The design and synthesis of novel heterocyclic inhibitors of the DNA-repair enzyme, poly(ADP-ribose) polymerase, as potential resistance-modifying agents
The abundant nuclear enzyme, poly(ADP-ribose) polymerase (PARP) is activated by DNA strand breaks and catalyses the transfer of ADP-ribose moieties from its substrate, nicotinamide adenine dinucleotide (NAD), to various histone- or non-histone nuclear acceptor proteins. The net result is the formation of long, homopolymeric chains, the exact purpose of which is not clearly understood. Since this process is thought to facilitate DNA repair, the PARP enzyme represents a possible therapeutic target. A well known mechanism by which tumours become resistant to anticancer treatments is increased DNA repair. Inhibition of PARP may thus be a strategy for the potentiation of DNA-damaging agents and PARP inhibitors may function as resistance-modifying agents in conjunction with cancer chemotherapeutic agents. The aim of this research was to design and synthesise novel heterocyclic inhibitors of PARP, based on the existing knowledge of structure-activity requirements. A great deal of information has already been gathered from the use of early inhibitors, such as nicotinamide and 3-aminobenzamide (3AB). However, these inhibitors lack potency, specificity for the enzyme, and aqueous solubility, and so are limited in their use as clinical agents. A novel series of quinazolin-4-[3H]-ones (structure A) has been synthesised by a highyielding, reproducible pathway, including derivatives bearing electron-withdrawing and electron-donating substituents in the 2-position. These derivatives exhibit excellent in vitro PARP inhibitory activity, with IC50 values in the micromolar concentration range, and the selected compound, NU1025 (8-hydroxy-2-methylquinazolin-4-[3H]-one) has been shown to potentiate the effects of a range of mechanistically diverse anticancer agents, including y-irradiation. A water-soluble phosphate prodrug derivative of NU1025 has been synthesised and this shows promising enzyme-mediated conversion to the parent compound in plasma. A second series of 1H-benzimidazole-4-carboxamides (structure B) has been synthesised bearing mono-, di- or trisubstituted aryl rings in the 2-position. Biological evaluation of this series has shown that these derivatives are among the most potent PARP inhibitors reported to date, with K; values in the low nanomolar concentration range.