Design,Synthesis,Antitumor Activity And Metabolic Stability Of PARP-1 Inhibitors Bearing Aromatic Cyclo-2-thiotetrahydropyrimidine-4(1H)-one Scaffolds

Poly ADP-ribose polymerase-1(PARP-1)is a key enzyme in the base excision repair pathway of DNA.For homologous recombination repair deficient tumors(such as breast cancer susceptibility gene 1/2 mutant),inhibiting the activity of PARP-1 will make damaged DNA fragments cannot be effectively repaired.With the launch of Olaparib,Niraparib,Rucaparib and Talazoparib,PARP-1 has become a popular target for cancer therapy.Herein,with Olaparib as lead compound,a series of compounds bearing aromaticcyclo-2thiotetrahydropyrimidine-(1H)-one scaffolds were designed,synthesised and evaluated for their anti-proliferative effects on MDA-MB-436 cell line.Preliminary results indicated that 6-fluoro2-thio-2,3-dihydroquinazolin-4(1H)-one derivatives tend to be more potent than 3a-3e with the terminal substituent an isopropyl group,a four-membered ring,a five-membered ring,a sixmembered ring,and an α-trifluoromethyl-substituted four-membered ring.Compounds 2-15,2-22,1a,1c,1d were further selected for the evaluation of in vitro liver microsomal metabolism stability and identification of metabolites.The results showed that the metabolic rate of the target compound was too fast compared to Olaparib.Metabolite identification of 2-22 showed that oxidation and amide hydrolysis were the main metabolic modes.In order to maintain the activity of the compound and improve its metabolic stability,two deuterium atoms at the benzylic position were introduced.The results showed that the activity was maintained,but the metabolic rate of 4b was faster than that of the non-deuterated compound 2-15.Therefore,further structural modification and drug-making optimization of the designed compound are still required.