Design,Synthesis And Activity Evaluation Of Phthasinone PARP Inhibitors

Malignant tumors endanger human life and health,and have received widespread attention worldwide.Finding effective,active and resistant anti-tumor drugs is an important task in the treatment of tumors.At present,the treatment of cancer is mainly radiotherapy and chemotherapy,but the overall survival rate is low.Breast cancer,ovarian cancer and cervical cancer are the three major cancers that harm women’s lives and health.Among them,the incidence of breast cancer is the highest,especially triple negative breast cancer has always been a difficult problem in clinical treatment.The study found that the occurrence of breast cancer and ovarian cancer is related to the mutation of BRCA1/2 gene,which is also the breakthrough point to overcome breast cancer and ovarian cancer.PARP is a poly-ADP ribose polymerase,called DNA repair enzyme,which can repair single-stranded DNA damage through base excision.PARP inhibitors can inhibit tumor growth through synthetic lethal effects.PARP inhibitors are very sensitive to cells with BRCA1/2 gene mutations,so PARP inhibitors can be used as a targeted drug to selectively kill tumor cells with BRCA1/2 gene mutations.However,the use of PARP inhibitors will cause drug resistance problems at a later stage,so the research on PARP inhibitors is of great significance.This paper describes the anti-tumor mechanism and research progress of PARP protein and PARP inhibitors,designs and synthesizes Olaparib derivatives,and in vitro activities of the target compounds were analyzed.This thesis mainly includes the following contents:1.The synthetic route of the lead compound Olaparib was optimized,and designed a better synthetic route.This route has high yield,easy availability of raw materials,and easy operation,the total yield is 57.63 %,and the ee value is 99.5 %.In the synthesis of compound X5,2-fluoro-5-formylbenzoic acid is used as a raw material,and hydrazine hydrate is directly added at the late stage of the reaction to heat the reaction to obtain intermediate X5,which shortens the reaction route and reaction time,and is more conducive to industrial production.2.Twelve Olaparib derivatives were designed and synthesized through molecular simulation technology,pharmacophore integration,bioelectronic isostere,homologous derivatization and other methods.3.In vitro activities of the target compounds were analyzed,such as the evaluation of PARP-1 enzyme activity on Olaparib derivatives,the PARylation experiment at the cellular level.In this dissertation,a series of Olaparib derivatives were designed and synthesized by using phthalazinone PARP inhibitor Olaparib as a lead compound,the activity analysis of the new compound evaluated the antitumor activity of the new compound,among which the activity of compound YS-4 was better than that of Olaparib.