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

1. A compound, having Formula (I):

wherein:

each R 0 , each R 1 , each R 2 , and each R 3 on each side of Formula (I) 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; or L 1 X n L 2 -; provided that at least one of the R 0 , R 1 , R 2 , or R 3 groups is L 1 X n L 2 -;

each L 1 is independently H, OH, NH 2 , halogen, —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, a hydoxylated group, a substituted hydroxylated group, substituted polyalkylene oxide, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkaryl, substituted alkaryl, aralkyl, or substituted aralkyl;

each X is independently a hydroxylated group, a substituted hydroxylated group, —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

each L 2 is independently 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;

optionally, at least one of R 0 , R 1 , R 2 , or R 3 on one side of Formula (I) may be attached by L or —L 1 X n L 2 - to at least one of R 0 , R 1 , R 2 , or R 3 on the other side of Formula (I);

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 , wherein each of R 0 , R 1 , R 2 , and R 3 is the same on each side of Formula (I), independently H, lower alkyl, (CH 2 ) v —OR y , OR y , NHR y , C(O)NHR y , wherein R y , is PEG or PPG; wherein PEG or PPG is —(O-alkylene or O-substituted alkylene) x -O—R z or -(alkylene-O or substituted alkylene-O) x —R z ; wherein R z is H or alkyl; v and x are independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.

3. The compound of claim 2 , wherein each R 0 , R 1 , R 2 , and R 3 are the same on each side of Formula (I).

4. The compound of claim 2 , wherein R 3 is OPEG; wherein x is 3; and R 0 , R 1 , and R 2 are H.

5. The compound of claim 2 , wherein R 1 is C(O)NHPEG; wherein x is 3; and R 0 , R 2 , and R 3 are H.

6. The compound of claim 2 , wherein R 1 is CH 2 —OPEG; wherein x is 3; and R 0 , R 2 , and R 3 are H.

7. The compound of claim 2 , wherein R 1 is CH 2 —OPEG; wherein x is 2; and R 0 , R 2 , and R 3 are H.

8. The compound of claim 2 , wherein R 1 is CH 2 —OPEG; wherein x is 1; and R 0 , R 2 , and R 3 are H.

9. The compound of claim 2 , wherein R 0 is CH 3 and R 3 is OPEG; wherein x is 1; and R 1 and R 2 are H.

10. The compound of claim 2 , wherein R 0 is CH 3 and R 3 is OPEG; wherein x is 2; and R 1 and R 2 are H.

11. The compound of claim 2 , wherein R 0 is CH 3 and R 3 is OPEG; wherein x is 3; and R 1 and R 2 are H.

12. A compound, having Formula (II):

wherein:

each R 0 , each R 1 , and each R 2 , on each side of Formula (II) 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; or L 1 X n L 2 -;

each L 1 is independently H, OH, halogen, alkyl, substituted alkyl, alkenyl, alkoxy, substituted alkoxy, alkylalkoxy, substituted alkylalkoxy, polyalkylene oxide, a hydoxylated group, a substituted hydroxylated group, substituted polyalkylene oxide, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkaryl, substituted alkaryl, aralkyl, or substituted aralkyl;

each X is independently a hydroxylated group, a substituted hydroxylated group, —O-(alkylene or substituted alkylene)-, —S-(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;

j is 0 or 1;

each L 2 is independently 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 a bond, alkylene, substituted alkylene, alkenylene, substituted alkenylene, alkynylene, substituted alkynylene, —O—, —O-(alkylene or substituted alkylene)-, -(alkylene or substituted alkylene)-O-(alkylene or substituted alkylene) m -, —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; m is an integral number selected from 1 to 20; and pharmaceutically acceptable salts.

13. The compound of claim 12 wherein j is 0; L is a bond; and R 0 , R 1 , and R 2 are H.

14. The compound of claim 12 wherein L is (CH 2 OCH 2 ) m , wherein m is an integral number from 0-4; j is 1, and R 0 , R 1 , and R 2 are H.

15. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable excipient.

16. A pharmaceutical composition comprising a compound of claim 12 and a pharmaceutically acceptable excipient.

17. 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 of Formula (I):

wherein:

each R 0 , each R 1 , each R 2 , and each R 3 on each side of Formula (I) 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; or L 1 X n L 2 -; provided that at least one of the R 0 , R 1 , R 2 , or R 3 groups is L 1 X n L 2 -;

each L 1 is independently H, OH, NH 2 , halogen, —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, a hydoxylated group, a substituted hydroxylated group, substituted polyalkylene oxide, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkaryl, substituted alkaryl, aralkyl, or substituted aralkyl;

each X is independently a hydroxylated group, a substituted hydroxylated group, —O-(alkylene or substituted alkylene)-, —S-(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

each L 2 is independently 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;

optionally, at least one of R 0 , R 1 , R 2 , or R 3 on one side of Formula (I) may be attached by L or —L 1 X n L 2 - to at least one of R 0 , R 1 , R 2 , or R 3 on the other side of Formula (I);

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 —C(O)N(R′)—, —CON(R′)-(alkylene or substituted alkylene)-, -(alkylene or substituted alkylene)-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, lung cancer, male breast cancer, pancreatic cancer, and prostate cancer.

18. The method of claim 17 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.

19. The method of claim 17 wherein the cancer is breast cancer.

20. The method of claim 17 wherein the cancer is lung cancer.

21. The method of claim 17 wherein the cancer is prostate cancer.

22. The method of claim 17 wherein the cancer is pancreatic cancer.