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 method for inhibiting telomere elongation, comprising contacting a cell with a compound of formula (I):
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 1 is different from R 2 ;
R 3a and R 3b are independently selected from hydrogen and halo;
W is O, S, or NH;
R 4 is selected from hydrogen, —OH, —NH 2 , N 3 , —CH═CH 2 , and optionally substituted C 1-2 alkyl, wherein alkyl is optionally 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 optionally 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 method of claim 1 , wherein:
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 method of claim 1 , wherein the compound of formula (I) is the enriched or isolated (R) enantiomer at the stereocenter bearing R 4 .
4. The method 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.
5. The method 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.
6. The method of claim 1 , wherein:
R 3a and R 3b are hydrogen; or
R 3a is halo and R 3b is hydrogen.
7. The method of claim 1 , wherein W is O.
8. The method of claim 1 , wherein:
R 4 is —OH; or
R 4 is selected from —NH 2 and N 3 ; or
R 4 is —CH═CH 2 ; or
R 4 is C 1-2 alkyl; or
R 4 is optionally substituted C 1-2 alkyl, wherein alkyl optionally is substituted with —OH, —NH 2 , or N 3 .
9. The method of claim 1 , wherein R 5a and R 5b are hydrogen.
10. The method of claim 1 , wherein R 7 is hydrogen.
11. The method of claim 1 , wherein R 7 is fluoro.
12. The method of claim 1 , wherein X is O.
13. The method of claim 1 , wherein the cell is a cancer cell.
14. A method for inhibiting telomere elongation, comprising contacting a cell with a compound of formula (II):
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 4 is selected from hydrogen, —OH, —NH 2 , N 3 , —CH═CH 2 , and optionally substituted C 1-2 alkyl, wherein alkyl is optionally 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 optionally 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.
15. The method of claim 14 , wherein X 1 and X 2 are O.
16. The method of claim 14 , wherein R 30 is C 1-20 alkyl.
17. The method of claim 14 , wherein;
R 1 carries a positive charge or a negative charge; or
R 1 is NR 1a R 1b .
18. The method of claim 14 , wherein the compound of formula (II) is the enriched or isolated (R) enantiomer at the stereocenter bearing R 4 .
19. The method of claim 14 , wherein:
one of R 1a and R 1b is C 1-20 alkyl; or
one of R 1a and R 1b is a polyamine; 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 .
20. The method of claim 14 , 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.
21. The method of claim 14 , wherein;
R 3a and R 3b are hydrogen; or
R 3a is halo and R 3b is hydrogen.
22. The method of claim 14 , wherein W is O.
23. The method of claim 14 , wherein:
R 4 is —OH; or
R 4 is selected from —NH 2 and N 3 ; or
R 4 is —CH═CH 2 ; or
R 4 is C 1-2 alkyl; or
R 4 is optionally substituted C 1-2 alkyl, wherein alkyl is optionally substituted with —OH, —NH 2 , or N 3 .
24. The method of claim 14 , wherein R 5a and R 5b are hydrogen.
25. The method of claim 14 , wherein R 7 is hydrogen.
26. The method of claim 14 , wherein R 7 is fluoro.
27. The method of claim 14 , wherein X is O.
28. The method of claim 14 , wherein the cell is a cancer cell.
29. A method for inhibiting telomere elongation comprising contacting a cell with a compound of formula (V):
wherein
R 1 and R 2 are independently selected from —OH, monophosphate, diphosphate and —OCH(R 1b )OC(O)OR 1a ; wherein R 1a and R 1b are independently selected from hydrogen and C 1-5 alkyl, wherein at least one of R 1 and R 2 is —OCH(R 1b )OC(O)OR 1a ;
R 3a and R 3b are independently selected from hydrogen and halo;
W is O, S, or NH;
R 4 is selected from —OH, —NH 2 , N 3 , —CH═CH 2 , and optionally substituted C 1-2 alkyl, wherein alkyl is optionally 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 optionally 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.
30. The method of claim 29 , wherein the cell is a cancer cell.