Design,Synthesis And Biological Evaluation Of Novel PARP-1 Inhibitors

Cancer has been affecting the survival and health of human beings for a long time.According to the report,there will be about 10 million cancer deaths worldwide in 2020.Among them,the number of cancer deaths in China also ranks first in the world.Breast cancer and ovarian cancer are two common gynecological malignant tumors,and their treatment has always been the focus of medical research.In recent years,PARP-1inhibitors alone or combined with other chemotherapy and radiotherapy drugs have become a focus in the treatment of BRCA1/2 deficient breast and ovarian cancer.Poly(ADP ribose)polymerases(PARPs)is a kind of DNA repair enzyme in the process of base excision and repair,which has many biological functions such as DNA repair,apoptosis,necrosis and synthetic lethality.PARP-1 is the largest and the most widely studied family which has 18 members.The discovery of synthetic lethal theory not only provides a theoretical basis for the research and development of PARP-1inhibitor,but also provides a new method for the treatment of breast cancer or ovarian cancer patients with BRCA1/2 defect alone.At the end of 2014,Olaparib was approved by FDA as the first PARP-1 inhibitor for the treatment of ovarian cancer patients with BRCA1/2 deficiency.In recent years,the inhibitor of PARP-1 has developed rapidly,and Niraparb,Rucaparb and Talazoparib have been approved to be listed successively.We found that:1)these PARP-1 inhibitors were designed on the basis of nicotinamide part of NAD~+.Although they have various structures,they all have common characteristics,that is,they contain amide group and rigid planar structure related to activity;2)they are located outside the active site of PARP-1 enzyme.In addition,there is a large hydrophobic cavity,which can accommodate a variety of different groups and provide a theoretical basis for further optimizing the physical and chemical properties of the compounds.In this paper,Olaparib was used as the template molecule for drug design.By changing its different side chain structure,two kinds of target compounds were obtained,which were monocyclic lactams and pyrido dihydropyrimidinone compounds.The interaction between the designed compounds and PARP-1 protein was analyzed by molecular docking software,and it was confirmed that they had better interaction between PARP-1 protein and molecules.Then,we will synthesis the compounds and test its biological activity.In this paper,the synthesis route of the target compounds was designed reasonably,and the reaction conditions were optimized,and the target compounds of monocyclic lactams and pyrido dihydropyrimidinone were successfully synthesized.For monocyclic lactams,the final target products were synthesized by acyl chloride method.For pyridine dihydropyrimidinone compounds,we designed three synthetic routes,mainly including Gabriel,hydrogenation,condensation,hydrolysis and other reactions.Based on the comprehensive consideration of by-product and post-treatment,the synthetic route of3-cyanobenzoic acid methyl ester was finally determined.A total of 44 target compounds were synthesized and their chemical structures were confirmed by MS and~1H NMR spectra.The target compound was determined in 1μM and the inhibition of PARP-1enzyme was also observed.The results showed that monocyclic lactams had no obvious inhibitory effect on PARP-1,while pyrido dihydropyrimidinone had relatively good inhibitory effect on PARP-1.Compounds B-1 and B-15 had the best inhibitory effect on PARP-1,with inhibition rates of 85.63%and 80.12%respectively.The structure-activity relationship analysis showed that the introduction of side chain amide group was beneficial to the activity,the o-substituted compounds had the best activity,the m-substituted compounds took the second place,the p-substituted compounds had the worst activity,and the electron withdrawing group was better than the electron donating group.The preliminary structure-activity relationship analysis has a certain guiding significance for the follow-up drug molecular design.