Design and synthesis of novel phthalazinone derivatives as potent poly(ADP-ribose)polymerase 1 inhibitors

摘要

Aim:The development of effective PARP-1 inhibitors has received great enthusiasm in medicinal chemistry communities.Results:A new series of novel phthalazinone derivatives were designed and synthesized. Among these,B1andB16displayed more potent PARP-1 inhibitory activities than olaparib.B16gave an IC(50)value of 7.8 nM against PARP-1, and a PF(50)value of 3.4 in the sensitizing effect assay. Thein vivopharmacokinetic properties evaluation showedB16displayed insufficient oral exposure, and it was also not stable in rat blood.Conclusion:The results indicated that our design phthalazinone derivatives were potent PARP-1 inhibitors, and compoundB16was a valuable lead compound with siginificantin vitroefficacy, deseaving further optimization so as to develop anticancer drug candidate.