Pyrido[2,3-d]pyrimidine and pyrimido[4,5-d]pyrimidine nucleosides
View Patent ↗A purine nucleoside analog includes a pyrido[2,3-d]pyrimidine or a pyrimido[4,5-d]pyrimidine and further has a sugar moiety that is optionally modified at the C2′, C3′, C4′ and/or C5′ position. Particularly contemplated compounds also include prodrug forms of the purine nucleoside analogs, and both purine nucleoside analogs and the corresponding prodrugs are employed in the reduction of growth of neoplastic cells.
1. A nucleoside analog according to the formula (I)
wherein
A is O;
R 2 , R 2 ′, R 3 , and R 3 ′ are independently selected from H, F, OH, NH 2 , CN, N 3 , CONH 2 , and R, where R is lower alkyl, lower alkenyl, lower alkynyl, or lower acyl;
or R 2 and R 2 ′ together, or R 3 and R 3 ′ together are selected from ═CH 2 , ═CHR″, ═CR″ 2 , ═NR″, where R″ is H, F, OH, CN, N 3 , CONH 2 , lower alkyl, lower alkenyl, lower alkynyl, or lower acyl;
R 4 is selected from H, lower alkyl, lower alkenyl, lower alkynyl, aralkyl, or hydroxymethyl; R 5 ′ is selected from H, lower alkyl, lower alkenyl, lower alkynyl, or aralkyl;
R 5 is H, OH, OP(O)(OH) 2 , or P(O)(OH) 2 ; and
B is selected from the group of heterocyclic radicals consisting of formulae (II) and (IV)
wherein X is H, NH 2 or OH;
Y is H, NH 2 , or halogen;
Z 1 is O, S, NR″, CHM, or CM 2 ;
Z 3 is N, CH, or CM;
Z 2 is N, CH, or CM;
where M is F, Cl, Br, OH, SH, NH 2 , CN, COOR″, C(═NH)NH 2 , lower alkyl, lower alkenyl, lower alkynyl, aralkyl, or aryl.
2. The nucleoside analog of claim 1 wherein A is O, and B is a heterocyclic radical according to formula (II).
3. The nucleoside analog of claim 2 wherein X is NH 2 , Z 1 is O, and Z 2 and Z 3 are CH.
4. The nucleoside analog of claim 3 wherein R 4 and R 5 ′ are hydrogen, and R 5 is OH.
5. The nucleoside analog of claim 1 having a structure according to formula (VI)
6. A prodrug comprising the nucleoside analog of claim 5 .
7. The prodrug of claim 6 wherein the prodrug comprises a phosphate or phosphonate covalently coupled to the C 5 atom of the ribose.
8. The prodrug of claim 6 wherein the prodrug comprises a moiety that is covalently bound to at least one of the hydroxyl groups of the ribose, and that is cleaved from the at least one hydroxyl groups within a target cell.
9. The prodrug of claim 6 wherein the prodrug comprises a moiety that is covalently bound to the amino group of the base, and that is cleaved from the amino group within a target cell.
10. A method of inhibiting growth of a neoplastic cell comprising:
providing a compound according to claim 1 ; and
presenting the compound to the cell in a dosage effective to inhibit the growth of a cell.
11. The method of claim 10 wherein A is O, and B is a heterocyclic radical according to formula (II).
12. The method of claim 11 wherein X is NH 2 , Z 1 is O, and Z 2 and Z 3 are CH.
13. The method of claim 12 wherein R 4 and R 5 ′ are hydrogen, and R 5 is OH.
14. The method of claim 10 wherein the compound has a structure according to formula (VI)
15. The method of claim 14 wherein the compound comprises a phosphate or phosphonate covalently coupled to the C 5 atom of the ribose.
16. The method of claim 14 wherein the compound comprises a moiety that is covalently bound to at least one of the hydroxyl groups of the ribose, and that is cleaved from the at least one hydroxyl groups within a target cell.
17. The method of claim 14 wherein the compound comprises a moiety that is covalently bound to the amino group of the base, and that is cleaved from the amino group within a target cell.
18. The use of claim 14 wherein the neoplastic cell is a cell selected from the group consisting of a colon cancer cell, a breast cancer cell, a melanoma cell, a glioma cell, prostate cancer cell, a lung cancer cell, a liver cancer cell, a pancreas cancer cell, and an ovarian cancer cell.
19. The method of claim 14 wherein the inhibition of the growth of the cell comprises apoptosis.
20. The method of claim 19 wherein the apoptosis is triggered at least in part by MEK-phosphorylation.
21. The method of claim 14 wherein the inhibition of the growth of the cell comprises inhibition of at least one of RNA polymerase I, RNA polymerase II, and RNA polymerase III.