Design,Synthesis And Activity Evaluation Of PARP Inhibitor Niraparib Derivatives

Cancer is a malignant tumor threatening human life,and its morbidity and mortality are increasing year by year.It is an important task to find effective anticancer drugs with small side effects.Women suffer from ovarian cancer and breast cancer for a long time,especially triple negative breast cancer,its aggressive sex is strong,survival is short,still do not have effective remedial method.BRCA mutations were found in nearly 20 percent of ovarian cancer patients,which could be a breakthrough in the treatment of these cancers.PARP inhibitors are cancer drugs that target poly(ADP-ribose)polymerase and use of synthetic lethal agents.The PARP protein plays a role in the DNA repair pathway.Small molecule PARP inhibitors can block single-strand DNA damage repair,and play a combined role in the synthesis of lethal effect and achieve the purpose of anti-tumor.Patients with BRCA1/2 gene mutations are sensitive to PARP inhibitors,and maintenance therapy can be achieved.However,as with other targeted drug therapies,resistance to PARP inhibitors in treatment,and determining the best use of PARP inhibitors in drug combinations has been challenging.Therefore,the study of anticancer drugs with PARP inhibitors has important clinical application value and significance.This paper introduces the PARP protein and summarizes the anticancer mechanism and research progress of PARP inhibitors.Niraparib derivatives were designed and synthesized based on small molecule Niraparib by means of molecular docking and homologous derivation.This paper mainly includes the following:1.A new synthesis route of Niraparib's key intermediate(S)-3-(4-bromophenyl)-1-piperidine carboxylate tert-butyl ester was designed.The route was easy to operate,and the total yield were 56.36%,ee value of 99.5%.2.Two series of Niraparib derivatives were designed and synthesized,and the route of the lead compound Niraparib was optimized.3.In vitro activities of the target compounds were analyzed,such as PARP-1 enzyme activity evaluation and PARylation assay at the cellular level.In this paper,two series of Niraparib derivatives were synthesized.The antitumor activity and safety of the new compounds were evaluated,and new strategies were provided for the design of antitumor drugs.The inhibitory activity of compound M3-2 was better than that of Niraparib.