Antineoplastic agents. 552. Oxidation of combretastatin A-1: trapping the o-quinone intermediate considered the metabolic product of the corresponding phosphate prodrug

J Nat Prod. 2008 Sep;71(9):1561-3. doi: 10.1021/np800179g. Epub 2008 Aug 27.

Abstract

The very unstable (<10 min at rt) o-quinone 5 derived from the vicinal diphenol anticancer drug combretastatin A-1 (1) has been obtained by careful oxidation with NaIO4 and tetrabutylammonium bromide in water/dichloromethane. Immediate reaction with phenylenediamine (6) allowed o-quinone 5 to be trapped as the stable phenazine derivative 7. For further confirmation, 5 was also captured as a dimethoxyphenylenediamine-derived phenazine (11). Both phenazines 7 and 11 significantly inhibited (ED50 approximately 0.2 microg/mL) growth of the murine P388 lymphocytic leukemia cell line and provided a new SAR insight in the combretastatin series of naturally occurring anticancer drugs.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents, Phytogenic / chemistry*
  • Antineoplastic Agents, Phytogenic / pharmacology
  • Biological Products / chemistry*
  • Biological Products / pharmacology
  • Drug Screening Assays, Antitumor
  • Leukemia P388
  • Molecular Structure
  • Oxidation-Reduction
  • Prodrugs / chemistry*
  • Prodrugs / pharmacology
  • Quinones / chemistry*
  • Stilbenes / chemistry*
  • Stilbenes / pharmacology
  • Structure-Activity Relationship

Substances

  • Antineoplastic Agents, Phytogenic
  • Biological Products
  • Prodrugs
  • Quinones
  • Stilbenes
  • combretastatin A-1
  • fosbretabulin