Antineoplastic agents. 410. Asymmetric hydroxylation of trans- combretastatin A-4

George Pettit, Brian E. Toki, Delbert L. Herald, Michael R. Boyd, Ernest Hamel, Robin Pettit, Jean Chapuis

Research output: Contribution to journalArticle

71 Scopus citations

Abstract

The South African willow tree Combretum caffrum has yielded a number of potent cancer cell growth inhibitors. The present SAR studies of the antineoplastic agent combretastatin A-4 (1c) were focused mainly on the olefinic bridge to determine the effects on cancer cell growth and, potentially, to better define the combretastatin A-4 binding site on tubulin. The geometric trans-isomer 3a of combretastatin A-4 was converted to the (1S,2S)- and (1R, 2R)-vicinal diols 4c and 4d, respectively, under Sharpless' asymmetric dihydroxylation conditions. Cancer cell line testing showed the (1S,2S-diol 4c to be more potent than its enantiomer 4d. Diol 4c weakly inhibited tubulin polymerization (IC50) = 22μM, versus 1.2 μM for combretastatin A-4), while 4d was inactive (IC50 > 40 μM). Esterification of either stereoisomer at the diol and/or phenolic positions resulted in elimination of inhibitory activity.

Original languageEnglish (US)
Pages (from-to)1459-1465
Number of pages7
JournalJournal of Medicinal Chemistry
Volume42
Issue number8
DOIs
StatePublished - Apr 22 1999

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ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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