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 (III):
wherein
R 1 and R 2 are independently 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;
wherein at least one of R 1 and R 2 is —NR 1a R 1b ;
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;
and salts, hydrates, solvates, and tautomers, thereof.
2. The compound of claim 1 , wherein:
R 1 is different from R 2 ; or
one of R 1 and R 2 carries a positive charge and the other carries a negative charge; or
R 1 is —NR 1a R 1b and R 2 is OR 1c .
3. The compound of claim 1 , wherein:
one of R 1a and R 1b is C 1-20 alkyl and R 2 is OH; or
one of R 1a and R 1b is a polyamine and R 2 is OH; or
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; or
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; or
one of R 1a and R 1b is —CH(R 1d )—C(O)OR 1e and R 2 is OH.
4. The compound of claim 1 , wherein:
R 1d is selected from hydrogen, alkyl, substituted alkyl, heteroaryl, and substituted heteroaryl; or
R 1d is a positively charged amino acid side chain.
5. The compound of claim 1 , wherein:
R 3a and R 3b are hydrogen; or
one of R 3a and R 3b is halo.
6. The compound of claim 1 , wherein W is O.
7. The compound of claim 1 , wherein R 4a and R 4b are hydrogen.
8. The compound of claim 1 , wherein:
one of R 5a and R 5b is —OH; or
one of R 5a and R 5b is selected from —NH 2 and N 3 ; or
one of R 5a and R 5b is —CH═CH 2 ; or
one of R 5a and R 5b is C 1-2 alkyl; or
one of R 5a and R 5b is C 1-2 alkyl, substituted with —OH, —NH 2 , or N 3 .
9. The compound of claim 1 , wherein R 6a and R 6b are hydrogen.
10. The compound of claim 1 , wherein R 7 is hydrogen.
11. The compound of claim 1 , wherein X is O.
12. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable excipient.
13. A method of treating breast or pancreatic cancer in an individual by administering an effective amount of the compound of claim 1 .
14. The method of claim 13 , wherein the cancer is pancreatic cancer.
15. The method of claim 13 , wherein the cancer is breast cancer.
16. A compound of formula (IV):
wherein
X 1 is NH or O;
X 2 is NH or O;
R 30 is hydrogen, optionally substituted C 1-20 alkyl, optionally substituted C 2-20 alkenyl, or optionally substituted C 2-20 alkynyl;
R 1 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 3 is O, S, or NH;
and salts, hydrates, solvates, and tautomers, thereof.
17. The compound of claim 16 , wherein X 1 and X 2 are O.
18. The compound of claim 16 , wherein R 30 is C 1-20 alkyl.
19. The compound of claim 16 , wherein:
R 1 carries a positive charge or a negative charge; or
R 1 is —NR 1a R 1b .
20. The compound of claim 19 , wherein:
one of R 1a and R 1b is C 1-20 alkyl; and R 2 is OH; or
one of R 1a and R 1b is a polyamine and R 2 is OH; or
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 )—NH 2 and n is independently a number from 2 to 4; or
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; or
one of R 1a and R 1b is —CH(R 1d )—C(O)OR 1e , and R 2 is OH.
21. The compound of claim 16 , wherein;
R 1d is selected from hydrogen, alkyl, substituted alkyl, heteroaryl, and substituted heteroaryl; or
R 1d is a positively charged amino acid side chain.
22. The compound of claim 16 , wherein:
R 3a and R 3b are hydrogen; or
one of R 3a and R 3b is halo.
23. The compound of claim 16 , wherein W is O.
24. The compound of claim 16 , wherein R 4a and R 4b are hydrogen.
25. The compound of claim 16 , wherein:
one of R 5a and R 5b is —OH; or
one of R 5a and R 5b is selected from —NH 2 and N 3 ; or
one of R 5a and R 5b is —CH═CH 2 ; or
one of R 5a and R 5b is C 1-2 alkyl; or
one of R 5a and R 5b is C 1-2 alkyl, substituted with —OH, —NH 2 , or N 3 .
26. The compound of claim 16 , wherein R 6a and R 6b are hydrogen.
27. The compound of claim 16 , wherein R 7 is hydrogen.
28. A pharmaceutical composition comprising the compound of claim 16 .
29. A method of treating breast or pancreatic cancer in an individual by administering an effective amount of the compound of claim 16 .
30. The method of claim 29 , wherein the cancer is pancreatic cancer.
31. The method of claim 29 , wherein the cancer is breast cancer.
32. A method of treating breast or pancreatic cancer in an individual by administering an effective amount of a compound of formula (VI):
wherein
R 1 and R 2 are independently —OCH(R 1b )OC(O)OR 1a ; wherein R 1a and R 1b are independently selected from hydrogen and C 1-5 alkyl;
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;
and salts, hydrates, solvates, and tautomers, thereof.
33. The method of claim 32 , wherein the cancer is pancreatic cancer.
34. The method of claim 32 , wherein the cancer is breast cancer.