Guanine analogs as telomerase substrates and telomere length affectors
This invention relates to compounds useful for inhibiting telomere elongation. More specifically, the invention provides nucleotide analogs that are incorporated into telomeres by telomerase thereby inhibiting elongation of telomeres. The compounds are use in treating cancer and other cell proliferative diseases.
1. A compound of Formula (VII):
wherein
R 2 is selected from —NR 1a R 1b and OR 1c ; wherein
R 1a and R 1b are independently selected from hydrogen, optionally substituted C 1-20 alkyl, optionally substituted polyamine, and —CH(R 1d )—C(O)OR 1e , wherein
R 1d is selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl; and
R 1e is hydrogen or C 1-6 alkyl;
R 1c is selected from hydrogen, alkyl, and aryl;
R 3a and R 3b are independently selected from hydrogen and halo;
W is O, S, or NH;
R 4a and R 4b are independently selected from hydrogen, —OH, —NH 2 , N 3 , —CH═CH 2 , and optionally substituted C 1-2 alkyl, wherein alkyl is substituted with —OH, —NH 2 , N 3 , or halogen;
R 5a and R 5b are independently selected from hydrogen, —OH, —NH 2 , N 3 , —CH═CH 2 , and optionally substituted C 1-2 alkyl, wherein alkyl is substituted with —OH, —NH 2 , N 3 , or halogen;
R 6a and R 6b are independently selected from hydrogen, —OH, —NH 2 , N 3 , —CH═CH 2 , and optionally substituted C 1-2 alkyl, wherein alkyl is substituted with —OH, —NH 2 , N 3 , or halogen;
R 7 is hydrogen or fluoro; and
X is O, S, or NH;
L 1 is an optionally substituted polyamine;
m is zero or one;
n is zero or one;
or a salt, hydrate, solvate, or a tautomer, thereof.
2. The compound of claim 1 , wherein L 1 is an unsubstituted polyamine.
3. The compound of claim 1 , wherein R2 is —NR 1a R 1b and R 2 is OR 1c .
4. The compound of claim 3 , wherein one of R 1a and R 1b is C 1-20 alkyl; and R 2 is OH.
5. The compound of claim 3 , wherein one of R 1a and R 1b is a polyamine; and R 2 is OH.
6. The compound of claim 3 , wherein one of R 1a and R 1b is —(CH 2 ) n NH(CH 2 ) n NHR x ; wherein R x is hydrogen or —(CH 2 ) n NH 2 ; and n is independently a number from 2 to 4.
7. The compound of claim 3 , wherein one of R 1a and R 1b is —(CH 2 ) n NHR x ; wherein R x is hydrogen or —(CH 2 ) n NH 2 ; and n is independently a number from 2 to 4.
8. The compound of claim 3 , wherein one of R 1a and R 1b is —CH(R 1d )—C(O)OR 1e , and R 2 is OH.
9. The compound of claim 8 , wherein R 1d is selected from hydrogen, alkyl, substituted alkyl, heteroaryl, and substituted heteroaryl.
10. The compound of claim 8 , wherein R 1d is a positively charged amino acid side chain.
11. The compound of claim 8 , wherein —CH(R 1d )—C(O)OR 1e is an amino acid selected from lysine, arginine, and histidine.
12. The compound of claim 1 , wherein R 1a and R 3b are hydrogen.
13. The compound of claim 1 , wherein one of R 1a and R 3b is halo.
14. The compound of claim 1 , wherein W is O.
15. The compound of claim 1 , wherein R 4a and R 4b are hydrogen.
16. The compound of claim 1 , wherein one of R 5a and R 5b is —OH.
17. The compound of claim 1 , wherein one of R 5a and R 5b is selected from —NH 2 and N 3 .
18. The compound of claim 1 , wherein one of R 5a and R 5b is —CH═CH 2 .
19. The compound of claim 1 , wherein one of R 5a and R 5b is C 1-2 alkyl.
20. The compound of claim 1 , wherein one of R 5a and R 5b is optionally substituted C 1-2 alkyl, wherein alkyl is substituted with —OH, —NH 2 , or N 3 .
21. The compound of claim 1 , wherein R 6a and R 6b are hydrogen.
22. The compound of claim 1 , wherein R 7 is hydrogen.
23. The compound of claim 1 , wherein R 7 is fluoro.
24. The compound of claim 1 , wherein X is O.
25. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable excipient.
26. A method for inhibiting telomere elongation comprising contacting a cell with the compound of claim 1 .
27. The method of claim 26 , wherein the cell is a cancer cell.
28. A method for shortening telomere length in a cell or tissue comprising contacting the cell or tissue with the compound of claim 1 .
29. A method of treating breast or pancreatic cancer in an individual by administering an effective amount of the compound of claim 1 .
30. The method of claim 29 , wherein the cancer is breast cancer.
31. The method of claim 30 , wherein the cancer is pancreatic cancer.
32. The method of claim 29 , wherein the compound or pharmaceutical composition is administered orally, intra-arterially, intranasally, intraperitoneally, intravenously, intramuscularly, subcutaneously, or transdermally.