Antineoplastic agents. 379. Synthesis of phenstatin phosphate

George Pettit, Brian Toki, Delbert L. Herald, Pascal Verdier-Pinard, Michael R. Boyd, Ernest Hamel, Robin Pettit

Research output: Contribution to journalArticle

223 Scopus citations

Abstract

A structure-activity relationship (SAR) study of the South African willow tree (Combretum caffrum) antineoplastic constituent combretastatin A- 4 (1b) directed at maintaining the (Z)stilbene relationship of the olefin diphenyl substituents led to synthesis of a potent cancer cell growth inhibitor designated phenstatin (3b). Initially phenstatin silyl ether (3a) was unexpectedly obtained by Jacobsen oxidation of combretastatin A-4 silyl ether (1c → 3a), and the parent phenstatin (3b) was later synthesized (6a → 3a → 3b) in quantity. Phenstatin was converted to the sodium phosphate prodrug (3d) by a dibenzyl phosphite phosphorylation and subsequent hydrogenolysis sequence (3b → 3c → 3d). Phenstatin (3b) inhibited growth of the pathogenic bacterium Neisseria gonorrhoeae and was a potent inhibitor of tubulin polymerization and the binding of colchicine to tubulin comparable to combretastatin A-4 (1b). Interestingly, the prodrugs were found to have reduced activity in these biochemical assays. While no significant tubulin activity was observed with the phosphorylated derivative of combretastatin A- 4 (1d), phosphate 3d retained detectable inhibitory effects in both assays.

Original languageEnglish (US)
Pages (from-to)1688-1695
Number of pages8
JournalJournal of Medicinal Chemistry
Volume41
Issue number10
DOIs
StatePublished - May 7 1998

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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    Pettit, G., Toki, B., Herald, D. L., Verdier-Pinard, P., Boyd, M. R., Hamel, E., & Pettit, R. (1998). Antineoplastic agents. 379. Synthesis of phenstatin phosphate. Journal of Medicinal Chemistry, 41(10), 1688-1695. https://doi.org/10.1021/jm970644q