Chemical Basis for the Biological Activity of Imexon and Related Cyanoaziridines

J Med Chem. 2004 Jan 1;47(1):218-23. doi: 10.1021/jm030225v.

Abstract

Chemical aspects of mode of action of imexon and related cyanoaziridines were studied. These compounds do not alkylate DNA nor react with the epsilon-amino groups of l-lysine, despite the presence of an aziridine ring. They do react readily with biologically important sulfhydryl compounds to give products derived from either aziridine ring opening, interaction with the cyano group of cyanoaziridines, or opening of the iminopyrrolidone ring of imexon. The products from reactions of imexon and related cyanoaziridines with thiols are not as potent as their parent compounds against tumor cells. These results are consistent with biological studies that show that the mechanism of cytotoxicity involves thiol depletion followed by oxidative stress leading to apoptosis.

Publication types

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

MeSH terms

  • Acetylcysteine / chemistry
  • Animals
  • Antineoplastic Agents / chemistry*
  • Antineoplastic Agents / pharmacology
  • Aziridines / chemistry*
  • Aziridines / pharmacology
  • Cell Line, Tumor
  • Drug Resistance, Neoplasm
  • Hexanones / chemistry*
  • Hexanones / pharmacology
  • Humans
  • Mice
  • Nitriles / chemistry*
  • Nitriles / pharmacology

Substances

  • Antineoplastic Agents
  • Aziridines
  • Hexanones
  • Nitriles
  • 4-imino-1,3-diazabicyclo(3.1.0)hexan-2-one
  • Acetylcysteine