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Synthesis and cytotoxicity of 4'-C- and 5'-C-substituted toyocamycins.

Abstract
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.
AuthorsE Gunic, J L Girardet, Z Pietrzkowski, C Esler, G Wang
JournalBioorganic & medicinal chemistry (Bioorg Med Chem) Vol. 9 Issue 1 Pg. 163-70 (Jan 2001) ISSN: 0968-0896 [Print] England
PMID11197336 (Publication Type: Comparative Study, Journal Article)
Chemical References
  • Cytotoxins
  • Toyocamycin
Topics
  • Animals
  • Cell Line (drug effects)
  • Cytotoxins (chemical synthesis, pharmacology)
  • Humans
  • Mice
  • Models, Chemical
  • Toyocamycin (analogs & derivatives, chemical synthesis, pharmacology)
  • Tumor Cells, Cultured (drug effects)

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