Potentiation of cytotoxic drug activity in human tumour cell lines, by amine-substituted 2-arylbenzimidazole-4-carboxamide PARP-1 inhibitors

Bioorg Med Chem Lett. 2004 May 17;14(10):2433-7. doi: 10.1016/j.bmcl.2004.03.017.

Abstract

The synthesis and biological evaluation of a new series of amine-substituted 2-arylbenzimidazole-4-carboxamide inhibitors of the DNA-repair enzyme poly(ADP-ribose) polymerase-1 (PARP-1) is reported. The introduction of an amine substituent at the 2-aryl position is not detrimental to activity, with most inhibitors exhibiting K(i) values for PARP-1 inhibition in the low nanomolar range. Two compounds in this series were found to potentiate the cytotoxicity of the DNA-methylating agent temozolomide by 4-5-fold in a human colorectal cancer cell line.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amides / chemical synthesis
  • Amides / pharmacology*
  • Animals
  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / pharmacology
  • Benzimidazoles / chemical synthesis
  • Benzimidazoles / pharmacology*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Colorectal Neoplasms / drug therapy
  • Colorectal Neoplasms / pathology
  • Dacarbazine / analogs & derivatives*
  • Dacarbazine / pharmacology
  • Drug Synergism
  • Humans
  • Lung Neoplasms / drug therapy
  • Lung Neoplasms / pathology
  • Poly(ADP-ribose) Polymerase Inhibitors*
  • Structure-Activity Relationship
  • Temozolomide

Substances

  • Amides
  • Antineoplastic Agents
  • Benzimidazoles
  • Poly(ADP-ribose) Polymerase Inhibitors
  • Dacarbazine
  • Temozolomide