Water-soluble zinc ionophores, zinc chelators, and/or zinc complexes and use for treating cancer

1. A compound having the structure:

wherein:

each R 0 , each R 1 , and each R 2 , is independently H, OH, NH 2 , NO 2 , CN, halogen, lower alkyl, substituted lower alkyl, lower cycloalkyl, substituted lower cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkaryl, substituted alkaryl, aralkyl, substituted aralkyl, substituted amino, alkoxy, substituted alkoxy, —S-(alkyl or substituted alkyl), —S(O) k (alkyl or substituted alkyl), where k is 1, 2, or 3, —C(O)-(alkyl or substituted alkyl), —C(O)O-(alkyl or substituted alkyl), —OC(O)-(alkyl or substituted alkyl), —C(S)-(alkyl or substituted alkyl), —CON(R′)-(alkyl or substituted alkyl), —O—CON(R′)-(alkyl or substituted alkyl), —CSN(R′)-(alkyl or substituted alkyl), —N(R′)CO-(alkyl or substituted alkyl), —N(R′)C(O)O-(alkyl or substituted alkyl), —N(R′)C(O)N(R′)-(alkyl or substituted alkyl), where each R′ is independently H, alkyl, or substituted alkyl;

L 1 is —C(O)-(alkyl or substituted alkyl), —C(O)O-(alkyl or substituted alkyl), —OC(O)-(alkyl or substituted alkyl), —CON(R′)-(alkyl or substituted alkyl), alkyl, substituted alkyl, alkenyl, alkoxy, substituted alkoxy, alkylalkoxy, substituted alkylalkoxy, polyalkylene oxide, substituted polyalkylene oxide, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkaryl, substituted alkaryl, aralkyl, or substituted aralkyl;

X is —O-(alkylene or substituted alkylene)-, or —S(O) k (alkylene or substituted alkylene)-, where k is 1, 2, or 3;

each n is an integral number selected from 1 to 20; and

L 2 is selected from the group consisting of a direct bond, alkylene, substituted alkylene, alkenylene, substituted alkenylene, alkynylene, substituted alkynylene, —O—, —O-(alkylene or substituted alkylene)-, —S—, —S-(alkylene or substituted alkylene)-, —S(O) k — where k is 1, 2, or 3, —S(O) k (alkylene or substituted alkylene)-, —C(O)—, —C(O)-(alkylene or substituted alkylene)-, —C(S)—, —C(S)-(alkylene or substituted alkylene)-, —N(R′) 2 —, —NR′-(alkylene or substituted alkylene)-, —C(O)N(R′)—, —CON(R′)-(alkylene or substituted alkylene)-, —O—CON(R′)-(alkylene or substituted alkylene)-, —CSN(R′)—, —CSN(R′)-(alkylene or substituted alkylene)-, —N(R′)CO-(alkylene or substituted alkylene)-, —N(R′)C(O)O—, —N(R′)C(O)O-(alkylene or substituted alkylene)-, —S(O) k N(R′)—, —N(R′)C(O)N(R′)—, —N(R′)C(O)N(R′)-(alkylene or substituted alkylene)-, —N(R′)C(S)N(R′)—, —N(R′)S(O) k N(R′)—, and —C(R′) 2 —N(R′)—N(R′)—; where each R′ is independently H, alkyl, or substituted alkyl;

L is selected from the group consisting of alkylene, substituted alkylene, alkenylene, substituted alkenylene, alkynylene, substituted alkynylene, -O—, —O-(alkylene or substituted alkylene)-, -(alkylene or substituted alkylene)-O-(alkylene or substituted alkylene)-, —O-(alkylene or substituted alkylene)-O—, —S—, —S-(alkylene or substituted alkylene)-, -(alkylene or substituted alkylene)-S-(alkylene or substituted alkylene)-, —S(O) k — where k is 1, 2, or 3, —S(O) k (alkylene or substituted alkylene)-, -(alkylene or substituted alkylene)-S(O) k -(alkylene or substituted alkylene)-, -(alkylene or substituted alkylene)-S—S-(alkylene or substituted alkylene)-, -(alkylene or substituted alkylene)-O-(alkylene or substituted alkylene)-S—S-(alkylene or substituted alkylene)-O-(alkylene or substituted alkylene)-, —C(O)—, —C(O)-(alkylene or substituted alkylene)-, -(alkylene or substituted alkylene)-C(O)-(alkylene or substituted alkylene)-, —C(S)—, —C(S)-(alkylene or substituted alkylene)-, -(alkylene or substituted alkylene)-C(S)-(alkylene or substituted alkylene)-, —N(R′) 2 —, —NR′-(alkylene or substituted alkylene)-, -(alkylene or substituted alkylene)-NR′-(alkylene or substituted alkylene)-, —C(O)N(R′)—, —CON(R′)-(alkylene or substituted alkylene)-, -(alkylene or substituted alkylene)-CON(R′)-(alkylene or substituted alkylene)-, —O—CON(R′)-(alkylene or substituted alkylene)-, -(alkylene or substituted alkylene)-O—CON(R′)-(alkylene or substituted alkylene)-, —CSN(R′)—, —CSN(R′)-(alkylene or substituted alkylene)-, -(alkylene or substituted alkylene)-CSN(R′)-(alkylene or substituted alkylene)-, —N(R′)CO-(alkylene or substituted alkylene)-, -(alkylene or substituted alkylene)-N(R′)CO-(alkylene or substituted alkylene)-, —N(R′)C(O)O—, —N(R′)C(O)O-(alkylene or substituted alkylene)-, -(alkylene or substituted alkylene)-N(R)C(O)O-(alkylene or substituted alkylene)-, —S(O) k N(R′)—, —N(R′)C(O)N(R′)—, —N(R′)C(O)N(R′)-(alkylene or substituted alkylene)-, -(alkylene or substituted alkylene)-N(R′)C(O)N(R′)-(alkylene or substituted alkylene)-, —N(R′)C(S)N(R′)—, —N(R′)S(O) k N(R′)—, and —C(R′) 2 —N(R′)—N(R′)—; where each R′ is independently H, alkyl, or substituted alkyl; and pharmaceutically acceptable salts.

2. The compound of claim 1 having the structure

3. The compound of claim 2 wherein each R 0 , each R 1 , and each R 2 are independently hydrogen.

4. The compound of claim 2 wherein each R 1 and each R 2 are independently hydrogen and each R 0 are independently lower alkyl.

5. The compound of claim 2 wherein L is selected from the group consisting of —O—, —O-(alkylene or substituted alkylene)-, -(alkylene or substituted alkylene)-O-(alkylene or substituted alkylene)-, and —O-(alkylene or substituted alkylene)-O—.

6. The compound of claim 5 wherein L is —O—.

7. The compound of claim 5 wherein L is —O-(alkylene or substituted alkylene)-O—.

8. The compound of claim 7 wherein alkylene is CH 2 CH 2 .

9. The compound of claim 1 having the structure

10. The compound of claim 9 wherein each R 0 , each R 1 , and each R 2 are independently hydrogen.

11. The compound of claim 9 wherein each R 1 and each R 2 are independently hydrogen and each R 0 are independently lower alkyl.

12. The compound of claim 9 wherein L 1 is —CON(R′)-(alkyl or substituted alkyl), alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkylalkoxy, substituted alkylalkoxy, polyalkylene oxide, or substituted polyalkylene oxide.

13. The compound of claim 12 wherein L 1 is O—CH 2 CH 2 —.

14. The compound of claim 9 wherein X is —O-(alkylene or substituted alkylene)-.

15. The compound of claim 14 wherein alkylene is CH 2 CH 2 .

16. The compound of claim 15 wherein n is 1 to 5.

17. The compound of claim 16 wherein n is 1.

18. The compound of claim 15 wherein n is 2.

19. The compound of claim 16 wherein L 2 is a direct bond alkylene, substituted alkylene, —O—, or —C(O)N(R′)—.

20. A pharmaceutical composition comprising a compound having the structure:

wherein:

each R 0 , each R 1 , and each R 2 , is independently H, OH, NH 2 , NO 2 , CN, halogen, lower alkyl, substituted lower alkyl, lower cycloalkyl, substituted lower cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkaryl, substituted alkaryl, aralkyl, substituted aralkyl, substituted amino, alkoxy, substituted alkoxy, —S-(alkyl or substituted alkyl), —S(O) k (alkyl or substituted alkyl), where k is 1, 2, or 3, —C(O)-(alkyl or substituted alkyl), —C(O)O-(alkyl or substituted alkyl), —OC(O)-(alkyl or substituted alkyl), —C(S)-(alkyl or substituted alkyl), —CON(R′)-(alkyl or substituted alkyl), —O—CON(R′)-(alkyl or substituted alkyl), —CSN(R′)-(alkyl or substituted alkyl), —N(R′)CO-(alkyl or substituted alkyl), —N(R′)C(O)O-(alkyl or substituted alkyl), —N(R′)C(O)N(R′)-(alkyl or substituted alkyl), where each R′ is independently H, alkyl, or substituted alkyl;

L 1 is —C(O)-(alkyl or substituted alkyl), —C(O)O-(alkyl or substituted alkyl), —OC(O)-(alkyl or substituted alkyl), —CON(R′)-(alkyl or substituted alkyl), alkyl, substituted alkyl, alkenyl, alkoxy, substituted alkoxy, alkylalkoxy, substituted alkylalkoxy, polyalkylene oxide, substituted polyalkylene oxide, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkaryl, substituted alkaryl, aralkyl, or substituted aralkyl;

X is —O-(alkylene or substituted alkylene)-, or —S(O) k (alkylene or substituted alkylene)-, where k is 1, 2, or 3;

each n is an integral number selected from 1 to 20; and

L 2 is selected from the group consisting of a direct bond, alkylene, substituted alkylene, alkenylene, substituted alkenylene, alkynylene, substituted alkynylene, —O—, —O-(alkylene or substituted alkylene)-, —S—, —S-(alkylene or substituted alkylene)-, —S(O) k — where k is 1, 2, or 3, —S(O) k (alkylene or substituted alkylene)-, —C(O)—, —C(O)-(alkylene or substituted alkylene)-, —C(S)—, —C(S)-(alkylene or substituted alkylene)-, —NR′-(alkylene or substituted alkylene)-, —C(O)N(R′)—, —CON(R′)-(alkylene or substituted alkylene)-, —O—CON(R′)-(alkylene or substituted alkylene)-, —CSN(R′)—, —CSN(R′)-(alkylene or substituted alkylene)-, —N(R′)CO-(alkylene or substituted alkylene)-, —N(R′)C(O)O—, —N(R′)C(O)O-(alkylene or substituted alkylene)-, —S(O) k N(R′)—, —N(R′)C(O)N(R′)—, —N(R′)C(O)N(R′)-(alkylene or substituted alkylene)-, —N(R′)C(S)N(R′)—, —N(R′)S(O) k N(R′)—, and —C(R′) 2 —N(R′)—N(R′)—; where each R′ is independently H, alkyl, or substituted alkyl;

L is selected from the group consisting of alkylene, substituted alkylene, alkenylene, substituted alkenylene, alkynylene, substituted alkynylene, —O—, —O-(alkylene or substituted alkylene)-, -(alkylene or substituted alkylene)-O-(alkylene or substituted alkylene)-, —O-(alkylene or substituted alkylene)-O—, —S—, —S-(alkylene or substituted alkylene)-, -(alkylene or substituted alkylene)-S-(alkylene or substituted alkylene)-, —S(O) k — where k is 1, 2, or 3, —S(O) k (alkylene or substituted alkylene)-, -(alkylene or substituted alkylene)-S(O) k -(alkylene or substituted alkylene)-, -(alkylene or substituted alkylene)-S—S-(alkylene or substituted alkylene)-, -(alkylene or substituted alkylene)-O-(alkylene or substituted alkylene)-S—S-(alkylene or substituted alkylene)-O-(alkylene or substituted alkylene)-, —C(O)—, —C(O)-(alkylene or substituted alkylene)-, -(alkylene or substituted alkylene)-C(O)-(alkylene or substituted alkylene)-, —C(S)—, —C(S)-(alkylene or substituted alkylene)-, -(alkylene or substituted alkylene)-C(S)-(alkylene or substituted alkylene)-, —N(R′) 2 —, —NR′-(alkylene or substituted alkylene)-, -(alkylene or substituted alkylene)-NR′-(alkylene or substituted alkylene)-, —C(O)N(R′)—, —CON(R′)-(alkylene or substituted alkylene)-, -(alkylene or substituted alkylene)-CON(R′)-(alkylene or substituted alkylene)-, —O—CON(R′)-(alkylene or substituted alkylene)-, -(alkylene or substituted alkylene)-O—CON(R′)-(alkylene or substituted alkylene)-, —CSN(R′)—, —CSN(R′)-(alkylene or substituted alkylene)-, -(alkylene or substituted alkylene)-CSN(R′)-(alkylene or substituted alkylene)-, —N(R′)CO-(alkylene or substituted alkylene)-, -(alkylene or substituted alkylene)-N(R′)CO-(alkylene or substituted alkylene)-, —N(R′)C(O)O—, —N(R′)C(O)O-(alkylene or substituted alkylene)-, -(alkylene or substituted alkylene)-N(R′)C(O)O-(alkylene or substituted alkylene)-, —S(O) k N(R′)—, —N(R′)C(O)N(R′)—, —N(R′)C(O)N(R′)-(alkylene or substituted alkylene)-, -(alkylene or substituted alkylene)-N(R′)C(O)N(R′)-(alkylene or substituted alkylene)-, —N(R′)C(S)N(R′)—, —N(R′)S(O) k N(R′)—, and —C(R′) 2 —N(R′)—N(R′)—; where each R′ is independently H, alkyl, or substituted alkyl; and pharmaceutically acceptable salts and a pharmaceutically acceptable excipient thereof.

21. A method of treating cancer comprising administering to a patient in need thereof a therapeutically effective amount of at least one compound having the structure

wherein:

each R 0 , each R 1 , and each R 2 , is independently H, OH, NH 2 , NO 2 , CN, halogen, lower alkyl, substituted lower alkyl, lower cycloalkyl, substituted lower cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkaryl, substituted alkaryl, aralkyl, substituted aralkyl, substituted amino, alkoxy, substituted alkoxy, —S-(alkyl or substituted alkyl), —S(O) k (alkyl or substituted alkyl), where k is 1, 2, or 3, —C(O)-(alkyl or substituted alkyl), —C(O)O-(alkyl or substituted alkyl), —OC(O)-(alkyl or substituted alkyl), —C(S)-(alkyl or substituted alkyl), —CON(R′)-(alkyl or substituted alkyl), —O—CON(R′)-(alkyl or substituted alkyl), —CSN(R′)-(alkyl or substituted alkyl), —N(R′)CO-(alkyl or substituted alkyl), —N(R′)C(O)O-(alkyl or substituted alkyl), —N(R′)C(O)N(R′)-(alkyl or substituted alkyl), where each R′ is independently H, alkyl, or substituted alkyl;

L 1 is —C(O)-(alkyl or substituted alkyl), —C(O)O-(alkyl or substituted alkyl), —OC(O)-(alkyl or substituted alkyl), —CON(R′)-(alkyl or substituted alkyl), alkyl, substituted alkyl, alkenyl, alkoxy, substituted alkoxy, alkylalkoxy, substituted alkylalkoxy, polyalkylene oxide, substituted polyalkylene oxide, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkaryl, substituted alkaryl, aralkyl, or substituted aralkyl;

X is —O-(alkylene or substituted alkylene)-, or —S(O) k (alkylene or substituted alkylene)-, where k is 1, 2, or 3;

each n is an integral number selected from 1 to 20; and

L 2 is selected from the group consisting of a direct bond, alkylene, substituted alkylene, alkenylene, substituted alkenylene, alkynylene, substituted alkynylene, —O—, —O-(alkylene or substituted alkylene)-, —S—, —S-(alkylene or substituted alkylene)-, —S(O) k — where k is 1, 2, or 3, —S(O) k (alkylene or substituted alkylene)-, —C(O)—, —C(O)-(alkylene or substituted alkylene)-, —C(S)—, —C(S)-(alkylene or substituted alkylene)-, —N(R′) 2 —, —NR′-(alkylene or substituted alkylene)-, —C(O)N(R′)—, —CON(R′)-(alkylene or substituted alkylene)-, —O—CON(R′)-(alkylene or substituted alkylene)-, —CSN(R′)—, —CSN(R′)-(alkylene or substituted alkylene)-, —N(R′)CO-(alkylene or substituted alkylene)-, —N(R′)C(O)O—, —N(R′)C(O)O-(alkylene or substituted alkylene)-, —S(O) k N(R′)—, —N(R′)C(O)N(R′)—, —N(R′)C(O)N(R′)-(alkylene or substituted alkylene)-, —N(R′)C(S)N(R′)—, —N(R′)S(O) k N(R′)—, and —C(R′) 2 —N(R′)—N(R′)—; where each R′ is independently H, alkyl, or substituted alkyl;

L is selected from the group consisting of alkylene, substituted alkylene, alkenylene, substituted alkenylene, alkynylene, substituted alkynylene, —O—, —O-(alkylene or substituted alkylene)-, -(alkylene or substituted alkylene)-O-(alkylene or substituted alkylene)-, —O-(alkylene or substituted alkylene)-O—, —S—, —S-(alkylene or substituted alkylene)-, -(alkylene or substituted alkylene)-S-(alkylene or substituted alkylene)-, —S(O) k — where k is 1, 2, or 3, —S(O) k (alkylene or substituted alkylene)-, -(alkylene or substituted alkylene)-S(O) k -(alkylene or substituted alkylene)-, -(alkylene or substituted alkylene)-S—S-(alkylene or substituted alkylene)-, -(alkylene or substituted alkylene)-O-(alkylene or substituted alkylene)-S—S-(alkylene or substituted alkylene)-O-(alkylene or substituted alkylene)-, —C(O)—, —C(O)-(alkylene or substituted alkylene)-, -(alkylene or substituted alkylene)-C(O)-(alkylene or substituted alkylene)-, —C(S)—, —C(S)-(alkylene or substituted alkylene)-, -(alkylene or substituted alkylene)-C(S)-(alkylene or substituted alkylene)-, —N(R′) 2 —, —NR′-(alkylene or substituted alkylene)-, -(alkylene or substituted alkylene)-NR′-(alkylene or substituted alkylene)-, —C(O)N(R′)—, —CON(R′)-(alkylene or substituted alkylene)-, -(alkylene or substituted alkylene)-CON(R′)-(alkylene or substituted alkylene)-, —O—CON(R′)-(alkylene or substituted alkylene)-, -(alkylene or substituted alkylene)-O—CON(R′)-(alkylene or substituted alkylene)-, —CSN(R′)—, —CSN(R′)-(alkylene or substituted alkylene)-, -(alkylene or substituted alkylene)-CSN(R′)-(alkylene or substituted alkylene)-, —N(R′)CO-(alkylene or substituted alkylene)-, -(alkylene or substituted alkylene)-N(R′)CO-(alkylene or substituted alkylene)-, —N(R′)C(O)O—, —N(R′)C(O)O-(alkylene or substituted alkylene)-, -(alkylene or substituted alkylene)-N(R′)C(O)O-(alkylene or substituted alkylene)-, —S(O) k N(R′)—, —N(R′)C(O)N(R′)—, —N(R′)C(O)N(R′)-(alkylene or substituted alkylene)-, -(alkylene or substituted alkylene)-N(R′)C(O)N(R′)-(alkylene or substituted alkylene)-, —N(R′)C(S)N(R′)—, —N(R′)S(O) k N(R′)—, and —C(R′) 2 —N(R′)—N(R′)—; where each R′ is independently H, alkyl, or substituted alkyl; and pharmaceutically acceptable salts; wherein the cancer is selected from breast cancer, colon cancer, lung cancer, male breast cancer, pancreatic cancer, Non-Hodgkin's lymphoma, melanoma skin cancer, and prostate cancer.

22. The method of claim 21 further comprising the step of administering to a patient in need thereof a therapeutically effective amount of motexafin gadolinium or a pharmaceutically acceptable texaphyrin derivative.