The design of novel inhibitors of poly (ADP-ribose) polymerase to potentiate cytotoxic drugs

Abstract

The abundant nuclear enzyme poly (ADP-ribose)polymerase (P ARP) catalyses the formation of long homopolymeric chains of ADP-ribose, utilising NAD+ as a substrate, as the immediate cellular response to DNA damage. PARP recognises a damaged section of DNA and initiates polymer synthesis, which is believed to act as a signal to effect the repair of the lesion. A selective, potent PARP inhibitor could block the recognition, and hence repair, of DNA damage induced by cancer chemotherapy. Since increased DNA repair is regarded as a mechanism whereby tumour cells can become resistant to treatment, PARP inhibitors have therapeutic potential as resistance modifying agents. From a study of PARP inhibitors such as 3-hydroxybenzarnide (A), benzimidazole derivatives (B) were proposed as inhibitors of the enzyme, and the synthesis and biological evaluation of a series of such molecules has been achieved. Substituted 2-aryl benzirnidazoles have proved to be highly potent PARP inhibitors (B;R= 4'NO2Ph, IC5o= 59 nM), under a permeabilised cell assay the nitro phenyl derivative (B; R= 4'N02Ph) is the most potent compound reported to date (IC50= 19 nM). 2-Methyl benzirnidazole-4-carboxamide (B; R= Me) has been shown to potentiate the in vitro cytotoxicity of the antitumour agent temozolomide in L1210 cells, and the synthesis of benzimidazole inhibitors suitable for pre-clinical in vivo eluation has also been investigated, This thesis demonstrates that benzimidazole PARP inhibitors have promising potential for clinical development as resistance modifying agents.