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

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 Ki 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.