the same, and R 21 and R' 21 may be a dimer in which

[0249] In some forms of formulas X-XII, L' can be phosphoryl, sulfinyl, sulfonyl, disulfide, ether, polyether.

[0250] In some forms of Formulas X-XII, the substituents on the substituted functional groups can be substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, substituted or unsubstituted aralkyl, substituted or unsubstituted carbonyl, substituted or unsubstituted alkoxy, amino, amido, phosphonium, phosphanyl, phosphoryl, phosphonyl, or a sugar group (such as a glucose group or acetylated glucose), or a combination thereof.

[0251] In some forms of Formulas X-XII, the substituents on the substituted functional groups can be unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted heterocyclyl, unsubstituted aryl, unsubstituted heteroaryl, unsubstituted aralkyl, unsubstituted carbonyl, unsubstituted alkoxy, amino, amido, phosphonium, or sugar groups (such as glucose groups or acetylated glucose), or combinations thereof.

[0252] The compounds may contain one or more chiral centers, or may be capable of existing as multiple stereoisomers. These may be pure (single) stereoisomers or mixtures of stereoisomers, such as enantiomers, diastereomers, and enantiomer- or diastereomer-enriched mixtures. The compounds may be capable of existing as geometric isomers. Thus, it should be understood that the present invention includes pure geometric isomers or mixtures of geometric isomers.

[0253] 2. Exemplary 1,2,4,5-Tetraoxane Derivatives Exemplary 1,2,4,5-tetraoxane derivatives are provided below.

[0254] [ka]

[0255] [ka]

[0256] [ka]

[0257] [ka]

[0258] 3. Pharmaceutically acceptable salts The compound may be neutral or may be one or more pharma- ceutically acceptable salts, crystalline forms, non-crystalline forms, hydrates, or solvates, or combinations thereof.When referring to a compound, the context may refer to the neutral molecule and / or its additional forms, collectively and individually.The pharma-ceutically acceptable salts of the compound include its acid addition salts and base salts.

[0259] Suitable acid addition salts are formed from acids which form non-toxic salts, examples of which include acetate, aspartate, benzoate, besylate, bicarbonate / carbonate, bisulfate / sulfate, borate, camsylate, citrate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hybenzate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulfate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogenphosphate / dihydrogenphosphate, sugarate, stearate, succinate, tartrate, tosylate and trifluoroacetate.

[0260] Suitable base salts are formed from bases which form non-toxic salts, examples of which include the aluminium, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts.

[0261] Hemi-salts of acids and bases may also be formed, for example, hemisulfate and hemicalcium salts.

[0262] B. Pharmaceutical Compositions Pharmaceutical compositions and pharmaceutical formulations (also referred to herein as "pharmaceutical formulations") in unit dosage form suitable for delivery of the compounds, and preparations thereof, are disclosed. In general, the pharmaceutical composition or pharmaceutical formulation contains a compound described herein and / or a pharmaceutical acceptable salt of the compound, and a pharmaceutical acceptable excipient. Here, the term "pharmaceutical acceptable excipient" is used to describe any ingredient in the formulation other than the compound described herein. The pharmaceutical composition or pharmaceutical formulation may contain an effective amount of one or more compounds of any formula described herein and / or a pharmaceutical acceptable salt thereof, including any one or any combination of the compounds of the formulas described herein and / or a pharmaceutical acceptable salt thereof, to treat cancer, reduce cancer, or treat or ameliorate one or more symptoms associated with cancer in a subject in need thereof. In some forms, the pharmaceutical composition or pharmaceutical formulation may contain an enzyme and / or iron oxide that catalyzes hydrogen peroxide production. In some forms, the pharmaceutical composition or pharmaceutical formulation does not contain an enzyme and / or iron oxide that catalyzes hydrogen peroxide production.

[0263] In some forms, the pharmaceutical composition or formulation may further contain, in addition to the compound, one or more active agents, such as one or more additional anti-cancer agents.

[0264] It should be understood that a composition or formulation may include combinations and / or mixtures of the compounds and / or pharma- ceutically acceptable salts thereof. In some forms, the pharmaceutical composition or formulation includes an amount of the compound and / or pharma- ceutically acceptable salt thereof effective to treat, reduce, or treat or ameliorate one or more symptoms associated with cancer in a subject in need thereof.

[0265] Any one or more of the compounds provided herein may be specifically included or specifically excluded from the pharmaceutical compositions, dosage units, and / or methods of use or treatment disclosed herein.

[0266] 1. Oral Formulations The compounds and / or their pharma- ceutically acceptable salts may be administered orally, which may involve swallowing, so that the compound enters the gastrointestinal tract, or buccal or sublingual administration may be employed by which the compound enters the blood stream directly from the mouth.

[0267] Formulations suitable for oral administration include solid formulations such as tablets, capsules containing particles, liquids, powders, lozenges (including liquid-filled lozenges), chewable tablets, multiparticulates and nanoparticles, gels, solid solutions, liposomes, films, vaginal suppositories, sprays, and liquid formulations.

[0268] Liquid formulations include suspensions, solutions, syrups and elixirs. Such formulations may be employed as fillers in soft or hard capsules, and typically include a carrier, such as water, ethanol, polyethylene glycol, propylene glycol, methylcellulose or a suitable oil, and one or more emulsifying agents and / or suspending agents. Liquid formulations may also be prepared by the reconstitution of a solid, for example, by a sachet.

[0269] The compounds and / or pharma- ceutically acceptable salts thereof may be used in fast dissolving, fast disintegrating dosage forms such as those described in Expert Opinion in Therapeutic Patents, 11(6), 981-986, by Liang and Chen (2001).

[0270] In the case of tablet or capsule dosage forms, depending on the dosage, the compound and / or its pharma- ceutically acceptable salt may comprise 1% to 80% by weight of the dosage form, more typically 5% to 60% by weight of the dosage form. In addition to the compounds described herein, tablets generally contain a disintegrant. Examples of disintegrants include sodium starch glycolate, sodium carboxymethylcellulose, calcium carboxymethylcellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methylcellulose, microcrystalline cellulose, lower alkyl substituted hydroxypropylcellulose, starch, pregelatinized starch, and sodium alginate. Generally, the disintegrant comprises 1% to 25% by weight of the dosage form, preferably 5% to 20% by weight.

[0271] Binders are generally used to impart cohesion to tablet formulations.Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinized starch, hydroxypropylcellulose and hydroxypropylmethylcellulose.Tablets may also contain diluents such as lactose (e.g., as monohydrate, spray-dried monohydrate or anhydrous form), mannitol, xylitol, glucose, sucrose, sorbitol, microcrystalline cellulose, starch and dicalcium phosphate dihydrate.

[0272] The tablet or capsule may also contain surface active agents such as sodium lauryl sulfate and polysorbate 80, and glidants such as silicon dioxide and talc. If present, the surface active agents may constitute from 0.2% to 5% by weight of the tablet, and the glidants may constitute from 0.2% to 1% by weight of the tablet.

[0273] The tablet or capsule will also generally contain a lubricant such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate with sodium lauryl sulfate. The lubricant will generally comprise from 0.25% to 10% by weight of the tablet, preferably from 0.5% to 3% by weight.

[0274] Other possible ingredients include flow agents (eg, about 0.1% to about 3% by weight of talc or colloidal anhydrous silica, etc.), antioxidants, colorants, flavoring agents, preservatives, and taste-masking agents.

[0275] An exemplary tablet contains up to about 80% of one or more compounds described herein, about 10% to about 90% by weight of a binder, about 0% to about 85% by weight of a diluent, about 2% to about 10% by weight of a disintegrant, and about 0.25% to about 10% by weight of a lubricant.

[0276] Tablet or capsule blends may be directly or roller compressed to form tablets. Alternatively, tablet or capsule blends or portions of blends may be wet-, dry-, or melt-granulated, melt congealed, or extruded prior to tabletting. The final dosage form may contain one or more layers and may be coated or uncoated; it may even be encapsulated.

[0277] Solid formulations for oral administration may be formulated to be immediate and / or modified release, including delayed-, sustained-, pulsed-, controlled-, targeted-, and programmed-release formulations.

[0278] 2. Parenteral Formulations Compound and / or its pharmaceutically acceptable salt can also be directly administered into bloodstream, muscle or internal organ.Suitable routes for such parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, epidural, intraventricular, intraurethral, ​​intrasternal, intracranial, intramuscular and subcutaneous delivery.Suitable means for parenteral administration include needle (including microneedle) injector, needle-free injector and infusion technology.

[0279] Parenteral formulations are typically aqueous solutions which may contain excipients such as salts, carbohydrates, and buffers (preferably pH 3-9), although for some applications they may be more suitably formulated as a dry form or as sterile non-aqueous solutions for use in combination with a suitable vehicle such as sterile pyrogen-free water.

[0280] The preparation of parenteral formulations under sterile conditions, for example, by lyophilization, may be readily accomplished using standard pharmaceutical techniques well known to those skilled in the art.

[0281] The solubility of compounds used in the preparation of parenteral formulations may be increased by the use of suitable pharmaceutical techniques, such as the incorporation of solubility-enhancing agents.

[0282] Formulations for parenteral administration may be formulated to be immediate release and / or modified release. Modified release formulations include delayed release, sustained release, pulsed release, controlled release, targeted release, and programmed release formulations. Thus, compounds may be formulated as solid, semi-solid, or thixotropic liquid for administration as an implanted depot that provides modified release of active compounds. Examples of such formulations include drug-coated stents and poly(dl-lactic-co-glycolic acid) (PGLA) microspheres.

[0283] 3. Lung and mucosal preparations The compounds and / or pharma- ceutically acceptable salts thereof may be formulated for pulmonary or mucosal administration, including delivery of the composition to the lungs, nasal mucosa, oral (sublingual, buccal) mucosa, vaginal mucosa, or rectal mucosa.

[0284] Also, for example, the compounds may be administered intranasally or by oral inhalation, typically in the form of an aerosol spray from a pressurized container, pump, spray, atomizer (preferably an atomizer that utilizes electrohydrodynamics to generate a fine mist) or nebulizer, with or without the use of a suitable propellant, such as water, ethanol-water mixtures, 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane, or in the form of a dry powder from a dry powder inhaler (alone, as a mixture, such as a dry blend with lactose, or as a mixed component particle, such as mixed with a phospholipid, such as phosphatidylcholine). For use in intranasal or oral inhalation, the powder may contain a bioadhesive agent, such as chitosan or cyclodextrin. The term aerosol, as used herein, refers to any preparation of a fine mist of particles that may be in solution or suspension, whether or not generated using a propellant. Aerosols may be generated using standard techniques, such as sonication or high pressure processing.

[0285] The pressurized container, pump, spray, atomizer, or nebulizer contains a solution or suspension of one or more compounds, for example, with ethanol, aqueous ethanol, or an alternative agent suitable for dispersing, solubilizing, or extending the release of the active, a propellant as a solvent, and an optional surfactant, such as sorbitan trioleate, oleic acid, or oligolactic acid.

[0286] Prior to use in a dry powder or suspension formulation, the drug product is micronized to a size suitable for delivery by inhalation (typically less than 5 microns). This may be accomplished by any suitable comminuting method, such as spiral jet milling, fluidized bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenization, or spray drying.

[0287] Capsules, blisters and cartridges (made, for example, of gelatin or hydroxypropylmethylcellulose) for use in an inhaler or insufflator may be formulated containing a powder mix of a compound as described herein, a suitable powder base such as lactose or starch and a performance modifier such as l-leucine, mannitol or magnesium stearate. The lactose may be in anhydrous or monohydrate form, the latter being preferred. Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose.

[0288] Suitable solution formulations for use in atomizers that utilize electrohydrodynamics to generate a fine mist may contain 1 μg to 20 mg of one or more compounds per actuation, and actuation volumes may vary from 1 μl to 100 μl. A typical formulation may contain one or more compounds described herein, propylene glycol, sterile water, ethanol, and sodium chloride. Alternative solvents that may be used in place of propylene glycol include glycerol and polyethylene glycol.

[0289] Suitable flavours, such as menthol and levomenthol, or sweeteners, such as saccharin or saccharin sodium, may be added to formulations intended for inhaled / intranasal administration.

[0290] Formulations for inhaled / intranasal administration may be formulated to be immediate and / or modified release, for example using PGLA. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted-, and programmed-release formulations.

[0291] In the case of dry powder inhalers and aerosols, the dosage unit is determined by a valve that delivers a metered amount. The unit according to the compound is typically arranged to administer a metered dose or "puff". The total daily dose is administered in a single dose or, more usually, in several doses throughout the day.

[0292] In some forms, the compound and / or its pharma- ceutically acceptable salts may be formulated for pulmonary delivery, such as intranasal administration or oral inhalation. Carriers for pulmonary formulations may be divided into carriers for dry powder formulations and carriers for administration as a solution. Aerosols for delivery of therapeutic agents to the respiratory tract are known in the art. For administration via the upper respiratory tract, the formulation may be formulated as an aqueous suspension for intranasal administration as drops or sprays, or in an aqueous solution, such as, for example, water or isotonic saline, buffered or unbuffered. Such aqueous solutions or suspensions may be isotonic with respect to nasal secretions and may have about the same pH, for example, in the range of about pH 4.0 to about 7.4, or pH 6.0 to pH 7.0. The buffer should be physiologically compatible, and by way of example only, includes phosphate buffers. Those skilled in the art can easily determine the appropriate saline content and pH for a non-toxic aqueous solution for nasal and / or upper respiratory tract administration.

[0293] In some forms, the aqueous solution is water, a physiologically acceptable aqueous solution containing salts and / or buffers such as phosphate buffered saline (PBS), or any other aqueous solution acceptable for administration to animals or humans. Such solutions are well known to those skilled in the art and include, but are not limited to, distilled water, deionized water, pure or ultrapure water, saline, phosphate buffered saline (PBS). Other suitable aqueous vehicles include, but are not limited to, Ringer's solution and isotonic sodium chloride. Aqueous suspensions may include suspending agents such as cellulose derivatives, sodium alginate, polyvinylpyrrolidone, and gum tragacanth, and wetting agents such as lecithin. Suitable preservatives for aqueous suspensions include ethyl p-hydroxybenzoate and n-propyl p-hydroxybenzoate.

[0294] In some forms, solvents that are low toxicity organic (i.e., non-aqueous) Class 3 residual solvents, such as, for example, ethanol, acetone, ethyl acetate, tetrahydrofuran, ethyl ether, and propanol, may be used in the formulation. Solvents are selected based on their ability to easily aerosolize the formulation. The solvent should not adversely react with the compound. A suitable solvent that dissolves the compound or forms a suspension of the compound should be used. The solvent should be sufficiently volatile to allow the formation of an aerosol of the solution or suspension. Additional solvents or aerosolizing agents, such as Freon, may be added as needed to increase the volatility of the solution or suspension.

[0295] In some forms, the pharmaceutical composition may contain small amounts of polymers, surfactants, or other excipients known to those skilled in the art. In this context, "small amounts" means the absence of excipients that may affect or mediate uptake of the compound by cells, and further, that the excipients are present in amounts that do not adversely affect uptake of the compound by cells.

[0296] Dry lipid powder can be directly dispersed in ethanol due to its hydrophobic characteristics. For example, for lipids stored in organic solvents such as chloroform, a desired amount of solution is placed in a vial, and the chloroform is evaporated under a stream of nitrogen to form a dry thin film on the glass vial surface. This thin film easily expands when reconstituted with ethanol. To completely disperse lipid molecules in the organic solvent, the suspension is sonicated. A non-aqueous suspension of lipids can also be prepared in absolute ethanol using a reusable PARI LC Jet+ nebulizer (PARI Respiratory Equipment, Monterey, CA).

[0297] 4. Topical Preparations The compound and / or its pharma- ceutically acceptable salt may be administered directly to the external surface of the skin or mucosa (including the membranes lining the nasal passages, lungs and oral cavity) such that the compound and / or its pharma- ceutically acceptable salt passes through the external surface of the skin or mucosa and enters the underlying tissue.

[0298] Formulations for topical administration generally contain a dermatologically acceptable carrier that is suitable for application to the skin, has good aesthetic properties, is compatible with the active agent and any other ingredients, and does not raise undue safety or toxicity concerns.

[0299] The carriers can take a wide variety of forms. For example, emulsion carriers are useful herein, including, but not limited to, oil-in-water, water-in-oil, water-in-oil-in-water, and oil-in-water-in-silicone emulsions. These emulsions can cover a wide range of viscosities, for example, from about 100 cps to about 200,000 cps. These emulsions can also be delivered in the form of a spray using either a mechanical pump container or a pressurized aerosol container using a conventional propellant. These carriers can also be delivered in the form of a mousse or a transdermal patch. Other suitable topical carriers include anhydrous liquid solvents such as oils, alcohols, and silicones (e.g., mineral oil, ethanol isopropanol, dimethicone, cyclomethicone, etc.); water-based single-phase liquid solvents (e.g., hydroalcoholic solvent systems such as mixtures of ethanol and / or isopropanol with water); and thickened versions of these anhydrous and water-based single-phase solvents (e.g., when the viscosity of the solvent is increased by the addition of a suitable gum, resin, wax, polymer, salt, etc. to form a solid or semi-solid). Examples of topical carrier systems useful in the formulations of the present invention are described in the following four references, which are incorporated by reference in their entireties: "Sun Products Formulary" Cosmetics & Toiletries, vol. 105, pp. 122-139 (December 1990); "Sun Products Formulary," Cosmetics & Toiletries, vol. 102, pp. 117-136 (March 1987); Blank et al., U.S. Pat. No. 5,605,894; and Bissett, U.S. Pat. No. 5,681,852.

[0300] Formulations for local administration may be formulated to provide immediate release and / or modified release. Modified release formulations include delayed release, sustained release, pulsed release, controlled release, targeted release, and programmed release formulations. Thus, compounds may be formulated as solid, semi-solid, or thixotropic liquid for administration as an implanted depot that provides modified release of active compounds. Examples of such formulations include drug-coated stents and poly(dl-lactic-co-glycolic acid) (PGLA) microspheres.

[0301] 5. Additional activators In some embodiments, the pharmaceutical composition or formulation may include one or more active agents, such as one or more additional anti-cancer drugs. Anti-cancer drugs that may be included in the pharmaceutical composition or formulation are known, see, for example, the National Cancer Institute's database "A to Z List of Cancer Drugs," website cancer.gov / about-cancer / treatment / drugs.

[0302] Exemplary anti-cancer drugs that may be included in the pharmaceutical composition or formulation include, but are not limited to, olaparib, abemaciclib, abiraterone acetate, methotrexate, paclitaxel, adriamycin, acalabrutinib, brentuximab vedotin, adotrastuzumab emtansine, aflibercept, afatinib, netupitant, palonosetron, imiquimod, aldesleukin, alectinib, alemtuzumab, pemetrexed disodium, copanlisib, melphalan, brigatinib, chlorambucil, amifostine, aminolevulinic acid, anastrozole, apalutamide, aprepitant, pamidronate disodium, exemest. Tan, nelarabine, arsenic trioxide, ofatumumab, atezolizumab, bevacizumab, avelumab, axicabtagene ciloreucel, axitinib, azacitidine, carmustine, belinostat, bendamustine, inotuzumab ozogamicin, bevacizumab, bexarotene, bicalutamide, bleomycin, blinatumomab, bortezomib, bosutinib, brentuximab Vedotin, brigatinib, busulfan, irinotecan, capecitabine, fluorouracil, carboplatin, carfilzomib, ceritinib, daunorubicin, cetuximab, cisplatin, cladribine, cyclophosphamide, clofarabine, cobimetinib, cabozantinib S-malate, dactinomycin, crizotinib, ifosfamide, ramucirumab , cytarabine, dabrafenib, dacarbazine, decitabine, daratumumab, dasatinib, defibrotide, degarelix, denileukin diftitox, denosumab, dexamethasone, dexrazoxane, dinutuximab, docetaxel, doxorubicin, durvalumab, rasburicase, epirubicin, elotuzumab, oxaliplatin, eltrombopag Olamine, enasidenib, enzalutamide, eribulin, vismodegib, erlotinib, etoposide, everolimus, raloxifene, toremifene, panobinostat, fulvestrant, letrozole, filgrastim, fludarabine, flutamide, pralatrexate, obinutuzumab, gefitinib, gemcitabine, gemtuzumab ozogamicin, glucarpidase, goserelin, propranolol, trastuzumab, topotecan, palbociclib,Ibritumomab tiusetan, ibrutinib, ponatinib, idarubicin, idelarib, imatinib, talimogene laherparepvec, ipilimumab, romidepsin, ixabepilone, ixazomib, ruxolitinib, cabazitaxel, palifermin, pembrolizumab, ribociclib, tisagenlecleucel, lanreotide, lapatinib, olaratumab, lenalidomide, lenvatinib, leucovorin, leuprolide, lomustine, trifluridine, olaparib, vincristine, procarbazine, mechlorethamine, megazine strom, trametinib, temozolomide, methylnaltrexone bromide, midostaurin, mitomycin C, mitoxantrone, plerixafor, vinorelbine, necitumumab, neratinib, sorafenib, nilutamide, nilotinib, niraparib, nivolumab, tamoxifen, romiplostim, sonidegib, omacetaxine, pegaspargase, ondansetron, osimertinib, panitumumab, pazopanib, interferon alfa-2b, pertuzumab, pomalidomide, mercaptopurine, regorafenib, Rituximab, rolapitant, rucaparib, siltuximab, sunitinib, thioguanine, temsirolimus, thalidomide, thiotepa, trabectedin, valrubicin, vandetanib, vinblastine, vemurafenib, vorinostat, zoledronic acid, or combinations thereof, such as cyclophosphamide, methotrexate, 5-fluorouracil (CMF); doxorubicin, cyclophosphamide (AC); mustine, vincristine, procarbazine, prednisolone (MOPP); sudriamycin, bleomycin , vinblastine, dacarbazine (ABVD); cyclophosphamide, doxorubicin, vincristine, prednisolone (CHOP); rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone (RCHOP); bleomycin, etoposide, cisplatin (BEP); epirubicin, cisplatin, 5-fluorouracil (ECF); epirubicin, cisplatin, capecitabine (ECX); methotrexate, vincristine, doxorubicin, cisplatin (MVAC).

[0303] 6. Effective amount The effective amount of the compound contained in the pharmaceutical composition or pharmaceutical preparation depends on many factors, including the indication being treated, the route of administration, the co-administration of other therapeutic compositions, and the overall condition of the patient. Exemplary effective amounts of the compound contained in the pharmaceutical preparation (in unit dosage form) are 0.01 mg to 1500 mg, 0.1 mg to 1500 mg, 1 mg to 1500 mg, 10 mg to 1500 mg, 20 mg to 1500 mg, 0.01 mg to 1000 mg, 0.1 mg to 1000 mg, 1 mg to 1000 mg, 10 mg to 1000 mg, 20 mg to 1000 mg, 0.01 mg The amount of the active ingredient may be from 0.01 mg to 500 mg, 0.1 mg to 500 mg, 1 mg to 500 mg, 10 mg to 500 mg, 20 mg to 500 mg, 50 mg to 500 mg, 0.01 mg to 100 mg, or 0.1 mg to 100 mg.

[0304] III. Manufacturing method The compounds can be synthesized using methods known in the art of organic synthesis, such as forming a tetraoxane using one or more starting materials in a suitable solvent medium; then derivatizing the formed tetraoxane with a targeting group. Typically, the starting materials that can be used to form the tetraoxane are ketones or acetyls. Exemplary ketones and acetals that form tetraoxanes include, but are not limited to, 4-tert-butylcyclohexanone, cyclohexanone, 2-adamantanone, and starting materials 1, 3, and 26 shown below. Typically, the targeting group contains an amine, such as N,N'-dimethylpropylamine, 3-bromopropylamine hydrobromide, and targeting group 68 shown below.

[0305] For example, as shown in the general reaction scheme below, starting materials 1, 3, or 26, or combinations thereof, are reacted with 4-tert-butylcyclohexanone, cyclohexanone, or 2-adamantanone, or combinations thereof to form a tetraoxane; the formed tetraoxane is then reacted with N,N'-dimethylpropylamine, 3-bromopropylamine hydrobromide, or a targeting group 68, or combinations thereof to form a compound disclosed herein.

[0306] [ka]

[0307] Additional exemplary starting materials and targeting groups, as well as more specific methods for synthesizing the exemplary compounds, are described in the Examples below.

[0308] IV.How to use A. Treating cancer, reducing cancer, or treating or ameliorating symptoms associated with cancer

[0309] Methods of using the compounds to treat cancer, reduce cancer, or treat or ameliorate one or more symptoms associated with cancer in a subject in need thereof are disclosed.

[0310] In general, the methods include (i) administering to the subject an amount of a compound effective to treat, reduce, or treat or ameliorate one or more symptoms associated with cancer in the subject. The subject may be a mammal. In some forms, the subject may be at risk for cancer, exhibit symptoms of cancer, or be diagnosed with cancer. The compound may be administered by a medical professional or by the subject to be treated (e.g., self-administered).

[0311] In some forms of the method, whether a cancer has been reduced may be identified by a variety of diagnostic modalities known to those of skill in the art, including, but not limited to, observing a decrease in the size or number of tumor masses, or whether an increase in apoptosis of cancer cells is observed, such as a greater than 5% increase in apoptosis of cancer cells for a sample compound compared to a control without the compound, etc. It may also be identified by changes in associated biomarkers or gene expression profiles, such as HER2 for breast cancer and PSA for prostate cancer.

[0312] In some forms, the compound and / or its pharma- ceutically acceptable salts may be administered in the form of a pharmaceutical composition or formulation in association with one or more pharma- ceutically acceptable excipients, such as those described above. The choice of a pharma- ceutically acceptable excipient will largely depend on factors such as the particular mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form.

[0313] 1. Cancer The term "cancer" as used herein refers to any of a variety of cellular diseases that have a malignant neoplasm characterized by cell proliferation. It is not intended that the affected cells must actually invade surrounding tissues and metastasize to new body sites. Cancer can involve any tissue of the body and can have many different forms in each body area.

[0314] In some forms of the method, the cancer can be a tumor, such as a tumor of hematopoietic and lymphatic tissue or hematopoietic and lymphatic malignancies, tumors affecting the blood, bone marrow, lymph, and lymphatic system, and tumors located in the colon, abdomen, bone, breast, digestive system, liver, pancreas, peritoneum, endocrine glands (adrenal glands, parathyroid gland, pituitary gland, testes, ovaries, thymus, thyroid gland), eye, head and neck, nervous system (central and nervous), lymphatic system, pelvis, skin, soft tissue, spleen, breast, and genitourinary system.

[0315] In some forms of the method, the cancer can be colon cancer, breast cancer, ovarian cancer, cervical cancer, lung cancer, rectal cancer, kidney cancer, liver cancer, brain cancer, or leukemia, or a combination thereof. In some forms of the method, the cancer can be breast cancer, such as triple-negative breast cancer (TNBC).

[0316] In some forms of the method, the cancer is selected from the group consisting of AIDS-related malignancies, anal cancer, astrocytoma, bile duct cancer, bladder cancer, bone cancer, brain stem glioma, brain tumor, breast cancer, renal pelvis and ureter cancer, primary central nervous system lymphoma, central nervous system lymphoma, cerebellar astrocytoma, brain astrocytoma, cervical cancer, childhood (primary) hepatocellular carcinoma, childhood (primary) liver cancer, childhood acute lymphoblastic leukemia, childhood acute myeloid leukemia, childhood brain stem glioma, childhood cerebellar astrocytoma, childhood cerebral astrocytoma, Pediatric extracranial germ cell tumors, childhood Hodgkin's disease, childhood Hodgkin's lymphoma, childhood optic nerve and hypothalamic glioma, childhood lymphoblastic leukemia, childhood medulloblastoma, childhood non-Hodgkin's lymphoma, childhood supratentorial primitive neuroectodermal and pineal tumors, childhood primary liver cancer, childhood rhabdomyosarcoma, childhood soft tissue sarcoma, childhood optic nerve and hypothalamic glioma, chronic lymphocytic leukemia, chronic myeloid leukemia, colorectal cancer, cutaneous T-cell lymphoma, endocrine pancreatic islet cell carcinoma, endometrial Cancer, ependymoma, epithelial carcinoma, esophageal cancer, Ewing's sarcoma and related tumors, exocrine pancreatic cancer, extracranial germ cell tumors, extragonadal germ cell tumors, extrahepatic bile duct cancer, eye cancer, female breast cancer, Gaucher's disease, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumors, gastrointestinal tumors, germ cell tumors, gestational trophoblastic neoplasms, hairy cell leukemia, head and neck cancer, hepatocellular carcinoma, Hodgkin's disease, Hodgkin's lymphoma, hypergammaglobulinemia, hypopharyngeal cancer, intestinal cancer , intraocular melanoma, islet cell carcinoma, islet cell pancreatic carcinoma, Kaposi's sarcoma, kidney cancer, laryngeal cancer, lip cancer, liver cancer, lung cancer, lymphoproliferative disorders, macroglobulinemia, male breast cancer, malignant mesothelioma, malignant thymoma, medulloblastoma, melanoma, mesothelioma, metastatic squamous cell neck cancer of unknown primary, metastatic squamous cell neck cancer of primary, metastatic squamous cell neck cancer, multiple myeloma, multiple myeloma / plasma cell neoplasia, myelodysplastic syndrome, myeloid leukemia, myeloid leukemialeukemia), myeloproliferative disorders, paranasal sinus and nasal cancer, nasopharyngeal cancer, neuroblastoma, non-Hodgkin's lymphoma during pregnancy, non-melanoma skin cancer, non-small cell lung cancer, metastatic squamous cell neck cancer of unknown primary, buccopharyngeal cancer, malignant fibrous histiocytoma, malignant fibrous osteosarcoma / histiocytoma of bone, epithelial ovarian cancer, ovarian germ cell tumor, ovarian low malignant potential tumor, pancreatic cancer, paraproteinemia, purpura, parathyroid cancer, penile cancer, pheochromocytoma, pituitary tumor, plasma cell neoplasia / multiple myeloma, primary central nervous system lymphoma, primary liver cancer, prostate cancer, rectal cancer, renal cell carcinoma, renal pelvis and ureter cancer, retinoblastoma , rhabdomyosarcoma, salivary gland cancer, sarcoidosis, sarcoma, skin cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, cervical squamous cell carcinoma, gastric cancer, pineal and supratentorial primitive neuroectodermal tumors, T-cell lymphoma, testicular cancer, thymoma, thyroid cancer, transitional cell carcinoma of the renal pelvis and ureter, transitional renal pelvis and ureter carcinoma, trophoblastic tumor, cell carcinoma of the renal pelvis and ureter, urethral cancer, uterine cancer, uterine sarcoma, vaginal cancer, optic nerve and hypothalamic glioma, vulvar cancer, Waldenstrom's macroglobulinemia, Wilms' tumor, and any other hyperproliferative disease and neoplasia located in the organ systems previously mentioned.

[0317] 2. Route of Administration The compound and / or its pharma- ceutically acceptable salt or a pharmaceutical composition or formulation containing the compound and / or its pharma- ceutically acceptable salt may be administered to a subject orally, parenterally, by inhalation, mucosally, topically, or a combination thereof.

[0318] For example, the compound and / or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition or formulation containing the compound and / or a pharma- ceutically acceptable salt thereof, may be orally administered to a subject by a medical professional or the subject being treated (e.g., self-administration).The compound or a pharmaceutical composition or formulation containing the compound and / or a pharma- ceutical acceptable salt thereof may be administered as a tablet, a capsule containing particles, a granule, a powder, a lozenge (including liquid-filled lozenges), a chewable tablet, multiparticulates and nanoparticles, a gel, or a liquid (e.g., a solution or suspension in an aqueous or non-aqueous solvent).

[0319] Optionally, the compound and / or its pharma- ceutically acceptable salt or a pharmaceutical composition or formulation containing the compound and / or its pharma- ceutically acceptable salt may be administered to the subject by intravenous or intraperitoneal injection, which may be performed by a medical professional or by the subject being treated (e.g., self-injection).

[0320] Alternatively, the compound and / or a pharma- ceutically acceptable salt thereof or a pharmaceutical composition or formulation containing the compound and / or a pharma- ceutically acceptable salt thereof may be administered to a subject by inhalation, such as mouth inhalation and / or nasal inhalation.

[0321] Optionally, the compound and / or a pharma- ceutical acceptable salt thereof, or a pharmaceutical composition or formulation containing the compound and / or a pharma- ceutical acceptable salt thereof, may be administered to a subject by topical application of the compound or the pharmaceutical composition or formulation onto one or more exposed surfaces of the subject.

[0322] 3. Effective amount The therapeutically effective amount of the compound will depend on a number of factors, including the indication being treated, the route of administration, co-administration of other therapeutic compositions, and the overall condition of the patient.

[0323] In general, treatment regimens utilizing the compounds include multiple or single administrations of about 0.1 mg to about 300 mg of the compound per kg of recipient body weight per day. In some embodiments, suitable doses may be within the range of 0.1-300 mg per kg of recipient body weight per day, optionally within the range of 6-150 mg per kg of body weight per day, optionally within the range of 15-100 mg per kg of body weight per day, optionally within the range of 15-80 mg per kg of body weight per day, optionally within the range of 15-50 mg per kg of body weight per day, and optionally within the range of 15-30 mg per kg of body weight per day.

[0324] The desired dose may be presented as two, three, four, five, six or more sub-doses administered at appropriate intervals throughout the day. These sub-doses may be, for example, 0.01 mg to 1500 mg, 0.1 mg to 1500 mg, 1 mg to 1500 mg, 10 mg to 1500 mg, 20 mg to 1500 mg, 0.01 mg to 1000 mg, 0.1 mg to 1000 mg, 1 mg to 1000 mg, 10 mg to 1000 mg, 20 mg to 1000 mg, 0.01 mg to 700 mg, 0.1 mg to 7 The compound may be administered in a unit dosage form containing 00 mg, 1 mg to 700 mg, 10 mg to 700 mg, 20 mg to 700 mg, 50 mg to 700 mg, 0.01 mg to 500 mg, 0.1 mg to 500 mg, 1 mg to 500 mg, 10 mg to 500 mg, 20 mg to 500 mg, 50 mg to 500 mg, 0.01 mg to 100 mg, or 0.1 mg to 100 mg of the compound.

[0325] 4. Optional Steps a. Administering additional active agent In addition to the compound, one or more active agents may be administered to the subject throughout the method or at different intervals during the method.For example, one or more additional active agents are administered to the subject before, during and / or after step (i).In some forms, one or more additional active agents are included in a pharmaceutical composition or pharmaceutical preparation that contains the compound, and are administered to the subject at the same time as the compound in the pharmaceutical composition or pharmaceutical preparation in association with one or more pharma- ceutically acceptable excipients.

[0326] In some forms, the one or more additional active agents are one or more anti-cancer agents as described above. The amount of the one or more additional anti-cancer agents required will vary from subject to subject depending on their needs.

[0327] B. Treating cancer cells In some forms, the compounds may be used in methods for treating cancer cells and / or cancer stem cells in a subject in need thereof.

[0328] The method may follow the steps of the above methods, such as administering an effective amount of a compound to a subject by oral administration, parenteral administration, inhalation, mucosal administration, topical administration, or a combination thereof. In some forms, the method may include additional steps as described above. For example, a user may administer one or more additional active agents to a subject before, during, and / or after administering a compound to a subject.

[0329] In some forms of the method, the compound can induce ferroptosis in cancer cells and / or cancer stem cells of the subject's cancer and kill them. Additionally or alternatively, the compound can selectively induce ferroptosis in cancer cells and cancer stem cells compared to non-cancerous cells of the subject. Additionally or alternatively, the compound can generate reactive oxygen species in the cancer cells and cancer stem cells independent of pH (e.g., generate hydroxyl radicals and lipid peroxides at neutral pH) to eliminate the need for an acidic intracellular environment in complex formulations containing multiple components (e.g., enzymes that catalyze hydrogen peroxide production, iron oxide, etc.) and chemokinetic therapy, i.e., ferroptosis. For example, the compound can induce ferroptosis in cancer cells and / or cancer stem cells in which the intracellular pH of the cancer cells and / or cancer stem cells is within the range of 6 to 7.5.

[0330] In some forms of the method, the compound has an IC 50 Values ​​are IC 50 Alternatively or additionally, the compound may have an IC 50 The IC values ​​are the IC of known compounds such as OZ277, OZ439, RKA182, FINO2, or cholic / deoxycholic / steroid derivatives of 1,2,4,5-tetraoxane against the same cancer cells or cancer stem cells tested under the same conditions. 50 may be lower than the value.

[0331] 1. Cancer cell lines The cancer cells and / or cancer stem cells treated in the subject can be any one of the cancer cells of the above cancers.For example, the cancer cells can be MDA-MB-231 cells, MCF7 cells, Hela cells, T47D cells, Huh7 cells, PLC cells, U2OS cells, HEK293 cells, HepG2 cells, Jurkat cells, HCT116 cells, HEYA8 cells, or HL-60 cells, or combinations thereof.In some forms of the method, the cancer cells or cancer stem cells can be MDA-MB-231 cells, HCT116 cells, HEYA8 cells, or HL-60 cells, or combinations thereof.In some forms of the method, the cancer cells or cancer stem cells are MDA-MB-231 cells.

[0332] IC of compounds against cancer cells or cancer stem cells 50 values ​​and IC of the same compounds against non-cancer cells 50 The non-cancerous cells for which the values ​​are compared may be derived from any normal tissue of the subject, such as NIH3T3 cells, MDCK cells, or bEnd.3 cells, or a combination thereof.

[0333] 2. Selectivity of the compound for cancer cells over non-cancerous cells In some forms of the method, the compound has an IC 50 Values ​​are IC 50 The term "same conditions" means that the test is performed using the same assay, such as the MTT assay, using the same protocol, e.g., the same amount of cells and enzymes, the same dyes and dye concentrations, and the same incubation times and temperatures.

[0334] For example, the compound may have an IC50 value for MDA-MB-231 cells, MCF7 cells, Hela cells, T47D cells, Huh7 cells, PLC cells, U2OS cells, HEK293 cells, HepG2 cells, Jurkat cells, HCT116 cells, HEYA8 cells, or HL-60 cells, or a combination thereof. 50Values ​​are IC of the same compound against NIH3T3 cells, MDCK cells, or bEnd.3 cells, or a combination thereof, tested under the same conditions. 50 For example, a compound may have an IC value lower than 0.01 for MDA-MB-231 cells, HCT116 cells, or HL-60 cells. 50 Values ​​are the IC of the same compound against NIH3T3 cells tested under the same conditions. 50 For example, a compound may have an IC 50 Values ​​are the IC of the same compound against NIH3T3 cells tested under the same conditions. 50 may be lower than the value.

[0335] In some embodiments, the IC of the compound against cancer cells or cancer stem cells. 50 Values ​​are IC of the same compound against non-cancer cells tested under the same conditions. 50 at least one-half, at least one-third, at least one-fourth, at least one-fifth, at least one-eighth, at least one-tenth, at least one-twelfth, at least one-fifth, at least one-twentieth, at least one-twenty-second, at least one-twentieth, at least one-twentieth, at least one-thirtieth, at least one-thirty-fifth, at least one-fortieth, at least one-fortieth, at least one-fortieth, at least one-fifth, at least one-fifth, at least one-fifth, at least one-sixtieth, at least one-sixth, at least one-sixth, It may be at least 1 / 70, at least 1 / 75, at least 1 / 80, at least 1 / 90, at least 1 / 100, in the range of 2 / 1000, in the range of 2 / 500, in the range of 2 / 250, in the range of 2 / 200, in the range of 2 / 150, in the range of 2 / 100, in the range of 5 / 1000, in the range of 5 / 500, in the range of 5 / 250, in the range of 5 / 200, in the range of 5 / 150, or in the range of 5 / 100.

[0336] For example, the compound may have an IC50 value for MDA-MB-231 cells, MCF7 cells, Hela cells, T47D cells, Huh7 cells, PLC cells, U2OS cells, HEK293 cells, HepG2 cells, Jurkat cells, HCT116 cells, HEYA8 cells, or HL-60 cells, or a combination thereof. 50 Values ​​are IC of the same compound against NIH3T3 cells, MDCK cells, or bEnd.3 cells, or a combination thereof, tested under the same conditions. 50 at least one-half, at least one-third, at least one-fourth, at least one-fifth, at least one-eighth, at least one-tenth, at least one-twelfth, at least one-fifth, at least one-twentieth, at least one-twenty-second, at least one-twentieth, at least one-twentieth, at least one-thirtieth, at least one-thirty-fifth, at least one-fortieth, at least one-fortieth, at least one-fortieth, at least one-fifth, at least one-fifth, at least one-fifth, at least one-sixtieth, at least one-sixth, at least one-sixth, It may be at least 1 / 70, at least 1 / 75, at least 1 / 80, at least 1 / 90, at least 1 / 100, in the range of 2 / 1000, in the range of 2 / 500, in the range of 2 / 250, in the range of 2 / 200, in the range of 2 / 150, in the range of 2 / 100, in the range of 5 / 1000, in the range of 5 / 500, in the range of 5 / 250, in the range of 5 / 200, in the range of 5 / 150, or in the range of 5 / 100.

[0337] For example, the compound may have an IC50 value for MDA-MB-231 cells, MCF7 cells, Hela cells, T47D cells, Huh7 cells, PLC cells, U2OS cells, HEK293 cells, HepG2 cells, Jurkat cells, HCT116 cells, HEYA8 cells, or HL-60 cells, or a combination thereof. 50 Values ​​are the IC of the same compound against NIH3T3 cells tested under the same conditions. 50at least one-half, at least one-third, at least one-fourth, at least one-fifth, at least one-eighth, at least one-tenth, at least one-twelfth, at least one-fifth, at least one-twentieth, at least one-twenty-second, at least one-twentieth, at least one-twentieth, at least one-thirtieth, at least one-thirty-fifth, at least one-fortieth, at least one-fortieth, at least one-fortieth, at least one-fifth, at least one-fifth, at least one-fifth, at least one-sixtieth, at least one-sixth, at least one-sixth, It may be at least 1 / 70, at least 1 / 75, at least 1 / 80, at least 1 / 90, at least 1 / 100, in the range of 2 / 1000, in the range of 2 / 500, in the range of 2 / 250, in the range of 2 / 200, in the range of 2 / 150, in the range of 2 / 100, in the range of 5 / 1000, in the range of 5 / 500, in the range of 5 / 250, in the range of 5 / 200, in the range of 5 / 150, or in the range of 5 / 100.

[0338] For example, the compound has an IC 50 Values ​​are the IC of the same compound against NIH3T3 cells tested under the same conditions. 50at least one-half, at least one-third, at least one-fourth, at least one-fifth, at least one-eighth, at least one-tenth, at least one-twelfth, at least one-fifth, at least one-twentieth, at least one-twenty-second, at least one-twentieth, at least one-twentieth, at least one-thirtieth, at least one-thirty-fifth, at least one-fortieth, at least one-fortieth, at least one-fortieth, at least one-fifth, at least one-fifth, at least one-fifth, at least one-sixtieth, at least one-sixth, at least one-sixth, It may be at least 1 / 70, at least 1 / 75, at least 1 / 80, at least 1 / 90, at least 1 / 100, in the range of 2 / 1000, in the range of 2 / 500, in the range of 2 / 250, in the range of 2 / 200, in the range of 2 / 150, in the range of 2 / 100, in the range of 5 / 1000, in the range of 5 / 500, in the range of 5 / 250, in the range of 5 / 200, in the range of 5 / 150, or in the range of 5 / 100.

[0339] For example, a compound has an IC 50 Values ​​are the IC of the same compound against NIH3T3 cells tested under the same conditions. 50at least one-half, at least one-third, at least one-fourth, at least one-fifth, at least one-eighth, at least one-tenth, at least one-twelfth, at least one-fifth, at least one-twentieth, at least one-twenty-second, at least one-twentieth, at least one-twentieth, at least one-thirtieth, at least one-thirty-fifth, at least one-fortieth, at least one-fortieth, at least one-fortieth, at least one-fifth, at least one-fifth, at least one-fifth, at least one-sixtieth, at least one-sixth, at least one-sixth, It may be at least 1 / 70, at least 1 / 75, at least 1 / 80, at least 1 / 90, at least 1 / 100, in the range of 2 / 1000, in the range of 2 / 500, in the range of 2 / 250, in the range of 2 / 200, in the range of 2 / 150, in the range of 2 / 100, in the range of 5 / 1000, in the range of 5 / 500, in the range of 5 / 250, in the range of 5 / 200, in the range of 5 / 150, or in the range of 5 / 100.

[0340] Exemplary IC of exemplary compounds against cancer cells and cancer stem cells, such as MDA-MB-231 cells, MCF7 cells, Hela cells, T47D cells, Huh7 cells, PLC cells, U2OS cells, HEK293 cells, HepG2 cells, Jurkat cells, HCT116 cells, HEYA8 cells, or HL-60 cells, tested under specified conditions. 50 values, as well as exemplary IC values ​​of exemplary compounds against non-cancer cells, such as NIH3T3 cells, MDCK cells, and bEnd.3 cells. 50 Values ​​are given in the examples below.

[0341] 3. Cytotoxicity of the compound against cancer cells compared to other compounds In some forms of the method, the compound has an IC 50 The IC values ​​are the IC of known compounds such as OZ277, OZ439, RKA182, FINO2, or cholic / deoxycholic / steroid derivatives of 1,2,4,5-tetraoxane against the same cancer cells or cancer stem cells tested under the same conditions. 50 may be lower than the value.

[0342] For example, the compound may have an IC50 value for MDA-MB-231 cells, MCF7 cells, Hela cells, T47D cells, Huh7 cells, PLC cells, U2OS cells, HEK293 cells, HepG2 cells, Jurkat cells, HCT116 cells, HEYA8 cells, or HL-60 cells, or a combination thereof. 50 The IC values ​​are the IC of known compounds such as OZ277, OZ439, RKA182, FINO2, or cholic / deoxycholic / steroid derivatives of 1,2,4,5-tetraoxane against the same cancer cells tested under the same conditions. 50 For example, a compound may have an IC value lower than 0.01 for MDA-MB-231 cells, HCT116 cells, or HL-60 cells. 50 The IC values ​​are the IC of known compounds such as OZ277, OZ439, RKA182, FINO2, or cholic / deoxycholic / steroid derivatives of 1,2,4,5-tetraoxane against the same cancer cells tested under the same conditions. 50 For example, a compound may have an IC 50 The IC values ​​are the IC of known compounds such as OZ277, OZ439, RKA182, FINO2, or cholic / deoxycholic / steroid derivatives of 1,2,4,5-tetraoxane against the same cancer cells tested under the same conditions. 50OZ277, OZ439, RKA182, FINO2, 1.2, 4.5-five-fill / fill / fill / fill-in-neighbourhood PM,et al.,Angew Chem Int Ed Engl,2010,49(33),5693-5697;Opsenica D.,et al.,Bioorg Med Chem.,2003,3;11(13):2761-8;Coghi P.,et al.,ChemMedChem.,2018(1988):Awu98(998). RK,et al.,Bioorg Med Chem.,2013,21(23),7392-7397;Marti F.,et al.,MedChemComm.,2011,2(7);Terzic N.,et al.,J Med Chem.,2007,50(21),5118-5127;Opsenica,J,Med. Chem.,2000,43(17),3274-3282;Solaja BA,et al.,J Med Chem.,202,45(16),3331-3336;Opsenica D.,et al.,Bioorg Med Chem.,2003,11(13),2761-276;Opsenica D.Et. al.,J.Serb.Chem.Soc.,2015,80(11)1339-1359;Dong YX,et al.,J.Org.Chem.,1998,63,23,8582-8585;Abrams RP,et al.,ACS Chem Biol,2016,1515(1313),Zhang; Y.,et al.,Cell Chem Biol.,2019,26(5):623-633;Friedmann Angeli JP,et al.,Nat Cell Biol.,2014,16(12):1180-91;Llabani E.,et al.,J.Nat Chem.,2019,121(5):Dolma,523;S. al.,Cancer Cell,2003,3(3),285-296;Mai TT,et al., Nat Chem, 2017, 9(10), 1025-1033; WO2008038030; WO2010134678; IN2008DE02103; US6906098; DE10205864; DE10205864; WO9307119; and WO2010109172.

[0343] In some embodiments, the IC of the compound against cancer cells or cancer stem cells. 50 Values ​​are the IC of known compounds against the same cancer cells tested under the same conditions. 50 at least one fifth of the value, at least one tenth, at least one fifteenth, at least one twentieth, at least one twenty-fifth, at least one thirtieth, at least one thirty-fifth, within the range of 5 to 1000th, within the range of 5 to 500th, within the range of 5 to 250th, within the range of 5 to 200th, within the range of 5 to 150th, within the range of 5 to 100th, within the range of 10 to 1000th, within the range of 10 to 500th, within the range of 10 to 250th, within the range of 10 to 200th, within the range of 10 to 150th, within the range of 15 to 1000th, within the range of 15 to 500th, within the range of 5 to 1 / 250, within the range of 15 to 1 / 200, within the range of 15 to 1 / 150, within the range of 20 to 1 / 1000, within the range of 20 to 1 / 500, within the range of 20 to 250, within the range of 20 to 200, within the range of 20 to 150, within the range of 25 to 1 / 1000, within the range of 25 to 1 / 500, within the range of 25 to 250, within the range of 25 to 1 / 200, within the range of 25 to 1 / 150, within the range of 30 to 1 / 1000, within the range of 30 to 1 / 500, within the range of 30 to 1 / 250, within the range of 30 to 1 / 200, or within the range of 30 to 1 / 150.

[0344] For example, the compound may have an IC50 value for MDA-MB-231 cells, MCF7 cells, Hela cells, T47D cells, Huh7 cells, PLC cells, U2OS cells, HEK293 cells, HepG2 cells, Jurkat cells, HCT116 cells, HEYA8 cells, or HL-60 cells, or a combination thereof. 50Values ​​are the IC of OZ277, OZ439, RKA182, FINO2, or cholic acid / deoxycholic acid / steroid derivatives of 1,2,4,5-tetraoxane against the same cancer cells tested under the same conditions. 50 at least one fifth of the value, at least one tenth, at least one fifteenth, at least one twentieth, at least one twenty-fifth, at least one thirtieth, at least one thirty-fifth, within the range of 5 to 1000th, within the range of 5 to 500th, within the range of 5 to 250th, within the range of 5 to 200th, within the range of 5 to 150th, within the range of 5 to 100th, within the range of 10 to 1000th, within the range of 10 to 500th, within the range of 10 to 250th, within the range of 10 to 200th, within the range of 10 to 150th, within the range of 15 to 1000th, within the range of 15 to 500th, 1 / 250, 1 / 150, 1 / 150, 1 / 20, 1 / 20, 1 / 20, 1 / 20, 1 / 20, 1 / 20, 1 / 20, 1 / 20, 1 / 20, 1 / 20, 1 / 25 ...30, 1 / 30, 1 / 150.

[0345] For example, the compound has an IC 50 The IC values ​​are the IC of known compounds such as OZ277, OZ439, RKA182, FINO2, or cholic / deoxycholic / steroid derivatives of 1,2,4,5-tetraoxane against the same cancer cells tested under the same conditions. 50at least one fifth of the value, at least one tenth, at least one fifteenth, at least one twentieth, at least one twenty-fifth, at least one thirtieth, at least one thirty-fifth, within the range of 5 to 1000th, within the range of 5 to 500th, within the range of 5 to 250th, within the range of 5 to 200th, within the range of 5 to 150th, within the range of 5 to 100th, within the range of 10 to 1000th, within the range of 10 to 500th, within the range of 10 to 250th, within the range of 10 to 200th, within the range of 10 to 150th, within the range of 15 to 1000th, within the range of 15 to 500th, 1 / 250, 1 / 150, 1 / 150, 1 / 20, 1 / 20, 1 / 20, 1 / 20, 1 / 20, 1 / 20, 1 / 20, 1 / 20, 1 / 20, 1 / 20, 1 / 25 ...30, 1 / 30, 1 / 150.

[0346] For example, a compound has an IC 50 The IC values ​​are the IC of known compounds such as OZ277, OZ439, RKA182, FINO2, or cholic / deoxycholic / steroid derivatives of 1,2,4,5-tetraoxane against the same cancer cells tested under the same conditions. 50at least one fifth of the value, at least one tenth, at least one fifteenth, at least one twentieth, at least one twenty-fifth, at least one thirtieth, at least one thirty-fifth, within the range of 5 to 1000th, within the range of 5 to 500th, within the range of 5 to 250th, within the range of 5 to 200th, within the range of 5 to 150th, within the range of 5 to 100th, within the range of 10 to 1000th, within the range of 10 to 500th, within the range of 10 to 250th, within the range of 10 to 200th, within the range of 10 to 150th, within the range of 15 to 1000th, within the range of 15 to 500th, 1 / 250, 1 / 150, 1 / 150, 1 / 20, 1 / 20, 1 / 20, 1 / 20, 1 / 20, 1 / 20, 1 / 20, 1 / 20, 1 / 20, 1 / 20, 1 / 25 ...30, 1 / 30, 1 / 150.

[0347] Exemplary ICs of exemplary compounds and exemplary known compounds against cancer cells or cancer stem cells, such as MDA-MB-231 cells, MCF7 cells, Hela cells, T47D cells, Huh7 cells, PLC cells, U2OS cells, HEK293 cells, HepG2 cells, Jurkat cells, HCT116 cells, HEYA8 cells, and HL-60 cells, tested under specified conditions. 50 values, as well as exemplary IC values ​​of exemplary compounds and exemplary known compounds against non-cancer cells, such as NIH3T3 cells, MDCK cells, and bEnd.3 cells. 50 Values ​​are given in the examples below.

[0348] The invention will be further understood by reference to the following non-limiting examples. EXAMPLES

[0349] Example 1. Synthesis of exemplary compounds compound structure

[0350] Adamantylidine-containing compounds

[0351] [ka]

[0352] [ka]

[0353] Compounds containing tert-butylcyclohexyl

[0354] [ka]

[0355] Alkyne-tagged tetraoxanes [ka]

[0356] Prodrugs and Dimers [ka]

[0357] Materials and Methods chemical synthesis All reagents and solvents for reactions were analytical or HPLC grade and were dried and distilled as necessary. Analytical thin layer chromatography was performed on silica gel 60 Å F254 plates and spots were visualized by UV and / or staining in phophomolybdic acid (PMA) or KMnO4 solutions followed by heating. Flash chromatography was performed on silica gel (230-400 mesh) using the solvent systems indicated. Tetrahydrofuran (THF), methylene chloride (CH2Cl2), diethyl ether (Et2O), ethyl acetate (EtOAc) and N,N-dimethylformamide (DMF) were dried by filtration through alumina. All dry reactions were carried out under an atmosphere of either argon or nitrogen in flame-dried glassware. In general, hydrogen peroxide and organic peroxides should be handled with care. Exposure to intense heat, light, mechanical shock, oxidizing organics, and metals should be avoided. All reactions should be carried out behind a blast shield. Excess hydrogen peroxide was quenched by slow addition to a sodium metabisulfite solution (Liu, et al. Water Res. 2003, 37, 15, 3697-3703; Keen et al. J. Environ Eng. 2013, 139, 137-140).

[0358] Synthesis scheme of compounds 6a and 6b:

[0359] [ka]

[0360] Compound 2 was prepared according to literature reports (O'Neill, et al. Angew Chem Int Ed. 2010, 49, 5693-5697; Yan, et al. Synlett. 2011, 2827-2830). To a solution of 1,4-cyclohexanedione monoethylene acetal (1) (5.00 g, 32 mmol) in toluene (76 mL) was added trimethylphosphonoacetate (16.00 g, 48 mmol). The mixture was heated to reflux overnight. The reaction mixture was cooled to room temperature and the solvent was removed under reduced pressure. The crude material was diluted with diethyl ether (70 mL) to precipitate triphenylphosphine oxide. The insoluble material was filtered through a short pad of Celite and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane / EtOAc = 4 / 1) to give 2 as a colorless oil (5.60 g, 78% yield). 3 was prepared according to literature reports (O'Neill, et al. Angew Chem Int Ed. 2010, 49, 5693-5697; Yan, et al. Synlett. 2011, 2827-2830). 2 (6.440 g, 30.3 mmol) was premixed with palladium on charcoal (10 wt%, 3.20 g, 30.3 mmol). The reaction solvent (EtOH, 50 mL) was degassed and refilled with hydrogen gas three times before being added to the reaction mixture. Et3N (0.1 mL, 2.3 mmol) was added. The reaction flask was then degassed and refilled with hydrogen gas three times before being stirred under hydrogen atmosphere (balloon). The reaction was monitored by TLC (n-hexane / EtOAc=4:1). 2 was consumed after 5 h. The reaction mixture was filtered through a pad of Celite and then rinsed with EtOH. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (n-hexane / EtOAc=4 / 1) to give 3 (5.011 g, 77% yield) as a colorless oil.

[0361] Compound 6 was prepared according to literature reports with modifications and isolated as a white solid after purification by flash column chromatography (16% for three steps) (O'Neill, et al. Angew Chem Int Ed. 2010, 49, 5693-5697; Yan, et al. Synlett. 2011, 2827-2830). To a stirred solution of 3 (1.30 g, 7.6 mmol) in formic acid / acetonitrile (1:1, 17 mL) at 0 °C, 50% aqueous hydrogen peroxide (1.1 mL, 38.2 mmol) was added and the mixture was stirred at room temperature. TLC analysis (n-hexane / EtOAc = 2:1) showed that 3 was consumed after 3 h. The mixture was then poured into ice-cold water and extracted with CHCl. ​​The combined organic extracts were washed with brine, dried over NaSO, filtered and concentrated under reduced pressure to give the corresponding geminal dihydroperoxide 4. The CH2Cl2 solvent was dried and distilled. Anhydrous PMA was prepared by the following procedure; commercially available PMA hydrate was dried to constant weight in a microwave oven. A mixture of 2-adamantanone (1.26 g, 8.4 mmol), PMA (0.14 g, 1 mol%), and anhydrous MgSO4 (1.38 g, 11.5 mmol) in CH2Cl2 (25 mL) was stirred at room temperature for 30 min. A solution of 4 (7.6 mmol) in CH2Cl2 (10 mL) was added dropwise in 15 min. The mixture was stirred at room temperature and monitored by TLC (n-hexane: EtOAc = 4:1). When 4 was completely consumed, deionized H2O (10 mL) was added. The aqueous layer was extracted with CH2Cl2 (3 x 10 mL). The combined organic phase was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane / EtOAc=8:1) to give a mixture of 5 and 2-adamantanone. Isolation of analytically pure 5 by flash chromatography on silica gel was not possible because it coelutes with 2-adamantanone. Therefore, the product mixture was carried on to the next step. To a solution of 5 and 2-adamantanone (total 1.308 g) in EtOH (17 mL) was added a solution of sodium hydroxide (0.45 g, 11.1 mmol) in deionized water (2.7 mL). The mixture was heated at 50° C. for 2 h. The solution was then allowed to cool to room temperature and concentrated under reduced pressure.The crude product was taken up in water (20 mL) and washed with diethyl ether (3×30 mL). The aqueous layer was acidified to pH 1 with 1M HCl and then extracted with EtOAc (3×30 mL). The combined organic phase was washed with brine (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give the pure compound. The carboxylic acid 6 was obtained as a white solid without the need for further purification (0.4199 g, 16% yield over three steps). The TPP salt 68 was prepared as reported in the literature and isolated as a white solid after recrystallization (Millard, et al. J Med Chem. 2013, 56, 22, 9170-9179). To a solution of compound 6 (0.010 g, 0.036 mmol) in CHCl (1 mL) was added DIPEA (0.1 mL) and HBTU (0.015 g, 0.046 mmol). After stirring for 5 min, 68 (0.014 g, 0.036 mmol) was added. The reaction was stirred at room temperature for 12 h. The solvent was removed under reduced pressure. The crude product was purified by silica gel column chromatography (10% EtOH in DCM) to give compound 6b (0.016 g, 87% yield) as a foam. DIPEA (19.1 μL, 0.11 mmol) was added to a solution of compound 6 (0.017 g, 0.050 mmol) in DMF (1 mL) at 0° C. After 5 min, EDCI (0.017 g, 0.11 mmol), HOBt (0.023 g, 0.11 mmol) and 3-(dimethylamino)-1-propylamine (0.014 mL, 0.11 mmol) were added successively. The reaction mixture was stirred at room temperature for 12 h. The reaction was quenched by NH4Cl (10 mL) and diluted with EtOAc. The aqueous layer was back-extracted with EtOAc (3×30 mL). The combined organic phase was washed with saturated NaHCO, brine (30 mL), dried over NaSO, filtered and concentrated under reduced pressure to give the crude product, which was purified by silica gel column chromatography (7% EtOH, 1% NHOH in DCM) to give compound 6a as a pink oil (0.011 g, 52% yield).

[0362] Synthesis scheme of compound 10:

[0363] [ka]

[0364] To a solution of tetradecylamine 7 (1.00 g, 4.7 mmol) in anhydrous CHCl (15 mL) were added EtN (1.3 mL, 9.37 mmol) and methyl 3-bromopropionate (0.74 mL, 6.6 mmol) successively. The reaction mixture was stirred for 12 h. The reaction mixture was filtered through sintered glass to remove the EtN salt. The solvent was removed under vacuum. The crude product was purified by silica gel column chromatography (n-hexane / EtOAc = 1:1) to give 8 as a yellow solid (0.25 g, 31% yield). To a solution of compound 6 (0.016 g, 0.044 mmol) in anhydrous CHCl (1 mL) were added DIPEA (0.2 mL) and HBTU (0.053 g, 0.13 mmol). After 5 min, 8 (0.014 g, 0.044 mmol) was added. The cloudy reaction mixture was stirred for 2 days. Water (5 mL) was added. The aqueous layer was extracted with CH2Cl2 (20 x 3 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane / EtOAc = 6:1) to give compound 9 as a colorless oil (0.027 g, 94% yield). To a solution of compound 9 (0.027 g, 0.043 mmol) in THF:H2O (4:1, 0.5 mL) was added LiOH (0.052 g, 0.22 mmol). The reaction mixture was stirred at room temperature for 2 h. Water (5 mL) was added. The aqueous layer was acidified with 1 M HCl and then extracted with EtOAc (20 x 3 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane / EtOAc = 1:1) to give compound 10 as a colorless oil (0.020 g, 75% yield).

[0365] Synthesis scheme of compound 18:

[0366] [ka]

[0367] 71 synthesis scheme:

[0368] [ka]

[0369] Chloromethyl chloroformate (3.2 mL, 36.3 mmol) was added to an ice-cold solution of p-nitrophenol (5.00 g, 35.9 mmol) in CHCl (60 mL), followed by dropwise addition of pyridine (4.3 mL, 53.9 mmol) over 20 min. The mixture was stirred in an ice-cooled bath for 15 min and then stirred at room temperature overnight. The reaction mixture was washed successively with water (10 mL x 2), 1N HCl (10 mL x 2), saturated NaHCO solution and brine. After drying over anhydrous sodium sulfate, the organic solution was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (EtOAc / n-hexane = 1 / 3) to give 69 as a white solid (4.5281 g, 54% yield). To a solution of 69 (1.500 g, 6.5 mmol) in acetone (40 mL) was added sodium iodide (1.070 g, 7.1 mmol). The mixture was stirred at 50 °C overnight. The solvent was evaporated. The residue was taken up in diethyl ether and washed with saturated NaHCO3 solution. After drying over anhydrous sodium sulfate, the organic solution was concentrated to give crude product 70, which was immediately dissolved in toluene (9 mL). To this solution was added silver acetate (1.30 g, 7.78 mmol). The mixture was refluxed overnight. The mixture was filtered through a short pad of Celite, and the filtrate was evaporated. The mixture was dissolved in diethyl ether and washed with saturated Na2SO3 solution and brine. After drying over anhydrous sodium sulfate, the organic solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (EtOAc / n-hexane=1 / 3) to give product 71 as a white solid (0.931 g, 56% yield for two steps). To a solution of 11 (1.50 g, 4.74 mmol) in anhydrous THF (18 mL) at 0° C. under Ar was added BH3-SMe2 (3.63 mL, 37.7 mmol) dropwise over 5 min. The cloudy solution was gradually warmed to room temperature and stirred for 12 h. Methanol (10 mL) was added dropwise to the reaction mixture until a red color appeared. The solvent was evaporated under reduced pressure, and the residue was redissolved in ethyl acetate and washed with saturated NaHCO3, water, and brine. After drying over anhydrous sodium sulfate, the organic solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (5% EtOH in CH2Cl2) to give 12 as a white solid (0.69 g, 53% yield).To a solution of 12 (0.44 g, 2.4 mmol) in anhydrous CHCl (15 mL) at 0° C. under Ar were successively added triphenylphosphine (1.89 g, 7.19 mmol) and CBr (2.39 g, 7.19 mmol). The yellow solution was stirred at 0° C. for 1.5 h. Water (10 mL) and diethyl ether (100 mL) were added. Any white solid was filtered through a short pad of Celite. The aqueous layer was back-extracted three times with diethyl ether. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / n-hexane=1:4) to give 13 as a white solid (0.61 g, 82% yield). To a stirred solution of 13 (1.00 g, 3.24 mmol) in ethanol (30 mL) at room temperature was added a solution of potassium cyanide (0.740 g, 11.3 mmol) in water (6.3 mL). The reaction mixture was stirred for 12 h and diluted with water and diethyl ether. The aqueous layer was extracted with ether three times. The organic phase was washed with saturated NaHCO3 solution, brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / n-hexane=3 / 1) to give 14 (0.274 g, 42% yield) as a white solid. To a stirred solution of 14 (0.100 g, 0.5 mmol) in anhydrous tetrahydrofuran (3 mL) at 0° C. under Ar was added a solution of borane-tetrahydrofuran complex (1.00 M in tetrahydrofuran; 5 mL, 4.97 mmol). The resulting mixture was warmed to room temperature and stirred for 2 h. At 0° C., 3N HCl (3 mL) was added slowly. EtOAc was added to dilute the mixture. 2N NaOH (15 mL) was added. The aqueous layer was back-extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give crude product 15, which was used in the next step. Product 15 (0.048 g, 0.23 mmol) was dissolved in anhydrous DMF (1.5 mL). To this solution were added 71 (0.122 g, 0.48 mmol) and Et3N (0.2 mL) successively under argon atmosphere. The reaction mixture was stirred for 12 h. Excess 71 was added until the starting material was completely consumed as monitored by TLC (EtOAc / n-hexane=3:2).EtOAc (60 mL) was added. The organic layer was washed with 1M K2CO3 solution (3 x 10 mL), brine, dried over anhydrous Na2SO4, filtered and concentrated to give the crude product, which was purified by flash column chromatography (EtOAc / n-hexane = 3:2) to give product 16 as a colorless oil (0.022 g, 13% yield for two steps). Product 16 (0.022 g, 0.050 mmol) was premixed with palladium on carbon (0.053 g of 10 wt% solid). The reaction solvent EtOH (1 mL) was placed under vacuum and refilled with hydrogen gas three times before being added to the reaction mixture. Et3N (7 μL) was added. The reaction flask was then evacuated and refilled with hydrogen gas three times before being stirred under hydrogen atmosphere (balloon). The reaction was monitored by TLC (n-hexane / EtOAc = 1:1). 16 was consumed after 2 h. The reaction mixture was filtered through a pad of Celite, which was then rinsed with EtOH. After removal of the solvent under reduced pressure, the crude product was purified by preparative TLC (80% EtOAc in n-hexane) to give 17 as a yellow oil (0.015 g, 71% yield). To a solution of compound 6 (0.017 g, 0.050 mmol) in anhydrous CHCl (1 mL) was added DIPEA (19.1 μL, 0.11 mmol). After 5 min, a solution of EDCI (0.017 g, 0.11 mmol), HOBt (0.023 g, 0.11 mmol) and 17 (19.1 μL, 0.11 mmol) in anhydrous CHCl (1 mL) was added successively. The reaction mixture was stirred at room temperature for 36 h. Excess EDCI and 6 were added until TLC (EtOAc / n-hexane=1:1) showed that the starting material was completely consumed. The reaction was quenched with NH4Cl (10 mL) and diluted with CH2Cl2. The aqueous layer was back-extracted with CH2Cl2 (3 x 30 mL). The combined organic phase was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give the crude product, which was purified by preparative TLC (EtOAc / n-hexane = 3:2) to give compound 18 (0.019 g, 75% yield) as a foam.

[0370] Synthesis scheme of compounds 24a and 24b:

[0371]

change

[0372] 21 was prepared from D-glucose (3.00 g, 16.7 mmol) as reported in the literature and isolated as a white powder by recrystallization (4.70 g, 72% yield) (Huo, et al. Chem Res Toxicol. 2004, 17, 8, 1112-1120). 22 was prepared from 21 (4.669 g, 11.9 mmol) as reported in the literature and isolated as a pale yellow syrup after purification by flash column chromatography (1.560 g, 37% yield) (Huo, et al. Chem Res Toxicol. 2004, 17, 8, 1112-1120). 23 was prepared from 22 (0.305 g, 0.88 mmol) according to literature reports with modifications and isolated by silica gel column chromatography (EtOAc / n-hexane=1 / 4) to give a white powder (0.31 g, 69% yield, mixture of α and β isomers) (Cai, et al. J Org Chem. 2005, 70, 9, 3518-3524). The α and β isomers were separated by silica gel chromatography (diethyl ether / n-hexane=1 / 4) with gradient elution to give the α-isomer (0.074 g) and β isomer (0.022 g). To a solution of compound 6 (0.030 g, 0.089 mmol) in anhydrous CHCl (1 mL) was added EtN (50 μL, 0.18 mmol) and HBTU (0.037 g, 0.098 mmol). After 5 min, 1,3-diaminopropane (7.4 μL, 0.089 mmol) was added. The reaction mixture was stirred for 12 h. Water (5 mL) was added. The aqueous layer was extracted with CH2Cl2 (20 × 3 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue 19 was used directly in the next step. To a stirred solution of 23b (0.022 g, 0.043 mmol) in anhydrous DCM (2 mL) was added 9 (0.019 g, 0.047 mmol) and Et3N (20 μL). The reaction mixture was stirred for 4 h. The solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography to give compound 24b (0.029 g, 87% yield) as a colorless oil. To a stirred solution of 23a (0.052 g, 0.10 mmol) in anhydrous DCM (3 mL) was added 9 (0.044 g, 0.11 mmol) and EtN (40 μL). The reaction mixture was stirred for 48 h.Then DMAP was added. The solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography to give compound 24a (0.048 g, 61% yield) as a white foam.

[0373] Synthesis scheme for compound 77:

[0374] [ka]

[0375] 72 was prepared from carbon disulfide (1.58 mL, 26.3 mmol) as reported in the literature and used immediately in the next step (Pervez, et al. Nat Prod Res. 2007, 1, 13, 1178-1186). 73 was prepared from 72 (26.3 mmol) as reported in the literature and isolated as a white solid without purification (1.40 g, 44% yield over two steps) (Pervez, et al. Nat Prod Res. 2007, 1, 13, 1178-1186). 74 was prepared from 73 (0.30 g, 2.5 mmol) as reported in the literature and isolated as a dark green solid after purification by flash column chromatography (4% EtOH in DCM) (0.074 g, 13% yield) (Greenbaum, et al. J Med Chem. 2004, 47, 12, 3212-3219). To a solution of 74 (0.030 g, 0.13 mmol) in EtOH (2 mL) was added 1,3-diaminopropane (11.1 μL). Reflux was set up and the reaction mixture was stirred overnight. EtOH was removed under reduced pressure. The crude product was purified by silica gel column chromatography (EtOH / DCM, 1% NH4OH) to give 75 as a yellow oil (0.020 g, 57% yield). To a solution of 29 (0.030 g, 0.10 mmol) in acetone (0.5 mL) was added Jones reagent (40 μL). The reaction mixture was stirred at room temperature for 30 min. EtOAc and H2O were added. Saturated NaHCO3 was added until the pH of the aqueous layer was 7. The crude product was extracted with EtOAc, washed with brine, and then dried by MgSO4. The EtOAc solution of 76 was filtered through a short pad of silica gel. The solvent was removed under reduced pressure. 76 was used immediately in the next step without purification. The crude product 76 was dissolved in DCM (1 mL). This solution was added to a solution of 75 (0.016 g, 0.064 mmol) in DCM and stirred for 30 min. Sodium triacetoxyborohydride (0.020 g, 0.094 mmol) was added. The reaction was stirred for 2 h. i-PrOH (0.2 mL) was added. Saturated NH4Cl was added. The aqueous layer was extracted with DCM. The combined organic layers were washed with brine and then dried with MgSO4.The concentrated filtrate was purified by silica gel column chromatography (4% EtOH in DCM) to give compound 77 (0.020 g, 87% yield).

[0376] Synthesis scheme of compounds 30a and 30b:

[0377] [ka]

[0378] 25 reported in the literature 21and isolated as an oil after purification by flash column chromatography (Uyanik, et al. J Am Chem Soc. 2009, 131, 1, 251-262). 26 was prepared as reported in the literature and isolated as an oil after purification by flash column chromatography (Kovalenko, et al. Chemistry 2015, 21, 7, 2785-2788). Tetraoxane 29 was prepared as reported in the literature with modifications (O'Neill, et al. Angew Chem Int Ed. 2010, 49, 5693-5697; Yan, et al. Synlett. 2011, 2827-2830). To a stirred solution of 26 (0.70 g, 3.5 mmol) in acetonitrile (3.8 mL) at 0° C. was added formic acid (2.6 mL, 69 mmol), followed by 50% aqueous hydrogen peroxide (1.3 mL, 46 mmol). The mixture was stirred at room temperature. TLC analysis (n-hexane / EtOAc=2:1) ​​showed that acetate 26 was consumed after 4 h. 1 mL of 50% H2O2 was added. Then, after 1 h, the mixture was poured into ice-cold water and extracted with CH2Cl2. The combined organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give the corresponding geminal dihydroperoxide 27, which was used immediately in the next step. A mixture of 2-adamantanone (0.79 g, 5.2 mmol), PMA (0.0627 g, 1 mol%), and anhydrous MgSO4 (0.63 g, 5.2 mmol) in CHCl2 (13 mL) was stirred at room temperature for 30 min. A solution of 27 (3.5 mmol) in CHCl2 (13 mL) was added dropwise to the solution in 15 min. The mixture was stirred at room temperature and monitored by TLC (n-hexane / EtOAc = 4:1). When 27 was completely consumed, deionized H2O (10 mL) was added. The aqueous layer was extracted with CHCl2 (3 × 10 mL). The combined organic phase was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane / EtOAc = 8:1) to give a mixture of 28 and 2-adamantanone.Isolation of analytically pure 28 by flash chromatography on silica gel was not possible because it coelutes with 2-adamantanone. Therefore, the product mixture was carried on to the next step. To a solution of the mixture of 28 and 2-adamantanone (total 0.94 g) in MeOH (62 mL) was added K2CO3 (2.64 g, 19.1 mmol) at room temperature. The product was extracted from the aqueous layer with CH2Cl2 (3 x 30 mL) supplemented with water (20 mL). The combined organic phase was washed with brine (2 x 10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane / EtOAc = 2 / 1) to give 29 as a white solid (0.252 g, 24% yield for three steps). To a solution of 29 (0.014 g, 0.049 mmol) in anhydrous dichloromethane (3 mL) was added p-nitrophenyl chloroformate (0.098 g, 0.49 mmol) and Et3N (0.1 mL, 0.71 mmol) successively under argon atmosphere. The reaction mixture was stirred for 12 h. DCM (60 mL) was added and the organic layer was washed with 1 M K2CO3 solution (3 x 10 mL), dried over anhydrous Na2SO4, filtered and concentrated to give the crude product. The crude product was dissolved in anhydrous dichloromethane (1 mL). To this solution was added 68 (0.021 g, 0.044 mmol) and Et3N (22 μL, 0.16 mmol) successively under argon atmosphere. The reaction mixture was stirred for 12 h. Dichloromethane (10 mL) was added. The organic layer was washed with 1M K2CO3 solution (3 x 5 mL), dried over anhydrous Na2SO4, filtered and concentrated to give the crude product, which was purified by flash column chromatography to give compound 30b as a yellow oil (0.068 g, 19% yield over two steps). Following the stoichiometry and procedure for the synthesis of compound 30b, compound 30a was obtained as a colorless oil (0.0083 g, 53% yield over two steps) from 29 (0.011 g, 0.037 mmol) and 3-(dimethylamino)-1-propylamine (5 μL, 0.037 mmol) (7% EtOH, 1% NH4OH in DCM).

[0379] Synthesis scheme of compound 35a:

[0380] [ka]

[0381] 32 was prepared according to literature reports and isolated as an oil without purification (An, et al. Chemistry 2015, 21, 30, 10786-10798). Following the stoichiometry and procedure for the synthesis of 6, 2-adamantanone (1.90 g, 12.7 mmol) and 32 (1.50 g, 11.5 mmol) gave 35 as a white solid (0.52 g, 15% yield over three steps) (EtOAc / n-hexane=1 / 3). Following the stoichiometry and procedure for the synthesis of compound 6a, 35 (0.009 g, 0.031 mmol) and 3-(dimethylamino)-1-propylamine (3.4 μL, 0.031 mmol) gave compound 35a as a yellow oil (0.010 g, 88% yield) (7% EtOH, 1% NH4OH in DCM).

[0382] Synthesis scheme of compounds 37a and 37b:

[0383] [ka]

[0384] Following the stoichiometric ratio and procedure for the synthesis of 29, compound 4-tert-butylcyclohexanone (0.57 g, 3.7 mmol) and 26 (0.73 g, 3.6 mmol) gave 37 as a white solid (0.18 g, 16% yield for three steps) (n-hexane / EtOAc=2 / 1). 37 appeared as a mixture of diastereomers (dr). Following the stoichiometric ratio and procedure for the synthesis of compound 30b, compound 37c was obtained as a white solid (0.534 g, 94% yield) from 37 (0.0367 g, 1.2 mmol) and p-nitrophenyl chloroformate (0.738 g, 3.7 mmol) (EtOAc / n-hexane=1 / 8). Compound 37c appeared as a mixture of diastereomers (dr). Following the stoichiometry and procedure for the synthesis of compound 30a, compound 37c (0.019 g, 0.04 mmol) and 3-(dimethylamino)-1-propylamine (28.5 μL, 0.044 mmol) gave compound 37a as a yellow oil (0.007 g, 40% yield over two steps) (3% EtOH in DCM). Compound 37a appeared as a mixture of diastereomers (dr). Following the stoichiometry and procedure for the synthesis of compound 30b, compound 37c (0.133 g, 0.29 mmol) and 68 (0.137 g, 0.28 mmol) gave compound 37b as a yellow foam (0.17 g, 82% yield) (3% EtOH in DCM). Compound 37b appeared as a mixture of diastereomers (dr).

[0385] [ka]

[0386] 72 was prepared according to literature reports and isolated as a yellow oil after purification by flash column chromatography (5% EtOH, 1% NH4OH in DCM) (Hou, et al. J Org Chem. 2004, 69, 18, 6094-6099). Following the stoichiometry and procedure for the synthesis of compound 30a, compound 37c (0.049 g, 0.11 mmol) and 72 (0.053 g, 0.16 mmol) gave compound 37d as a yellow oil (0.019 g, 30% yield) (1% EtOH in DCM). Compound 37d appeared as a mixture of diastereomers (dr). 73 was prepared according to literature reports and isolated as a yellow oil after purification by flash column chromatography (5% EtOH, 1% NH4OH in DCM) (Ghedira, et al. J Med Chem. 2018, 158, 51-67). Following the stoichiometry and procedure for the synthesis of compound 30a, compound 37c (0.031 g, 0.066 mmol) and 73 (0.012 g, 0.066 mmol) gave compound 37e as a yellow oil (0.013 g, 40% yield) (1% EtOH in DCM). Compound 37e appeared as a mixture of diastereomers (dr).

[0387] Synthesis scheme of compound 37g:

[0388] [ka]

[0389] Compound 37c (0.031 g, 0.066 mmol) was dissolved in anhydrous dichloromethane (1 mL). To this solution, piperazine (0.011 g, 0.133 mmol) and Et3N (60 μL, 0.4 mmol) were added sequentially under argon atmosphere. The reaction mixture was stirred for 12 h. Dichloromethane (60 mL) was added. The organic layer was washed with 1 M K2CO3 solution (3×10 mL), dried over anhydrous Na2SO4, filtered and concentrated to give the crude product, which was purified by flash column chromatography to give product 37f (0.025 g, 90% yield) as a yellow oil. Compound 37f appeared as a mixture of diastereomers (dr). 41 was prepared according to literature reports and isolated as an off-white solid without any further purification and characterization (Ji, et al. J. ACS Med Chem Lett. 2015, 6, 6, 707-710). 42 was prepared according to literature reports and isolated as an off-white solid without any further purification and characterization (Ji, et al. J. ACS Med Chem Lett. 2015, 6, 6, 707-710). 43 was prepared according to literature reports and isolated as a yellow solid after purification by flash column chromatography (Ji, et al. J. ACS Med Chem Lett. 2015, 6, 6, 707-710). To a solution of 43 (0.008 g, 0.035 mmol) in anhydrous CHCl (1 mL) was added EtN (12 μL, 0.087 mmol) and HBTU (0.020 g, 0.052 mmol) successively. After 5 min, compound 37f (0.014 g, 0.035 mmol) was added. The reaction was stirred at room temperature for 12 h. When TLC (EtOAc / n-hexane=1:1) showed that 43 was completely consumed, the solvent was removed under reduced pressure. The crude product was purified by preparative TLC (EtOAc / n-hexane=1:4) to give compound 37g as a light yellow oil (0.016 g, 70% yield). Compound 37g appeared as a mixture of diastereomers (dr).

[0390] Synthesis scheme of compound 37i:

[0391]

change

[0392] 44 was prepared from 4-amino-1-butanol (0.5 mL, 5.4 mmol) as reported in the literature and isolated as a light yellow oil (0.255 g, 17%) after purification by flash column chromatography (EtOAc / n-hexane = 1:4) (De, et al. J Enzyme Inhib Med Chem. 2016, 31, 106-113). To a solution of 1,2,3,4,6-penta-O-acetyl-D-pyranoglucose (0.349 g, 0.89 mmol) in anhydrous DCM containing 4 Å MS was subsequently added 44 (0.255 g, 0.95 mmol) and BF3·Et2O (0.55 mL, 4.5 mmol). The reaction mixture was stirred at room temperature with sonication until the starting material was completely consumed (as monitored by TLC) (Deng, et al. J Org Chem. 2006, 71, 5179-5185). The reaction mixture was quenched by the addition of NaHCO3 and then filtered through Celite. The filtrate was concentrated under reduced pressure to give crude product 45, which was used in the next step without further purification. To a solution of crude product 45 (0.070 g, 0.93 mmol) in methanol (15 mL) was added 20 wt% Pd / C (0.099 g, 10 mol%) with stirring at room temperature. The air in the flask was replaced with hydrogen and the mixture was stirred under hydrogen atmosphere for 2 days. The reaction mixture was filtered through a pad of Celite, which was then rinsed with EtOH and concentrated to give the crude product, which was purified by flash column chromatography to give 46 as a yellow oil (0.026 g, 7% yield for two steps). Compound 37c (0.0436 g, 0.094 mmol) was dissolved in anhydrous dichloromethane (1 mL). To this solution, 46 (0.023 mg, 0.055 mmol) and Et3N (30 μL, 0.22 mmol) were added sequentially under argon atmosphere. The reaction mixture was stirred for 12 h. Dichloromethane (60 mL) was added. The organic layer was washed with 1 M K2CO3 solution (3×10 mL), dried over anhydrous Na2SO4, filtered and concentrated to give the crude product, which was purified by flash column chromatography to give compound 37h (0.0133 g, 33% yield) as a yellow oil. Compound 37h appeared as a mixture of diastereomers (dr).A solution of NaOMe in MeOH (0.03 M, 0.5 mL) was added to compound 37h (0.013 g, 0.018 mmol) at 0° C. The reaction mixture was stirred at room temperature for 1 h. Dichloromethane and water were added. The aqueous layer was extracted with DCM (3×10 mL). The combined organic layers were stirred with anhydrous Na2SO4, filtered and concentrated to give the crude product, which was purified by flash column chromatography to give compound 37i (0.0015 g, 15% yield) as a white solid. Compound 37i appeared as a mixture of diastereomers (dr).

[0393] To a solution of 2,2'-(ethylenedioxy)bis(ethylamine) (1.8 μL, 0.0125 mmol) in CHCl was added a solution of 37c (0.012 g, 0.025 mmol) in CHCl, followed by 4-(dimethylamino)pyridine (DMAP) and EtN (10 μL, 0.025 mmol). The reaction mixture was stirred at room temperature for 48 h. The solvent was concentrated under reduced pressure to give the crude product, which was purified by flash column chromatography to give 37j (0.010 g, 50% yield) as an oil. 37j appeared as a mixture of diastereomers (dr). To a solution of 37 (0.100 g, 0.32 mmol) in THF (7 mL) at 0 °C was added sodium hexamethyldisilazide [NaHMDS, 1.0 M in THF] (0.33 mL, 0.32 mmol). The resulting mixture was stirred at 0° C. for 10 min and the appropriate dichlorophosphate (0.024 mL, 0.16 mmol) was added. The reaction mixture was kept at 0° C. for 2 h, then warmed to room temperature and stirred for 12 h. The mixture was then recooled to 0° C. and quenched with water. The organic layer was extracted three times with ether and the combined organic portions were washed with saturated NaCl and dried over MgSO4. The organic extracts were removed under reduced pressure and the product was purified by flash column chromatography to give compound 37k (0.030 g, 26% yield) as an oil. Compound 37k appeared as a mixture of diastereomers (dr).

[0394] Synthesis scheme of compound 37l:

[0395] [ka]

[0396] 47 was prepared from 2-mercaptoethanol (2 mL, 28.5 mmol) as reported in the literature and isolated as an oil after purification by flash column chromatography (EtOAc / n-hexane = 1 / 1) (1.036 g, 30% yield) (Chen, et al. J. Mater. Sci. 2018, 53 16169-16181). To a solution of compound 37c (0.017 g, 0.036 mmol) in CHCl was added 2,2'-disulfanediylbis(ethan-1-ol) (0.0086 g, 0.018 mmol), EtN (10 μL) and DMAP. The reaction mixture was stirred at room temperature for 48 h. The crude product was purified by preparative TLC with EtOAc / n-hexane (1:8) to give compound 37l (0.005 g, 7% yield). Compound 37l appeared as a mixture of diastereomers (dr).

[0397] Synthesis scheme for compounds 49, 50, 51, 53, 54, 56, and 57:

[0398] [ka]

[0399] [ka]

[0400] Methyl iodide:acetonitrile (1:1) was added to the tertiary amine. The reaction mixture was stirred at room temperature for 4-12 hours. The conversion was checked using UPLC. The solvent was removed under reduced pressure. The crude product was purified by flash column chromatography (100% EtOAc, then 4% EtOH / DCM) to give the quaternary ammonium ("QA") as a light yellow oil. Following the procedure for the synthesis of QA compounds, compound 37d (0.018 g, 0.031 mmol) gave compound 48 as an oil (0.016 g, 70% yield). Compound 48 appeared as a mixture of diastereomers (dr). 55 was prepared from 3-bromopropylamine hydrobromide (3.00 g, 13.7 mmol) as reported in the literature and isolated as an oil (2.644 g, 46% yield) without any further purification or characterization (Millard, et al. J Med Chem. 2013, 56, 22, 9170-9179). Following the stoichiometry and procedure for the synthesis of compound 37b, compound 56 was obtained from 55 (0.066 g, 0.156 mmol) as an oil (0.020 g, 20% yield) (3% EtOH in DCM). Compound 37l appeared as a mixture of diastereomers (dr). According to the stoichiometry and procedure for the synthesis of compound 30a and QA compounds, compound 50 was obtained as an oil from 37 (0.020 g, 0.067 mmol) (0.006 g, 17% yield over three steps) (3% EtOH in DCM). Compound 50 appeared as a mixture of diastereomers (dr). According to the stoichiometry and procedure for the synthesis of compound 30a and QA compounds, compound 51 was obtained as an oil from 37 (0.030 g, 0.10 mmol) (0.027 g, 48% yield over two steps) (3% EtOH in DCM). Compound 51 appeared as a mixture of diastereomers (dr). According to the stoichiometry and procedure for the synthesis of QA compounds, compound 49 was obtained as an oil from compound 37a (0.042 g, 0.097 mmol) (0.0086 g, 16%) (3% EtOH in DCM). Compound 49 appeared as a mixture of diastereomers (dr).Compound 52 was prepared from 3-bromopropylamine hydrobromide (2.00 g, 9.1 mmol) as reported in the literature and isolated as an oil after purification by flash column chromatography (1.33 g, 78% yield) (5% EtOH, 1% NH4OH in DCM) (Labadie, et al. Bioorg Med Chem Lett. 2004, 14, 3, 615-619). Following the stoichiometric ratios and procedures for the synthesis of compound 30a and the QA compound, compound 53 was obtained from compound 37c (0.031 g, 0.16 mmol) as an oil (0.058 g, 55% yield for two steps) (3% EtOH in DCM). Compound 53 appeared as a mixture of diastereomers (dr). Following the stoichiometry and procedure for the synthesis of QA compounds, compound 54 was obtained as an oil (0.004 g, 58% yield) from compound 37e (0.0054 g, 0.011 mmol) (3% EtOH in DCM). Compound 54 appeared as a mixture of diastereomers (dr). Benzyl iodide was prepared according to literature reports and isolated as an oil without any further purification or characterization (Hoang, et al. J Org Chem. 2009, 74, 11, 4177-4187). To a solution of 37d (0.020 g, 0.034 mmol) in acetonitrile was added benzyl iodide (0.022 g, 0.10 mmol). The reaction mixture was stirred at room temperature for 72 h. The solvent was removed under reduced pressure. The crude product was purified by silica gel column chromatography (100% EtOAc, then 6% EtOH / DCM) to give compound 57 as a light yellow oil (0.0065 g, 24% yield). Compound 57 appeared as a mixture of diastereomers (dr).

[0401] Synthesis scheme of compounds 59a and 59b:

[0402] [ka]

[0403] Following the stoichiometry and procedure for the synthesis of compound 30a, 26 (2.00 g, 9.9 mmol) and cyclohexanone (0.49 mL, 4.7 mmol) gave 59 as an oil (0.106 g, 9% yield over two steps) (EtOAc / n-hexane=1 / 2). Following the stoichiometry and procedure for the synthesis of compound 30a and the QA compounds, 59 (0.028 g, 0.35 mmol) and 72 (0.034 g, 0.14 mmol) gave compound 59a as a yellow oil (0.018 g, 38% yield over two steps). Following the procedure for the synthesis of compound 30b, compound 59b was obtained from 59 (0.010 g, 0.023 mmol) and 68 (0.012 g, 0.023 mmol) as a white solid (0.006 g, 39% yield over two steps) (2% EtOH in DCM).

[0404] [ka]

[0405] To a solution of 72 (0.113 g, 0.44 mmol) in DCM (1 mL) was added 4-bromo-1-butyne (22.2 μL, 0.24 mmol), followed by Et3N (47.4 μL, 0.34 mmol). The reaction was stirred at room temperature for 24 h. The solvent was removed under reduced pressure. The crude product was purified by flash chromatography (20% EtOH, 1% NH4OH in DCM) to give alk-72 as an oil (0.0154 g, 21% yield). Following the stoichiometry and procedure for the synthesis of 30a and QA compounds described above, compound alk-R-48 was obtained as a yellow oil (0.0071 g, 18% yield for two steps) from compound 37c (0.0432 g, 0.093 mmol) and alk-72 (0.0154 g, 0.05 mmol). Compound alk-R-48 appeared as a mixture of diastereomers (dr). To a solution of 68 (0.105 g, 0.22 mmol) in DMF (1 mL) was added 4-bromo-1-butyne (20.5 μL, 0.22 mmol), followed by Et3N (33.8 μL, 0.24 mmol). The reaction was stirred at room temperature for 24 h. The solvent was removed under reduced pressure. The crude product was purified by flash chromatography (20% EtOH, 1% NH4OH in DCM) to give alk-68 (0.0224 g, 23%) as an oil. Following the stoichiometric ratios and procedures for the synthesis of compound 30a and quaternary amine compounds described above, compound alk-R-37b was obtained as a yellow oil (0.0067 g, 18% yield over two steps) from compound 37 (0.020 g, 0.067 mmol) and alk-68 (0.022 g, 0.049 mmol) (3% EtOH in DCM). Compound alk-R-37b appeared as a mixture of diastereomers (dr).

[0406] Synthesis scheme of compound alk-L-37b:

[0407] [ka]

[0408] Synthesis of 67:

[0409]

change

[0410] 62 and 63 were prepared according to literature reports with modifications and isolated as a mixed product after purification by flash column chromatography (WO2010039789A1 by Stamford, et al.). Anhydrous N,N-diisopropylamine (DIPA) was freshly prepared by distillation. A solution of DIPA (1.3 mL, 9 mmol) in THF (10 mL) was kept at −78° C. under argon. A solution of n-butyllithium in hexane (1 M, 8.9 mL, 8 mmol) was added dropwise to the DIPA solution. The reaction mixture was stirred at −78° C. for 30 min. Half of the LDA solution was transferred to an argon-purged round-bottom flask and kept at 0° C. The methyl ester 3 (0.949 g, 4.4 mmol) was dissolved in THF (8 mL) and kept at 0° C. under argon. This solution was added dropwise to half of the LDA solution at −78° C. The reaction mixture was stirred at −78° C. for 15 min. Methyl iodide (0.58 mL, 8.8 mmol) was then added. The reaction mixture was warmed to 0° C. and stirred for 15 min. The reaction mixture was cooled to −78° C., then half of the LDA solution was added and stirred for 30 min. Methyl iodide (0.58 mL, 8.8 mmol) was then added. The reaction mixture was warmed to 0° C. for 5 min, then stirred at room temperature for 2 h. The mixture was then diluted with diethyl ether and acidified with 1N HCl. The crude product was extracted with diethyl ether (3×30 mL). The combined organic layers were washed with saturated NaHCO3, followed by brine and dried over Na2SO4. The solvent was removed under reduced pressure and the crude product was purified by silica gel column chromatography (n-hexane / EtOAc=4 / 1) to give an inseparable mixture of 62 and 63 (total 0.465 g). 64 was prepared as reported in the literature with modifications and isolated as an oil after purification by flash column chromatography (WO2010039789A1 by Stamford, et al.). A mixture of 62 and 63 (0.387 g) was added dropwise to a suspension of LiAlH4 (0.091 g, 2.4 mmol) in THF (20 mL) at 0° C. The reaction was allowed to warm to room temperature and stirred for 4 h. The reaction mixture was cooled to 0° C., then water, NaOH (1N) and water were added sequentially. It was stirred at room temperature for 15 min. MgSO4 was added. The solid was filtered off and rinsed with EtOAc.The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (n-hexane / EtOAc=4 / 1) to give 64 as a colorless oil (0.25 g, 26% yield for two steps). 65 (CAS: 156042-33-0) was reported in the literature. 32Prepared from 64 (0.415 g, 1.9 mmol) according to and isolated as an oil after purification by flash column chromatography (0.257 g, 78% yield) (n-hexane / EtOAc = 4 / 1). To a solution of 65 (0.25 g, 1.5 mmol) in anhydrous CHCl (30 mL) were added p-nitrophenyl chloroformate (0.89 g, 4.4 mmol) and triethylamine (0.6 mL, 4.4 mmol) successively. After stirring at room temperature for 12 h, the crude mixture was diluted with another portion of CHCl (50 mL) and then washed with brine and water. The CHCl layer was dried over anhydrous NaSO and then concentrated. The crude product 66 was used in the next step without further purification. To a stirred solution of crude product 66 (1.5 mmol) in anhydrous CHCl (8 mL) was added 1-amino-3-butyne hydrochloride (0.186 g, 1.7 mmol) and EtN (0.63 mL, 4.4 mmol). The reaction mixture was stirred for 12 h. The crude mixture was diluted with CHCl (50 mL) and then washed with 1 M KCO, followed by brine, dried over anhydrous NaSO, and then concentrated. The crude product was purified by silica gel column chromatography to give 67 as a colorless oil (0.179 g, 46% yield over two steps). Following the procedure for the synthesis of compound 29 described above, compound alk-L-37 was obtained as an oil (0.0576 g, 21% yield over three steps) from compound 26 (0.800 g, 3.99 mmol) and 67 (0.179 g, 0.67 mmol) (EtOAc / n-hexane=1:3). Compound alk-L-37 appeared as a mixture of diastereomers (dr). Following the procedure for the synthesis of compound 30a and compound QA above, compound alk-L-37 (0.0501 g, 0.12 mmol) and 72 (0.017 g, 0.067 mmol) gave compound alk-L-48 as an oil (0.0389 g, 74% yield over three steps). Compound alk-L-48 appeared as a mixture of diastereomers (dr). Following the procedure for the synthesis of compound 30b above, compound alk-L-37 (0.0501 g, 0.12 mmol) and 68 (0.026 g, 0.054 mmol) gave compound alk-L-37b as an oil (0.0197 g, 39% yield over two steps) (3% EtOH / DCM).Compound alk-L-37b appeared as a mixture of diastereomers (dr).

[0411] Compound characterization Routine NMR spectra were recorded in CDCl3 at ambient temperature on a Bruker Avance DPX 300 Fourier transform spectrometer, a Bruker Avance DRX 400 Fourier transform spectrometer or an AVIII 600 spectrometer at ambient temperature or at the temperature stated on the spectrometer. 1 H NMR spectra were recorded at 400, 500, or 600 MHz, respectively. 13 C NMR spectra were recorded at 100, 125, or 150 MHz, respectively. Chemical shifts are reported in ppm on the δ scale relative to the internal standard tetramethylsilane (δ 0.00) or residual solvent.

[0412]

number

[0413] Two-dimensional NMR spectra were recorded on a Bruker Avance DRX 500 Fourier transform spectrometer at room temperature or at the temperature indicated on the spectrometer. The following abbreviations were used in the reported spectra: brs (broad singlet), s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), dd (doublet of doublets). High-resolution mass spectra were acquired on a Bruker maxis II high-resolution QTOF using ESI mode. All LCMS analyses were performed using an AQUITY UPLC@BEH C 18 The analysis was performed using a Waters SQ detector V4.1 SCN 805 equipped with a column (17 μm) with water (containing 0.1% TFA) and acetonitrile at a flow rate of 0.3 mL / min.

[0414] Methyl 2-(1,4-dioxaspiro[4.5]decan-8-ylidene)acetate (2):

[0415]

number

[0416] Methyl 2-(1,4-dioxaspiro[4.5]decan-8-yl)acetate (3):

[0417]

number

[0418] 2-((1r,3r,5r,7r)-dispiro[adamantane-2,3'-[1,2,4,5]tetraoxane-6',1"-cyclohexan]-4"-yl)acetic acid (6):

[0419]

number

[0420] (3-(bromo-15-azanyl)propyl)triphenylphosphonium bromide (68):

[0421]

number

[0422] (3-(2-((1r,3r,5r,7r)-dispiro[adamantane-2,3'-[1,2,4,5]tetraoxane-6',1"cyclohexane]-4"-yl)acetamido)propyl)triphenylphosphonium bromide (6b):

[0423]

number

[0424] N-(3-(dimethylamino)propyl)-2-((1r,3r,5r,7r)-dispiro[adamantane-2,3'-[1,2,4,5]tetraoxane-6',1"-cyclohexan]-4"-yl)acetamide (6a):

[0425]

number

[0426] Methyl 3-(tetradecylamino)propanoate (8):

[0427]

number

[0428] Methyl 3-(2-((1r,3r,5r,7r)-dispiro[adamantane-2,3'-[1,2,4,5]tetraoxane-6',1"-cyclohexane]-4"-yl)-N-tetradecylacetamido)propanoate (9):

[0429]

number

[0430] 3-(2-((1r,3r,5r,7r)-dispiro[adamantane-2,3'-[1,2,4,5]tetraoxane-6',1"-cyclohexane]-4"-yl)-N-tetradecylacetamido)propanoic acid (10):

[0431]

number

[0432] Chloromethyl(4-nitrophenyl)carbonate (69):

[0433]

number

[0434] (((4-nitrophenoxy)carbonyl)oxy)methyl acetate (71):

[0435]

number

[0436] (5-nitro-1,3-phenylene)dimethanol (12):

[0437]

number

[0438] 1,3-Bis(bromomethyl)-5-nitrobenzene (13):

[0439]

number

[0440] 2,2'-(5-nitro-1,3-phenylene)diacetonitrile (14):

[0441]

number

[0442] (((((5-nitro-1,3-phenylene)bis(ethane-2,1-diyl))bis(azanediyl))bis(carbonyl))bis(oxy))bis(methylene)diacetate (16):

[0443]

number

[0444] (((((5-amino-1,3-phenylene)bis(ethane-2,1-diyl))bis(azanediyl))bis(carbonyl))bis(oxy))bis(methylene)diacetate (17):

[0445]

number

[0446] ((((5-(2-((1r,3r)-dispiro[adamantane-2,3'-[1,2,4,5]tetraoxane-6',1"-cyclohexane]-4"-yl)acetamido)-1,3-phenylene)bis(ethane-2,1-diyl))bis(azanediyl))bis(carbonyl))bis(oxy))bis(methylene)diacetate (18):

[0447]

number

[0448] (2R,3R,4S,5R,6S)-2-(acetoxymethyl)-6-(((4-nitrophenoxy)carbonyl)oxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate (23):

[0449]

number

[0450] (2R,3R,4S,5R,6S)-2-(acetoxymethyl)-6-(((3-(2-((1r,3r,5r,7r)-dispiro[adamantane-2,3'-[1,2,4,5]tetraoxane-6',1"-cyclohexane]-4"-yl)acetamido)propyl)carbamoyl)oxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate (24b).

[0451]

number

[0452] (2R,3R,4S,5R,6R)-2-(acetoxymethyl)-6-(((3-(2-((1r,3r,5r,7r)-dispiro[adamantane-2,3'-[1,2,4,5]tetraoxane-6',1"-cyclohexane]-4"-yl)acetamido)propyl)carbamoyl)oxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate (24a).

[0453]

number

[0454] 1,4-Dioxaspiro[4.5]decan-8-ol (25):

[0455]

number

[0456] 1,4-Dioxaspiro[4.5]decan-8-yl acetate (26):

[0457]

number

[0458] (1r,3r,5r,7r)-Dispiro[adamantan-2,3'-[1,2,4,5]tetraoxan-6',1"-cyclohexan]-4"-ol (29):

[0459]

number

[0460] (3-(((((1r,3r,5r,7r)-dispiro[adamantane-2,3'-[1,2,4,5]tetraoxane-6',1"-cyclohexane]-4"-yl)oxy)carbonyl)amino)propyl)triphenylphosphonium bromide (30b):

[0461]

number

[0462] (1r,3r,5r,7r)-Dispiro[adamantane-2,3'-[1,2,4,5]tetraoxane-6',1"-cyclohexan]-4"-yl(3-(dimethylamino)propyl)carbamate (30a):

[0463]

number

[0464] 3-((1r,3r,5r,7r)-6'-methylspiro[adamantane-2,3'-[1,2,4,5]tetraoxan]-6'-yl)propanoic acid (35):

[0465]

number

[0466] N-(3-(dimethylamino)propyl)-3-((1r,3r,5r,7r)-6'-methylspiro[adamantane-2,3'-[1,2,4,5]tetraoxane]-6'-yl)propenamide (35a):

[0467]

number

[0468] 12-(tert-butyl)-7,8,15,16-tetraoxadispiro[5.2.59.26]hexadecan-3-ol (37):

[0469]

number

[0470] 12-(tert-butyl)-7,8,15,16-tetraoxadispiro[5.2.59.26]hexadecan-3-yl(4-nitrophenyl)carbonate (37c):

[0471]

number

[0472] 12-(tert-butyl)-7,8,15,16-tetraoxadispiro[5.2.59.26]hexadecan-3-yl(3-(dimethylamino)propyl)carbamate (37a):

[0473]

number

[0474] (3-((((12-(tert-butyl)-7,8,15,16-tetraoxadispiro[5.2.59.26]hexadecan-3-yl)oxy)carbonyl)amino)propyl)triphenylphosphonium bromide (37b):

[0475]

number

[0476] N1,N1-dibenzylpropane-1,3-diamine (72):

[0477]

number

[0478] 12-(tert-butyl)-7,8,15,16-tetraoxadispiro[5.2.59.26]hexadecan-3-yl(3-(dibenzylamino)propyl)carbamate (37d):

[0479]

number

[0480] N1-benzyl-N1-methylpropane-1,3-diamine (73):

[0481]

number

[0482] 12-(tert-butyl)-7,8,15,16-tetraoxadispiro[5.2.59.26]hexadecan-3-yl(3-(benzyl(methyl)amino)propyl)carbamate (37e):

[0483]

number

[0484] 12-(tert-butyl)-7,8,15,16-tetraoxadispiro[5.2.59.26]hexadecan-3-ylpiperazine-1-carboxylate (37f):

[0485]

number

[0486] 3-(2,4-Dimethyl-3,6-dioxocyclohexa-1,4-dien-1-yl)-3-methylbutanoic acid (43):

[0487]

number

[0488] 12-(tert-butyl)-7,8,15,16-tetraoxadispiro[5.2.59.26]hexadecan-3-yl 4-(3-(2,4-dimethyl-3,6-dioxocyclohexa-1,4-dien-1-yl)-3-methylbutanoyl)piperazine-1-carboxylate (37g):

[0489]

number

[0490] 4-(Dibenzylamino)butan-1-ol (44):

[0491]

number

[0492] (2R,3R,4S,5R,6R)-2-(acetoxymethyl)-6-(4-aminobutoxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate (46):

[0493]

number

[0494] (2R,3R,4S,5R,6R)-2-(acetoxymethyl)-6-(4-((((12-(tert-butyl)-7,8,15,16-tetraoxadispiro[5.2.59.26]hexadecan-3-yl)oxy)carbonyl)amino)butoxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate (37h):

[0495]

number

[0496] 12-(tert-butyl)-7,8,15,16-tetraoxadispiro[5.2.59.26]hexadecan-3-yl(4-(((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)butyl)carbamate (37i).

[0497]

number

[0498] Bis(12-(tert-butyl)-7,8,15,16-tetraoxadispiro[5.2.59.26]hexadecan-3-yl)((ethane-1,2-diylbis(oxy))bis(ethane-2,1-diyl))dicarbamate (37j):

[0499]

number

[0500] Bis(12-(tert-butyl)-7,8,15,16-tetraoxadispiro[5.2.59.26]hexadecan-3-yl)methyl phosphate (37k):

[0501]

number

[0502] 2,2'-Disulfanediylbis(ethan-1-ol) (47):

[0503]

number

[0504] Bis(12-(tert-butyl)-7,8,15,16-tetraoxadispiro[5.2.59.26]hexadecan-3-yl)(disulfanediylbis(ethane-2,1-diyl))bis(carbonate) (37l):

[0505]

number

[0506] N,N-dibenzyl-3-((((12-(tert-butyl)-7,8,15,16-tetraoxadispiro[5.2.59.26]hexadecan-3-yl)oxy)carbonyl)amino)-N-methylpropan-1-aminium iodide (48):

[0507]

number

[0508] Tributyl(3-((((12-(tert-butyl)-7,8,15,16-tetraoxadispiro[5.2.59.26]hexadecan-3-yl)oxy)carbonyl)amino)propyl)phosphonium bromide (56):

[0509]

number

[0510] 4-(((((12-(tert-butyl)-7,8,15,16-tetraoxadispiro[5.2.59.26]hexadecan-3-yl)oxy)carbonyl)amino)methyl)-1-methylpyridin-1-ium iodide (50):

[0511]

number

[0512] 4-(((12-(tert-butyl)-7,8,15,16-tetraoxadispiro[5.2.59.26]hexadecan-3-yl)oxy)carbonyl)-1,1-dimethylpiperazin-1-ium iodide (51):

[0513]

number

[0514] 3-((((12-(tert-butyl)-7,8,15,16-tetraoxadispiro[5.2.59.26]hexadecan-3-yl)oxy)carbonyl)amino)-N,N,N-trimethylpropan-1-aminium iodide (49):

[0515]

number

[0516] N1,N1-dibutylpropane-1,3-diamine (52):

[0517]

number

[0518] N-Butyl-N-(3-((((12-(tert-butyl)-7,8,15,16-tetraoxadispiro[5.2.59.26]hexadecan-3-yl)oxy)carbonyl)amino)propyl)-N-methylbutan-1-aminium iodide (53):

[0519]

number

[0520] N-benzyl-3-((((12-(tert-butyl)-7,8,15,16-tetraoxadispiro[5.2.59.26]hexadecan-3-yl)oxy)carbonyl)amino)-N,N-dimethylpropan-1-aminium iodide (54):

[0521]

number

[0522] N,N,N-tribenzyl-3-((((12-(tert-butyl)-7,8,15,16-tetraoxadispiro[5.2.59.26]hexadecan-3-yl)oxy)carbonyl)amino)propan-1-aminium iodide (57):

[0523]

number

[0524] 7,8,15,16-Tetraoxadispiro[5.2.59.26]hexadecan-3-ol (59):

[0525]

number

[0526] 3-((((7,8,15,16-tetraoxadispiro[5.2.59.26]hexadecan-3-yl)oxy)carbonyl)amino)-N,N-dibenzyl-N-methylpropan-1-aminium iodide (59a):

[0527]

number

[0528] (3-((((7,8,15,16-tetraoxadispiro[5.2.59.26]hexadecan-3-yl)oxy)carbonyl)amino)propyl)triphenylphosphonium bromide (59b):

[0529]

number

[0530] Deferasirox (61):

[0531]

number

[0532] N1,N1-Dibenzyl-N3-(but-3-yn-1-yl)propane-1,3-diamine (alk-72):

[0533]

number

[0534] N,N-dibenzyl-3-(but-3-yn-1-yl(((12-(tert-butyl)-7,8,15,16-tetraoxadispiro[5.2.59.26]hexadecan-3-yl)oxy)carbonyl)amino)-N-methylpropan-1-aminium iodide (alk-R-48):

[0535]

number

[0536] (3-(but-3-yn-1-ylamino)propyl)triphenylphosphonium bromide (alk-68):

[0537]

number

[0538] (3-(but-3-yn-1-yl(((12-(tert-butyl)-7,8,15,16-tetraoxadispiro[5.2.59.26]hexadecan-3-yl)oxy)carbonyl)amino)propyl)triphenylphosphonium bromide (alk-R-37b):

[0539]

number

[0540] 2-Methyl-2-(1,4-dioxaspiro[4.5]decan-8-yl)propan-1-ol (64):

[0541]

number

[0542] 4-(1-hydroxy-2-methylpropan-2-yl)cyclohexan-1-one (65):

[0543]

number

[0544] of 2-methyl-2-(4-oxocyclohexyl)propyl but-3-yn-1-yl carbamate (37):

[0545]

number

[0546] 2-(12-hydroxy-7,8,15,16-tetraoxadispiro[5.2.59.26]hexadecan-3-yl)-2-methylpropylbut-3-yn-1-ylcarbamate (alk-L-37):

[0547]

number

[0548] N,N-dibenzyl-3-((((12-(1-((but-3-yn-1-ylcarbamoyl)oxy)-2-methylpropan-2-yl)-7,8,15,16-tetraoxadispiro[5.2.59.26]hexadecan-3-yl)oxy)carbonyl)amino)-N-methylpropan-1-aminium iodide (alk-L-48):

[0549]

number

[0550] (3-((((12-(1-((but-3-yn-1-ylcarbamoyl)oxy)-2-methylpropan-2-yl)-7,8,15,16-tetraoxadispiro[5.2.59.26]hexadecan-3-yl)oxy)carbonyl)amino)propyl)triphenylphosphonium bromide (alk-L-37b):

[0551]

number

[0552] Methyl (E)-2-(1-(pyridin-2-yl)ethylidene)hydrazine-1-carbodithioate (74):

[0553]

number

[0554] N-(3-aminopropyl)-2-(1-(pyridin-2-yl)ethylidene)hydrazine-1-carbothioamide (75):

[0555]

number

[0556] N-(3-(((1r,3r,5r,7r)-dispiro[adamantane-2,3'-[1,2,4,5]tetraoxane-6',1"-cyclohexan]-4"-yl)amino)propyl)-2-(1-(pyridin-2-yl)ethylidene)hydrazine-1-carbothioamide (77).

[0557]

number

[0558] result These exemplary compounds demonstrate that the cytotoxicity of 1,2,4,5-tetraoxanes can be tuned by modifying the targeting group. 1,2,4,5-tetraoxanes with carbamate linkers show better activity than those with amide linkers. Furthermore, compounds with targeting groups provided better anticancer efficacy and selectivity. When the targeting group contains a phosphonium or quaternary ammonium moiety, the cytotoxicity and selectivity of the present invention are greatly improved. The biological characteristics of the exemplary compounds are shown in FIG. 1.

[0559] Generally, from the formula "cyclic ring + 1,2,4,5-tetraoxane + targeting group", the cyclic ring provides lipid solubility for cell permeability, and the targeting group provides water solubility. The tert-butylcyclohexyl ring has been identified as the component that maintains lethality against cancer cells, and the phosphonium or quaternary ammonium group is the element in the targeting group that provides cytotoxicity and selectivity. EXAMPLES

[0560] Example 2. Compounds exhibit anti-cancer activity Materials and Methods The anti-cancer activity of the exemplary compounds listed in Example 1 was tested against human cervical Hela cells, breast cancer MDA-MB-231 cells, human hepatocyte HepG2 cells, human colorectal HCT116 cells, mammary ductal T47D cells, non-cancerous NIH3T3 cells, canine kidney MDCK cells, and mouse brain bEnd.3 cells, respectively.

[0561] result The viability test results of the compounds are summarized in Tables 1-12a. In general, the tetraoxane compounds show broad-spectrum anticancer activity against colon HCT116, breast MDA-MB-231 and MCF-7, ovarian HEYA8, leukemia HL-60, liver Huh7 and PLC, and bone U2OS cancer cells. Elastin, RSL3, and artesunate are known compounds. However, their performance in breast cancer MDA-MB-231 cells and non-cancerous NIH3T3 cells has not been reported so far. Some of the compounds that induced good selectivity between cancer and non-cancerous cell lines are summarized in Table 12b. Moreover, this is the first report showing that 1,2,4,5-tetraoxane derivatives selectively eradicate cancer cells by the ferroptosis pathway. The IC of compound 37b and compound 48 compared to known drugs, i.e., OZ277, OZ439, and RKA182. 50 The activity and selectivity of OZ422 and OZ439 (Vennerstrom et al.) are in the 1,2,4-trioxolane class, but showed poor activity against MDA-MB-231, HCT116, and HL-60 cells (general IC 50values ​​>10 μM).

[0562] Tetraoxanes 37b, 48, 37f, 53, 56 and alk-R-48 generally showed IC 50 They have an IC value of <4 μM. They are at least 10 times more cytotoxic to MDA-MB-231 cells than to non-cancerous NIH3T3 and MDCK. For example, compound 48 has an IC 50 = 29.0 ± 5.7 μM) than breast cancer MDA-MB-231 cells (IC 50 =2.4±0.7μM), colon HCT116 cells (IC 50 = 2.2 ± 0.3 μM), and leukemia HL-60 cells (IC 50 = 1.2 ± 0.9 μM) were 12-, 13-, and 24-fold more cytotoxic to non-cancer cells than to cancer cells, respectively. In contrast, eratin and RSL3 were more cytotoxic to non-cancer cells than to cancer cells, indicating their lack of selectivity.

[0563] Compounds reported in the literature, such as OZ422, OZ439, and FINO2, showed poor activity against MDA-MB-231 cells (generally IC 50 Compound 48 (IC value >10 μM against MDA-MB-231) 50 : 2.4 ± 0.7 μM) and compound 37b (IC 50 Compound 37b is 87 times more cytotoxic to breast cancer MDA-MB-231 cells than OZ277. Compound 48 (IC against HCT116) is 10 times and 64 times more cytotoxic to the same breast cancer cell line than the literature example OZ439, respectively. 50 : 2.2 ± 0.3 μM) and compound 37b (IC 50Compounds 48 and 37b are 44-fold and 113-fold more cytotoxic, respectively, against colon cancer HCT116 cells than OZ277. Compound 48 is at least 9-fold more cytotoxic against leukemia HL-60 cells than OZ439. FINO2 (Woerpel et al.), which belongs to the class of 1,2-dioxolanes, shows poor performance against TNBC MDA-MB-231 cells (IC 50 >10 μM). Compounds 48 and 37b are at least 4-fold and 25-fold more potent than FINO2 in eradicating MDA-MB-231 cells. FINO2 has been reported to induce ferroptosis, oxidize iron, and indirectly target GPX4. The compounds disclosed herein can induce ferroptosis and oxidize iron without a protein target. In addition, the compounds disclosed herein have IC 50 <2 μM can kill CSCs.

[0564] RKA182 (a compound reported in the literature) shows lower activity against HL-60 cells (IC 50 = 11.6 ± 0.4 μM) is a second example of a 1,2,4,5-tetraoxane. Compared to the 1,2,4,5-tetraoxane RKA182, compound 48 is 9 times more potent than RKA182 in leukemia HL-60 cells. The maximum selectivity index of RKA182 is 4 (PMBC:IC 50 = 46.6 ± 0.7 μM vs. HL-60: IC 50 In contrast, compound 48 has a selectivity of 24-fold or less (NIH3T3:IC 50 = 29.0 ± 5.7 μM vs. HL-60: IC 50 = 1.2 ± 0.9 μM). Furthermore, RKA182 was not effective enough to kill cervical cancer HeLa cells, liver cancer HepG2 cells, and kidney cancer HEK293 cells, and had an overall IC 50 In contrast, exemplary compounds have overall IC 50values ​​<3 μM. In particular, compound 37b is 36 times more cytotoxic than RKA182 for HepG2 cells. Furthermore, RKA182 has been reported to induce apoptosis but not ferroptosis in cancer. A second generation RKA182 has been published by O'Neill's group for malaria treatment, but its anticancer activity has not been reported. Tetraoxane E209 is another example that targets malaria. However, no anticancer activity has been reported.

[0565] [Table 1]

[0566] [Table 2]

[0567] [Table 3]

[0568] [Table 4]

[0569] [Table 5]

[0570] [Table 6]

[0571] [Table 7]

[0572] [Table 8]

[0573] [Table 9]

[0574] [Table 10]

[0575] [Table 11]

[0576] [Table 12a]

[0577] [Table 12b]

[0578] [Table 13] EXAMPLES

[0579] Example 3. Compounds exhibit anti-cancer stem cell effects Materials and Methods The cytotoxicity of 1,2,4,5-tetraoxanes 48 and 37b against a cancer stem cell (CSC) model of HEY A8 CSCs and mouse xenograft ovarian tumors was examined (Figure 2). Nude mice were cultured with HEYA8 CSC cells (10 6) were subcutaneously injected into the ovarian tissue and randomly assigned to one of six treatment groups (n=4): (i) DMSO, (ii) paclitaxel (PTX), 5 mg / kg, (iii) compound 37b, 5 mg / kg, (iv) compound 37b, 10 mg / kg, (v) compound 48, 5 mg / kg, and (vi) compound 48, 10 mg / kg. When tumor ulceration began to appear in control animals (DMSO) (day 25), all animals in the experiment were sacrificed and photographed. Taxol was used as a negative control because ovarian CSCs are known to be resistant to taxol.

[0580] result IC of compounds 48 and 37b against adherent cancer cells HEY A8 50 The values ​​were 2.3±0.7 μM and 1.4±0.07 μM, respectively (Table 14). Unlike taxol, both peroxide compounds were able to eradicate almost all CSC spheroids (i.e., more than 90%) at a concentration of 5 μM (Figures 3A and 3B). Notably, erastin at 5 μM and artesunate at 50 μM also showed no cytotoxic effect on HEYA8 CSCs. This is the first report to demonstrate that 1,2,4,5-tetraoxane derivatives can arrest cancer stem cells at the micromolar scale (e.g., tetraoxane 48:IC against HEYA8 CSCs). 50 = 1.2 ± 0.5 μM). The 1,2,4,5-tetraoxane derivatives simultaneously eliminate both cancer and CSCs with the same small molecule.

[0581] [Table 14]

[0582] Pretreatment of adherent HEY A8 cells with iron chelators DFO or ferrostatin-1 (Fer-1) reversed the cell death induced by compound 48 but not by taxol (Figure 4). The lipophilic iron chelator deferasirox (DFX) could rescue part of the cell death in compound 48-treated HEYA8 CSCs, but the majority of CSCs remained unaffected by co-treatment with compound 48 and Fer-1 (Figures 5A and 5B). It indicates that compound 48 exerted cytotoxicity on both cancer and CSCs by ferroptosis. Compound 37b also induced ferroptosis but not apoptosis in HEYA8 CSCs. Conversely, known drugs such as cholic acid, deoxycholic acid, and steroid derivatives of 1,2,4,5-tetraoxane have been reported to exhibit anticancer effects. The cholic acid group has several protected polar groups that help to improve the bioavailability of the compounds. However, as shown, cholic acid derivatives of tetraoxanes induce apoptosis in cancer. In contrast, the compounds disclosed herein generate hydroxyl radicals and lipid peroxides in cancer cells, inducing ferroptosis. The compounds disclosed herein are structurally distinct from cholic acid, deoxycholic acid, and steroid derivatives of 1,2,4,5-tetraoxane in that the compounds herein contain a charged targeting group, such as a phosphonium moiety or a quaternary ammonium moiety, for water solubility, and do not contain two to three protected polar groups.

[0583] Elastin and RSL3 are selective agents against tumor cells with oncogenic RAS. However, their lethality against CSCs has not been thoroughly studied. Although both erastin and RSL3 could eliminate most of the adherent HEYA8 cells at 5 μM, high concentrations of artesunate were required to achieve nearly 50% cell death (Figure 6). In contrast, HEYA8 CSCs were almost insensitive to erastin and artesunate at a single dose, except for RSL3 (Figure 6). GPX4 inhibition appears to be effective in suppressing the growth of CSCs. However, when considering the cytotoxicity of RSL3 against NIH3T3 cells (IC 50 = 28.3 ± 8.6 nM), there is no advantage to using RSL3 as an anti-CSC agent due to the loss of selectivity. 50 Not only eradicated HEYA8 cancer cells by <3 μM, but also by IC 50 <2 μM also eliminates CSCs. Notably, compound 48 is at least 24-fold more cytotoxic to HEYA8 CSCs than to non-cancerous cells. The disclosed compounds perform better than erastin, RSL3, taxol and artesunate in terms of both lethality and selectivity towards CSCs.

[0584] The compounds were then evaluated for their antitumor potential using mouse xenograft ovarian tumors. Treatment with compound 37b (5 mg / kg and 10 mg / kg) alone was effective in inhibiting tumor growth compared to vehicle control (Figures 7A and 7B). Compound 48 (10 mg / kg) reduced tumor size. In general, the compound 37b and 48 regimen was well tolerated by the test animals. No abnormal behavior or weight loss was observed during the entire treatment period (Figure 7C). In vivo experiments successfully demonstrated the use of tetraoxane compounds as anticancer agents and ensured a safety profile.

[0585] The antitumor ability of the compounds was also evaluated using mouse xenograft breast tumors. Treatment with compound 37b (10 mg / kg) alone was effective in inhibiting tumor growth compared to vehicle control (Figures 12A and 12B). Compound 48 (5 mg / kg and 10 mg / kg) reduced tumor size. No abnormal behavior or weight loss was observed during the entire treatment period for both compounds 48 and 37c (Figure 12C). Histopathological observation of the liver, heart, kidney, spleen, and lungs in treated animals showed no histological changes compared to controls (Figure 12D). EXAMPLES

[0586] Example 4. Targeted delivery of 1,2,4,5-tetraoxane eradicated cancer cells by ferroptosis Materials and Methods Fer-1 was used to investigate the cell death pathway induced by the compounds described herein. Lipoxstatin-1 was used to further confirm whether 48 and 37b induce ferroptosis in MDA-MB-231 cells.

[0587] result The viability results show that Fer-1 reversed MDA-MB-231 cell death after treatment with a number of tetraoxanes, including 48 and 37b (Figures 8A-8C). Liproxstatin 1 was used to further confirm whether 48 and 37b induce ferroptosis in MDA-MB-231 cells. As illustrated in Figure 9, pretreatment of cells with this inhibitor prevented cell death caused by the two tetraoxanes.

[0588] Reactive oxygen species are associated with the event of ferroptosis cell death. The oxidative stress induced by 48 and 37b can be indicated by the fluorogenic probe HKOH-1r, which emits at 520 nm upon oxidation by cytoplasmic hydroxyl radicals. By using HKOH-1r, it is possible to identify the type of ROS that tetraoxane can generate in MDA-MB-231 cells.

[0589] Confocal images of MDA-MB-231 cells after tetraoxane treatment were captured and the relative mean fluorescence intensity of cells with HKOH-1r was quantified (Figure 10). The results show that significant amounts of hydroxyl radicals were observed approximately 5.5 hours after the addition of 48 and 37b, after which significant cell death occurred. This phenomenon is consistent with one of the hallmarks of ferroptosis.

[0590] Since lipid peroxidation is evidence for ferroptosis, the C11-BODIPY probe is used to verify lipid ROS generated by tetraoxane. It is a ratiometric membrane-targeted probe that changes emission from 590 nm to 510 nm upon detection of lipid ROS. Here, MDA-MB-231 cells were treated with 48, 37b and RSL3, respectively. Lipid ROS levels were quantified by flow cytometry. The untreated group showed a weak signal in the FL1 channel (Figure 11). This indicates that most of the system conjugated to C11-BODIPY did not react with lipid ROS and remained unchanged. For the RSL3-treated group, an enhancement of fluorescence in FL1 was observed. Similar to RSL3, lipid ROS was generated in 48 or 37b-treated cells.

[0591] Some cancer cells can escape the cytotoxicity of anticancer drugs by upregulating some anti-apoptotic proteins, which can develop resistance to apoptotic cell death. Conversely, ferroptosis is an iron-dependent and reactive oxygen species (ROS)-dependent cell death pathway. It is known that cancer cells have elevated iron levels, which favors ferroptosis, and is advantageous because it induces harmful lipid peroxidation and irreversible cell death, bypassing anti-apoptotic pathways. The data presented above demonstrate that the tetraoxane compounds described herein eradicate both cancer cells and CSCs by ferroptosis.

[0592] The tetraoxane compounds described herein generate ROS in cancer cells for therapeutic purposes. Unlike photodynamic therapy, these tetraoxane compounds do not rely on any external irradiation for ROS generation, thus eliminating the challenges associated with shallow laser penetration. In addition, the efficacy of the treatment is not affected by intracellular pH. For example, tetraoxane compounds generate hydroxyl radicals and lipid peroxides in breast cancer MDA-MB-231. This is advantageous because chemodynamic therapy (CDT) is known to be critically dependent on the acidity of the tumor microenvironment and high levels of intracellular hydrogen peroxide to generate hydroxyl radicals, a powerful oxidant. If the blood supply at the tumor site is abundant and the pH is neutral, CDT may not be effective. The H2O2 concentration in the cancer cells is not sufficient to generate lethal levels of hydroxyl radicals for therapeutic purposes.

[0593] Furthermore, the tetraoxane compounds described herein are small molecules that can be used for ferroptosis therapy, eliminating the need for complex nanoparticle formulations containing multiple components (e.g., enzymes that catalyze hydrogen peroxide production, iron oxide, etc.) to generate oxidative stress and eliminate cancer cells. [Industrial Applicability]

[0594] The present invention provides anti-cancer compounds useful for treating cancer, reducing cancer, or treating or ameliorating one or more symptoms associated with cancer, which may therefore be prepared into corresponding medicaments and have industrial applicability.

Claims

1. having the following structure: 【Chemistry 1】 or 【Chemistry 2】 (a) a is 1; (b) a′ is 1; (c) Z' is hydrogen; (d) X′ is O; (e) R ５ and R ８ are independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted alkynyl; ５ and R ８ together with the nitrogen to which they are attached form a substituted or unsubstituted piperazinyl; (f) R １０ teeth 【Chemistry 3】 and G′ is 【Chemistry 4】 where p is 0; R 11 is hydrogen or 【Chemistry 5】 R 12 and R 13 are independently hydrogen or alkynyl, e is 0 or 1, and d is 0; (g) the substituents are independently alkyl, 【Chemistry 6】 or 【Chemistry 7】 Amino represented by the formula: 【Chemistry 8】 or a glucose group represented by the formula: E does not exist, Compounds wherein, independent of E, Rx, Rxi, Rxii, Rvi, Rvii, and Rviii are each independently alkyl, aralkyl, or aryl.

2. R １２ is hydrogen, R １３ The compound of claim 1 , wherein is alkynyl.

3. R ５ is hydrogen, R ８ teeth, 【Chemistry 9】 where h and i are independently an integer from 0 to 3; R １５ ~R ２０ is independently hydrogen, alkyl, aryl, or arylalkyl.

4. A compound having the following structure: 【Chemistry 10】 【Chemistry 11】 【Chemistry 12】

5. having the following structure: 【Chemistry 13】 (a) A′ and A″ are independently substituted or unsubstituted cyclohexyl; (b) a and a″ are 1; (c) Z′ and Z″ are hydrogen; (d) X′ and X″ are O; (e) W′ and W″ are C; (f) Y′ and Y″ are independently NR ８ or O; (g) R ２２ and R' ２２ is, independently, 【Chemistry 14】 where j is an integer from 0 to 3; (h) R ８ is hydrogen; (i) L' is a disulfide or a polyether; (j) The compound, wherein the substituents are, independently, alkyl.

6. 6. The compound of claim 5 having the structure: 【Chemistry 15】

7. A compound according to any one of claims 1 to 6; and a pharma- ceutically acceptable excipient; The pharmaceutical composition, wherein the compound is in an amount effective to treat cancer, reduce cancer, or treat or ameliorate one or more symptoms associated with cancer in a subject.

8. The pharmaceutical composition of claim 7, further comprising a second active agent or a plurality of second active agents.

9. 9. The pharmaceutical composition of claim 8, wherein the second active agent is an anti-cancer agent.

10. 7. A compound according to any one of claims 1 to 6 for use in treating cancer, reducing cancer, or treating or ameliorating one or more symptoms associated with cancer in a subject in need thereof.

11. The compound of claim 10, wherein the subject is a mammal.

12. 12. The compound of claim 10 or 11, wherein the compound is administered orally, parenterally, by inhalation, mucosally, topically, or a combination thereof.

13. The compound according to any one of claims 10 to 12, wherein the cancer is colon cancer, breast cancer, ovarian cancer, cervical cancer, lung cancer, rectal cancer, kidney cancer, liver cancer, brain cancer, or leukemia, or a combination thereof.

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