Design,Synthesis And Biological Activity Evaluation Of A Novel PARP1 Inhibitor

In recent years,because of the impact of the environment,the incidence rate of cancer is getting higher and higher,which seriously threatens human life and health.It is a global health problem.Although major breakthroughs have been made in cancer immunotherapy and targeted therapy in recent years,and cancer mortality continues to decline,the current situation of cancer treatment is still grim.The traditional means of cancer treatment,radiotherapy,chemotherapy and surgery,have serious limitations,and new treatment methods are urgently needed.Molecular targeted therapy suppresses the key molecules in the signal pathway of cancer occurrence and development,and has little impact on normal cells.Small molecular inhibitors,as an important strategy of cancer targeted therapy,have become the focus of anti-tumor research.With the study of the mechanism of tumor occurrence and development,the target of DNA damage repair related signal pathway has been paid more attention.Among them,the development of poly(ADP-ribose)polymerase(PARP)inhibitors is a hot spot in the development of antitumor drugs in recent years.PARP inhibitors are used alone or in combination with chemotherapy and radiotherapy to treat ovarian cancer and breast cancer.From 2014,the first PARP inhibitor,Orapari,was approved for the treatment of ovarian cancer,and Lucapari,Tarazopari,and Nilapari were successively approved for the treatment of related cancer.It has achieved remarkable results in clinical treatment,but also exposed the defects of existing PARP inhibitors.There are large adverse reactions in clinical use.The adverse reactions caused by existing PARP inhibitors are due to poor selectivity,which can inhibit both PARP1 and PARP2.Improving selectivity is an important strategy to overcome adverse reactions,and the research of selective PARP1 inhibitors is a hot spot in the development of PARP inhibitors.At present,many selective PARP1 inhibitors are in the clinical research stage,and the published clinical data show good anti-tumor effects.The research and development of selective PARP1 inhibitors can overcome the adverse reactions of existing PARP inhibitors and obtain better clinical effects,whether it is used alone or in combination with chemotherapy and radiotherapy drugs to treat cancer patients.It is of great significance to improve the current clinical treatment status of PARP inhibitors.AZD5305 is a new generation of PARP inhibitor that can effectively inhibit PARP1 and has high selectivity to PARP1.Recent clinical research shows that it has good application prospects and is the representative drug of the new generation of selective PARP1 inhibitor.It has good oral effect.It has excellent effect on BRCA mutation breast cancer and ovarian cancer patients.In terms of adverse reactions,it has high selectivity for PARP1,low inhibitory activity for PARP2,and low safety risk.China has a large population,and the incidence rate of breast cancer and ovarian cancer is increasing year by year.The development of selective PARP1 inhibitors has broad prospects and significance for improving the status of clinical treatment of cancer in China.In this paper,AZD5305 was selected as the lead compound to analyze the structure-activity relationship of PARP inhibitors reported in the literature and combine the binding of AZD5305 with PARP1 enzyme.On the basis of the structure of AZD5305,the methods of electronic isoarrangement and splicing of preponderant fragments are combined with the relevant principles of pharmaceutical chemistry.Eleven compounds were designed and their structures were confirmed by hydrogen spectrum,.In the synthesis work,the synthesis of key intermediates was studied,and a more suitable route was explored to provide a reference for the scale-up synthesis of target compounds.Through the preliminary in vitro activity evaluation of the target compound,it is concluded that deuterization of some groups of AZD5305 can maintain its inhibitory activity and selectivity,which is a preliminary exploration for the development of deuterized drugs of AZD5305.The other synthesized target compounds have good inhibitory activity against PARP1 and good selectivity for the subtype of PARP1.