Targeting redox-active pyridinium cations to mitochondria to inhibit proliferation of drug-resistant cancer cells
The present invention provides novel mito-pyridinium compounds, prodrugs and the uses thereof for the treatment of cancer, particularly drug resistant cancer.
1. A compound, which is of formula I or a prodrug thereof:
wherein
n is an integer selected from 1-18,
R 1 , R 2 , R 3 , R 4 and R 5 are independently selected from —H, —OCH 3 , —CH 3 , —CF 3 , —C(O)NH 2 , —CN, —C(O)CH 3 , and —NO 2 ,
provide that the compound is not and provided that, where R 2 is —C(O)NH 2 and R 1 , R 3 , R 4 and R 5 are —H, then n is an integer 0 selected from 5-18.
2. The compound of claim 1 , wherein n is an integer from 4-10, provided that, where R 2 is —C(O)NH 2 and R 1 , R 3 , R 4 and R 5 are —H, then n is an integer selected from 5-10.
3. The compound of claim 1 , wherein R 2 is —CH 3 , and R 1 , R 3 , R 4 and R 5 are —H.
4. The compound of claim 3 , wherein the compound is Mito-MeP-C 10
5. The compound of claim 1 , wherein R 2 is —C(O)NH 2 , R 1 , R 3 , R 4 and R 5 are —H, and n is an integer selected from 5-18.
6. The compound of claim 5 , wherein the compound is Mito-NA-C 10 .
7. The compound of claim 1 , wherein R 2 is —CN and R 1 , R 3 , R 4 and R 5 are —H.
8. The compound of claim 7 , wherein the compound is Mito-CNP-C 10
9. The compound of claim 1 , wherein R 2 is —NO 2 and R 1 , R 3 , R 4 and R 5 are —H.
10. The compound of claim 9 , wherein n is 4, 6, 8 or 10.
11. The compound of claim 10 , wherein the compound is Mito-NP-C 4 , Mito-NP-C 6 , Mito-NP-C 8 , or Mito-NP-C 10 :
12. The compound of claim 1 , wherein the compound is a prodrug.
13. The compound of claim 1 , wherein the compound is a prodrug of formula:
wherein R 1 , R 2 , R 3 , R 4 and R 5 , and n are as defined in claim 1 .
14. The compound of claim 12 , wherein the prodrug is:
15. A method of stimulating superoxide production within a cell, the method comprising:
contacting the cancer cell with the compound of claim 1 in an amount effective to inhibit cancer cell growth or proliferation.
16. The method of claim 15 , wherein the cell is a colon cancer cell or pancreatic cancer cell.
17. The method of claim 15 , wherein the cell is a drug-resistant cancer cell.
18. A method of inhibiting cancer cell growth or proliferation, the method comprising
contacting the cancer cell with the compound of claim 1 in an amount effective to inhibit cancer cell growth or proliferation.
19. The method of claim 18 , wherein the cancer cell is a cancer selected from the group consisting of colon cancer, rectum cancer, pancreas cancer, prostate cancer, lung and bronchus cancer, breast cancer, brain cancer, liver cancer, oral cancer, bladder cancer, stomach cancer, and leukemia.
20. The method of claim 19 , wherein the cancer is drug resistant cancer.
21. The method of claim 18 , wherein the cancer cell is in a subject and wherein the contacting comprises administering an effective amount of the compound to the subject.
22. The method of claim 21 , wherein the method further comprises:
administering radiation or chemotherapy in combination with the compound.
23. A method of treating cancer in a subject, the method comprising:
administering a therapeutically effective amount of the compound of claim 1 in order to treat the cancer.
24. The method of claim 23 , wherein the cancer is drug resistant cancer.
25. The method of claim 23 , wherein the cancer cell is a cancer selected from the group consisting of colon cancer, rectum cancer, pancreas cancer, prostate cancer, lung and bronchus cancer, breast cancer, brain cancer, liver cancer, oral cancer, bladder cancer, stomach cancer, and leukemia.
26. The method of claim 23 , wherein the method further comprises:
administering the subject cancer treatment selected from radiation, chemotherapy, immunotherapy and combinations thereof.
27. The compound of claim 1 , wherein R 2 is —C(O)NH 2 , R 1 , R 3 , R 4 and R 5 are —H, and n is an integer selected from 8-18.