Toyocamycin and some analogues have shown potent antitumor activities; however, none of them could be used clinically primarily owing to their cytotoxicity to normal human cells. In order to overcome the weakness of these
nucleoside analogues, substitution of a variety of modified
sugars for the ribofuranose was explored in our laboratories with expectation that certain
sugar-modified
toyocamycin analogues may be selectively cytotoxic to
cancer cells. In this article, we report synthesis and cytotoxicity of 4'-C- and 5'-C-substituted toyocamycins, which were prepared via the condensations of 4-C- and 5-C-substituted ribofuranose derivatives 11, 12, 13, 20, 21, and 26 with the silylated form of 4-amino-6-bromo-5-cyanopyrrolo[2,3-]
pyrimidine (27) and subsequent debromination and debenzoylation. When compared to the parent
toyocamycin, all these analogues showed much lower cytotoxicity to human
prostate cancer cells (HTB-81), mouse
melanoma cancer cells (B16) as well as normal human fibroblasts. Compound 1e showed a significant cytotoxicity to the
prostate cancer cells and a moderate selectivity. The results suggested that
sugar modifications, especially those that may affect phosphorylation of
nucleosides, could alter cytotoxicity profile significantly.