Tricyclic benzimidazoles as potent poly(ADP-ribose) polymerase-1 inhibitors

J Med Chem. 2003 Jan 16;46(2):210-3. doi: 10.1021/jm0255769.

Abstract

Novel tricyclic benzimidazole carboxamide poly(ADP-ribose) polymerase-1 (PARP-1) inhibitors have been synthesized. Several compounds were found to be powerful chemopotentiators of temozolomide and topotecan in both A549 and LoVo cell lines. In vitro inhibition of PARP-1 was confirmed by direct measurement of NAD+ depletion and ADP-ribose polymer formation caused by chemically induced DNA damage.

MeSH terms

  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Benzimidazoles / chemical synthesis*
  • Benzimidazoles / chemistry
  • Benzimidazoles / pharmacology
  • Binding Sites
  • Cell Line
  • Crystallography, X-Ray
  • Dacarbazine / analogs & derivatives*
  • Dacarbazine / metabolism
  • Dacarbazine / pharmacology
  • Drug Resistance, Neoplasm
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology
  • Heterocyclic Compounds, 3-Ring / chemical synthesis*
  • Heterocyclic Compounds, 3-Ring / chemistry
  • Heterocyclic Compounds, 3-Ring / pharmacology
  • Humans
  • Models, Molecular
  • Poly(ADP-ribose) Polymerase Inhibitors*
  • Prodrugs / chemical synthesis
  • Prodrugs / chemistry
  • Prodrugs / pharmacology
  • Stereoisomerism
  • Structure-Activity Relationship
  • Temozolomide
  • Topotecan / metabolism
  • Topotecan / pharmacology

Substances

  • Antineoplastic Agents
  • Benzimidazoles
  • Enzyme Inhibitors
  • Heterocyclic Compounds, 3-Ring
  • Poly(ADP-ribose) Polymerase Inhibitors
  • Prodrugs
  • Dacarbazine
  • Topotecan
  • Temozolomide