Design, Synthesis And Antitumor Activity Of Pyrimidin/7-azaindol/Phthalazinone Derivatives As PARP1Inhibitors

Poly(ADP-ribose) polymerase1(PARP1) plays a key role in DNA-based excision repair. PARP1inhibition is a promising strategy for anticancer therapy in enhancing drug selectivity and lowering side effects.PARP1inhibitors share common binding modes with nicotinamide-ribose binding site (NI site) including three pivotal hydrogen bonds between the carboxamide of PARP1inhibitors and two residues, known as Gly863and Ser904, as well as a π-π stacking interaction with Tyr907. Furthermore, the potent PARP1inhibition is attributed to the intermolecular hydrogen bond restricting the carboxamide. Based on the structural features of small-molecule PARP1inhibitors that have been in clinical trials, phthalazinone derivative AZD2281and indol derivative AG014699are selected as lead compounds to design and synthesize three series of pyrimidin-4(3H)-one, uracil and7-azaindol analogues guided by basic principles of drug design. Fifteen pyrido[2,3-d]pyrimidin-4(3H)-one derivatives (1-20～1-34), eight uracil derivatives (1-47-1-54) and one7-azaindol derivative (1-61) have been synthesized. All compounds have been tested for PARP1inhibitory activities. It is benifical that the carboxamide group is at the pyrrole ring with high electron density for PARP1inhibition, rather than at the ring with poor electron density, such as pyridine and uracil. Compound3-7have acceptable PARP1inhibitory activity (48.95%@1μM), while PARP1inhibitory activity of other two series is very low.Moreover, since AZD2281has excellent PARP1inhibitory activity and chemosensitization against tumor cells, eighteen phthalazinone derivatives (2-8～2-18,2-25～2-30) have been synthesized in order to study the change of PARP1inhibitory activity when substituents at4-position have rigid structures. Unfortunately, PARP1inhibitory activity drops significantly while methylene is replaced by4-carbamoyl. We hold the viewpoint that clinical candidate AZD2281has other underlying binding sites with PARP1besides NI site. Further optimization and biological evaluation for these compounds are currently under investigation.