Synthesis and cytotoxicity of 4'-C- and 5'-C-substituted toyocamycins.
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.
Gunic
E
E
Chemistry Laboratories, ICN Phartmaceuticals. Inc., Costa Mesa, California 92626, USA.
Girardet
J L
JL
Pietrzkowski
Z
Z
Esler
C
C
Wang
G
G
D000818:Animals; D002460:Cell Line / Q000187:drug effects; D003603:Cytotoxins / Q000138:chemical synthesis* / Q000494:pharmacology; D006801:Humans; D051379:Mice; D008956:Models, Chemical; D014127:Toyocamycin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000187:drug effects
D003603:Cytotoxins; D014127:Toyocamycin