Synthesis and cytotoxicity of 4-amino-5-oxopyrido[2,3-d]pyrimidine nucleosides

A number of nucleoside analogues have been either used clinically as antica ncer drugs or evaluated in clinical studies, while new nucleoside analogues continue to show promise. In this article, we report synthesis and cytotox icity of a series of new pyrido[2,3-d]pyrimidine nucleosides. 2-Amino-3-cya no-4-methoxypyridine was converted, in two steps, to 4-amino-5-oxopyrido[2, 3-d]pyrimidine. A variety of 1-0-acetylated pentose sugar derivatives were condensed with silylated 4-amino-5-oxopyrido[2,3-d]pyrimidine, followed by protection, to afford a series of 4-amino-5-oxopyridol[2,3-d]pyrimidine nuc leosides. Further derivatizations provided an additional group of pyrido[2, 3-d]pyrimidine nucleosides. These nucleosides were evaluated for in vitro c ytotoxicity to human prostate cancer (HTB-81) and mouse melanoma (B16) cell s as well as normal human fibroblasts (NHF). A number of compounds (1a,b, 2 a-c,f, 3f+4d) showed significant cytotoxicity to cancer cells, with 4-amino -5-oxo-8-(beta-D-ribofuranosyl)pyrido-[2,3-d]pyrimidine (Ib) being the most potent proliferation inhibitor (EC50: 0.06-0.08 mu M) to all types of cell s tested. However, a selective inhibition to the cancer cells was observed for 4-amino-5-oxo-8-(beta-D-xylofuranosyl)pyrimidine (2b), which is a poten t inhibitor of HTB-81 (EC50: 0.73 mu M) and has a favorable in vitro select ivity index (28).