Synthesis and biological activity of thiazolylindolequinones, analogues of the natural product BE 10988

J Med Chem. 1995 Mar 17;38(6):1039-43. doi: 10.1021/jm00006a024.

Abstract

A number of analogues of the naturally occurring thiazolylindolequinone BE 10988, a reported potent inhibitor of topoisomerase II, have been prepared and evaluated. The compounds were synthesized from 4-(benzyloxy)-5-methoxy-1-methylindole by appropriate substitution at the indole 3-position followed by standard thiazole ring-forming reactions. The toxicity of these potentially bioreductively activated indolequinones was measured in Chinese hamster V79 cells under aerobic and hypoxic conditions. In addition, toxicity was measured in a human breast cancer cell line that shows amplification of the topo II alpha gene and hypersensitivity to known topo II inhibitors such as mAMSA and mitoxantrone. Using a DNA decatenation assay, a comparison was also made of the inhibitory effects of BE 10988 and mitoxantrone on topo II activity.

Publication types

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

MeSH terms

  • Aerobiosis
  • Animals
  • Breast Neoplasms / drug therapy
  • CHO Cells
  • Cell Hypoxia
  • Cricetinae
  • Cricetulus
  • Drug Evaluation, Preclinical
  • HeLa Cells
  • Humans
  • Indoles / chemical synthesis*
  • Indoles / pharmacology*
  • Quinones / chemical synthesis*
  • Quinones / pharmacology*
  • Structure-Activity Relationship
  • Thiazoles / chemical synthesis*
  • Thiazoles / pharmacology*
  • Topoisomerase II Inhibitors*
  • Tumor Cells, Cultured

Substances

  • Indoles
  • Quinones
  • Thiazoles
  • Topoisomerase II Inhibitors
  • BE 10988