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

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.

• Authors: Alex W White, Nicola J Curtin, Brian W Eastman, Bernard T Golding, Zdenek Hostomsky, Suzanne Kyle, Jianke Li, Karen A Maegley, Donald J Skalitzky, Stephen E Webber, Xiao-Hong Yu, Roger J Griffin
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 14 Issue 10 Pg. 2433-7 (May 17 2004) ISSN: 0960-894X [Print] England
• PMID: 15109627 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

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

Topics

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