Compositions and methods of diazeniumdiolate-based prodrugs for treating cancer
The present disclosure provides methods utilizing the diazeniumdiolate-based prodrugs for the treatment of cancer via various mechanisms and procedures. The disclosure also provides kits comprising the diazeniumdiolate-based prodrugs.
1. A method of treating breast cancer, said method comprising the step of administering a combination of a therapeutically effective amount of:
(i) a tumor-targeted drug and
(ii) a therapeutic agent selected from the group consisting of a cryptophycin, bortezomib, thiobortezomib, a tubulysin, aminopterin, rapamycin, paclitaxel, docetaxel, doxorubicin, daunorubicin, everolimus, α-amanatin, verucarin, didemnin B, geldanomycin, purvalanol A, everolimus, ispinesib, budesonide, dasatinib, an epothilone, a maytansine, and tamoxifen,
to a subject in need of such a treatment, wherein said tumor-targeted drug is a compound of the formula (I) or a pharmaceutically acceptable salt thereof:
wherein:
R 1 is selected from C 1-12 alkyl, C 3-12 alkenyl, C 3-12 alkynyl, C 3-8 cycloalkyl, and heterocyclyl, each of which is optionally substituted with one or more moieties selected from the group consisting of halo, OH, CN, hydroxy-C 1-12 alkyl, halo-C 1-12 alkyl, amino-C 1-12 alkyl, C 1-12 alkoxy, aryloxy, C 1-12 thioalkoxy, nitro, sulfonato, C 1-12 acyl, C 2-12 acyloxy, carboxyl, mercapto, C 1-12 alkoxy-carbonyl, C 1-12 alkoxy-carbonyloxy, amido, amino, C 1-12 alkylamino, and di-C 1-12 alkyl-amino;
R 2 and R 3 are the same or different and each is selected from hydrogen, C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 3-8 cycloalkyl, heterocyclyl, aryl, and heteroaryl, each of which, other than hydrogen, is optionally substituted with one or more moieties selected from the group consisting of halo, OH, CN, hydroxy-C 1-12 alkyl, halo-C 1-12 alkyl, amino-C 1-12 alkyl, C 1-12 alkoxy, aryloxy, C 1-12 thioalkoxy, nitro, sulfonato, C 1-12 acyl, C 2-12 acyloxy, carboxyl, mercapto, C 1-12 alkoxy-carbonyl, C 1-12 alkoxy-carbonyloxy, amido, amino, C 1-12 alkylamino, and di-C 1-12 alkyl-amino; and
R 4 is —C(═O)R 5 , wherein R 5 is selected from hydrogen, C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 3-8 cycloalkyl, heterocyclyl, aryl, and heteroaryl, each of which, other than hydrogen, is optionally substituted with one or more moieties selected from the group consisting of halo, OH, CN, hydroxy-C 1-12 alkyl, halo-C 1-12 alkyl, amino-C 1-12 alkyl, C 1-12 alkoxy, aryloxy, C 1-12 thioalkoxy, nitro, sulfonato, C 1-12 acyl, C 2-12 acyloxy, carboxyl, mercapto, C 1-12 alkoxy-carbonyl, C 1-12 alkoxy-carbonyloxy, amido, amino, C 1-12 alkylamino, and di-C 1-12 alkyl-amino;
wherein the compound of the formula (I) or pharmaceutically acceptable salt and the therapeutic agent are effective in treating cancer in the mammal.
2. The method of claim 1 , wherein the therapeutic agent is tamoxifen.
3. The method of claim 1 , wherein the breast cancer is an estrogen receptor negative (ER(−)) breast cancer.
4. The method of claim 1 , wherein R 1 is optionally substituted C 1-12 alkyl, optionally substituted C 3-12 alkenyl, or optionally substituted C 3-8 cycloalkyl.
5. The method of claim 1 , wherein R 2 and R 3 are the same or different and each is hydrogen, C 1-12 alkyl, aryl, or heteroaryl, each of which, other than hydrogen, is optionally substituted.
6. The method of claim 1 , wherein R 2 and R 3 are hydrogen.
7. The method of claim 1 , wherein R 1 is isopropyl.
8. The method of claim 1 , wherein R 4 is —C(═O)R 5 , wherein R 5 is selected from hydrogen, C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 3-8 cycloalkyl, heterocyclyl, aryl, and heteroaryl, each of which, other than hydrogen, is optionally substituted with one or more moieties selected from the group consisting of halo, OH, CN, hydroxy-C 1-12 alkyl, halo-C 1-12 alkyl, amino-C 1-12 alkyl, C 1-12 alkoxy, aryloxy, C 1-12 thioalkoxy, nitro, sulfonato, C 1-12 acyl, C 2-12 acyloxy, carboxyl, mercapto, C 1-12 alkoxy-carbonyl, C 1-12 alkoxy-carbonyloxy, amido, amino, C 1-12 alkylamino, and di-C 1-12 alkyl-amino.
9. The method of claim 1 , wherein R 5 is an optionally substituted C 1-12 alkyl.
10. The method of claim 1 , wherein the compound of formula (I) is
11. The method of claim 1 , wherein the tumor-targeted drug is selected from the group consisting of:
wherein:
L is a linking group selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, carbonyl, thiocarbonyl, iminocarbonyl, carboxyl, and carbamoyl;
R 1 is selected from C 1-12 alkyl, C 3-12 alkenyl, C 3-12 alkynyl, C 3-8 cycloalkyl, and heterocyclyl, each of which is optionally substituted with one or more moieties selected from the group consisting of halo, OH, CN, hydroxy-C 1-12 alkyl, halo-C 1-12 alkyl, amino-C 1-12 alkyl, C 1-12 alkoxy, aryloxy, C 1-12 thioalkoxy, nitro, sulfonato, C 1-12 acyl, C 2-12 acyloxy, carboxyl, mercapto, C 1-12 alkoxy-carbonyl, C 1-12 alkoxy-carbonyloxy, amido, amino, C 1-12 alkylamino, and di-C 1-12 alkyl-amino; and
R 2 and R 3 are the same or different and each is selected from hydrogen, C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 3-8 cycloalkyl, heterocyclyl, aryl, and heteroaryl, each of which, other than hydrogen, is optionally substituted with one or more moieties selected from the group consisting of halo, OH, CN, hydroxy-C 1-12 alkyl, halo-C 1-12 alkyl, amino-C 1-12 alkyl, C 1-12 alkoxy, aryloxy, C 1-12 thioalkoxy, nitro, sulfonato, C 1-12 acyl, C 2-12 acyloxy, carboxyl, mercapto, C 1-12 alkoxy-carbonyl, C 1-12 alkoxy-carbonyloxy, amido, amino, C 1-12 alkylamino, and di-C 1-12 alkyl-amino;
or a pharmaceutically acceptable salt thereof.
12. The method of claim 1 , wherein the tumor-targeted drug is selected from the group consisting of:
wherein:
L is a linking group selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, carbonyl, thiocarbonyl, iminocarbonyl, carboxyl, and carbamoyl;
R 1 is selected from C 1-12 alkyl, C 3-12 alkenyl, C 3-12 alkynyl, C 3-8 cycloalkyl, and heterocyclyl, each of which is optionally substituted with one or more moieties selected from the group consisting of halo, OH, CN, hydroxy-C 1-12 alkyl, halo-C 1-12 alkyl, amino-C 1-12 alkyl, C 1-12 alkoxy, aryloxy, C 1-12 thioalkoxy, nitro, sulfonato, C 1-12 acyl, C 2-12 acyloxy, carboxyl, mercapto, C 1-12 alkoxy-carbonyl, C 1-12 alkoxy-carbonyloxy, amido, amino, C 1-12 alkylamino, and di-C 1-12 alkyl-amino; and
R 2 and R 3 are the same or different and each is selected from hydrogen, C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 3-8 cycloalkyl, heterocyclyl, aryl, and heteroaryl, each of which, other than hydrogen, is optionally substituted with one or more moieties selected from the group consisting of halo, OH, CN, hydroxy-C 1-12 alkyl, halo-C 1-12 alkyl, amino-C 1-12 alkyl, C 1-12 alkoxy, aryloxy, C 1-12 thioalkoxy, nitro, sulfonato, C 1-12 acyl, C 2-12 acyloxy, carboxyl, mercapto, C 1-12 alkoxy-carbonyl, C 1-12 alkoxy-carbonyloxy, amido, amino, C 1-12 alkylamino, and di-C 1-12 alkyl-amino;
or a pharmaceutically acceptable salt thereof.
13. The method of claim 1 , wherein the tumor-targeted drug is selected from the group consisting of:
14. The method of claim 1 , wherein the tumor-targeted drug is of the formula:
or a salt thereof.