DNA alkylating agents

1. A method of treating cancer expressing AKR1C3 reductase, comprising:

administering to a patient in need thereof a therapeutically effective amount of a compound of formula I or a composition comprising the compound and at least a pharmaceutically acceptable excipient or carrier thereby treating the cancer

or a pharmaceutically acceptable salt, or a solvate of each thereof, wherein

X 10 is O, S, SO, or SO 2 ;

A is C 6 -C 10 aryl, 5-15 membered heteroaryl, or —N═CR 1 R 2 ;

each R 1 and R 2 independently is hydrogen, —CN, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4-15 membered heterocycle, 5-15 membered heteroaryl, ether, —CONR 13 R 14 , or —NR 13 COR 14 ;

each X and Z independently is hydrogen or C 1 -C 6 alkyl;

Y is hydrogen, halo, or C 1 -C 6 alkyl;

R is hydrogen or C 1 -C 6 alkyl;

each R 13 and R 14 independently is hydrogen, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4-15 membered heterocycle, 5-15 membered heteroaryl, or ether;

T is OP(Z 1 )(NHCH 2 CH 2 Cl) 2 , OP(Z 1 )(NHCH 2 CH 2 Br) 2 , OP(Z 1 )(NH 2 )(N(CH 2 CH 2 X 1 ) 2 ), OP(Z 1 )(N(CH 2 ) 2 ) 2 , or OP(Z 1 )(N(CH 2 CH 2 Cl) 2 ) 2 , wherein Z 1 is O or S, and X 1 is Cl, Br, or OMs; and

wherein the alkyl, cycloalkyl, aryl, heterocycle, heteroaryl, ether groups are optionally substituted, and wherein the cancer is selected from the group consisting of a cancer of the adrenal gland, bone, brain, breast, bronchi, colon and/or rectum, gallbladder, head and neck, kidneys, larynx, liver, lung, neural tissue, pancreas, prostate, parathyroid, skin, stomach, and thyroid; and acute and chronic lymphocytic and granulocytic tumors, adenocarcinoma, adenoma, basal cell carcinoma, cervical dysplasia and in situ carcinoma, Ewing's sarcoma, epidermoid carcinomas, giant cell tumor, glioblastoma multiforma, hairy-cell tumor, intestinal ganglioneuroma, hyperplastic corneal nerve tumor, islet cell carcinoma, Kaposi's sarcoma, leiomyoma, leukemias, lymphomas, malignant carcinoid, malignant melanomas, malignant hypercalcemia, marfanoid habitus tumor, medullary carcinoma, metastatic skin carcinoma, mucosal neuroma, myeloma, mycosis fungoides, neuroblastoma, osteo sarcoma, osteogenic and other sarcoma, ovarian tumor, pheochromocytoma, polycythermia vera, primary brain tumor, small-cell lung tumor, squamous cell carcinoma of both ulcerating and papillary type, hyperplasia, seminoma, soft tissue sarcoma, retinoblastoma, rhabdomyo sarcoma, renal cell tumor, topical skin lesion, veticulum cell sarcoma, and Wilm's tumor.

2. The method of claim 1 , further comprising

determining the AKR1C3 reductase level of the cancer in the patient using an AKR1C3 antibody prior to the administration.

3. The method of claim 1 , further comprising

isolating a sample from the patient, and

determining an intratumoral AKR1C3 reductase level of the cancer in the sample using an AKR1C3 antibody prior to the administration.

4. The method of claim 1 , wherein T is OP(O)(N(CH 2 CH 2 )) 2 , OP(O)(NHCH 2 CH 2 Cl) 2 , OP(O)(NHCH 2 CH 2 Br) 2 , or OP(O)(NH 2 )(N(CH 2 CH 2 Cl) 2 ).

5. The method of claim 1 , wherein A is optionally substituted C 6 -C 10 aryl.

6. The method of claim 1 , wherein A is optionally substituted phenyl.

7. The method of claim 1 , wherein A is optionally substituted 5-15 membered heteroaryl.

8. The method of claim 7 , wherein A is optionally substituted pyridyl.

9. The method of claim 1 , wherein A is —N═CR 1 R 2 where R 1 and R 2 are defined as in claim 1 .

10. The method of claim 1 , wherein R is methyl.

11. The method of claim 1 , wherein the compound is

12. The method of claim 1 , wherein the cancer is AKR1C3 reductase overexpressing cancer.

13. The method of claim 1 , wherein the cancer is liver cancer, non-small cell lung cancer, melanoma, renal cell carcinoma, or prostate cancer.

14. The method of claim 1 , wherein the patient is human.