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

J Med Chem. 1999 Apr 22;42(8):1459-65. doi: 10.1021/jm9807149.

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 = 22 microM, versus 1.2 microM for combretastatin A-4), while 4d was inactive (IC50 > 40 microM). Esterification of either stereoisomer at the diol and/or phenolic positions resulted in elimination of inhibitory activity.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Anti-Bacterial Agents
  • Anti-Infective Agents / chemical synthesis
  • Anti-Infective Agents / chemistry
  • Anti-Infective Agents / pharmacology
  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Bacteria / drug effects
  • Biopolymers
  • Crystallography, X-Ray
  • Drug Screening Assays, Antitumor
  • Fungi / drug effects
  • Humans
  • Hydroxylation
  • Mice
  • Models, Molecular
  • Stereoisomerism
  • Stilbenes / chemistry*
  • Structure-Activity Relationship
  • Tubulin / metabolism
  • Tumor Cells, Cultured

Substances

  • Anti-Bacterial Agents
  • Anti-Infective Agents
  • Antineoplastic Agents
  • Biopolymers
  • Stilbenes
  • Tubulin
  • fosbretabulin