Design,Synthesis And Activity Evaluation Of PARP-1 Selective Inhibitors

Cancer is a serious disease that threatens human life and health worldwide.With the continuous exploration of the molecular biology of cancer pathogenesis,molecular targeted therapy has gradually become the focus of anti-tumor research.PARP inhibitors are anticancer drugs that target DNA damage repair mechanisms.They can exert antitumor effects not only as sensitizers for tumor radiotherapy and chemotherapy,but also as single drugs to selectively kill homologous recombination-deficient tumor cells.Currently approved PARP inhibitors include Olaparib,Niraparib,Rucaparib,Talazoparib,Fluzoparib,and Pamiparib.The clinical applications of these drugs were limited by some hematological toxicities that may be related to the simultaneous inhibition of PARP-1 and PARP-2.Studies have shown that mice with simultaneous knockout of PARP-1 and PARP-2 die in embryonic period.Meanwhile,some studies have confirmed that PARP-1 inhibition is sufficient to induce anti-proliferative effects on tumors.Selective PARP-1 inhibitors not only achieve anti-tumor effects,but also have the potential to reduce toxic side effects.It is important to study and discover PARP-1 selective inhibitors.However,the high homology of PARP-1 and PARP-2 in the catalytic structural domain poses difficulties for the development of PARP-1 selective inhibitors,making the number of reported PARP-1 selective inhibitors still relatively small.Based on the structure and function of PARP-1,this thesis introduced the anti-tumor mechanism of PARP-1 inhibitors and summarized the research progress of PARP-1 selective inhibitors.In addition,by analyzing the amino acid residues near the catalytic regions of PARP1 and PARP-2,it was found that the key amino acids on the PARP-1 α-helix were Gln759,Glu763,Asp766 and Asp770,while the key amino acids on the PARP-2 α-helix were Ser328,Gln332 and Glu335.These differentiated key residues with distinct properties are close to the small ligands.For example,compared to PARP-2,Glu763 and Asp766 of PARP-1 occupy a smaller volume and are prone to form strong interactions with larger substituents,which can be used as key points for the design of PARP-1 selective inhibitors.Targeting this selective region,two series of 142 compounds were designed and synthesized by taking G11,a previous research result of our group,as the lead compound.The active sites were occupied with aminothiourea and benzimidazole carboxamide,respectively,and various groups such as substituted phenyl groups were tried to occupy the selective sites.The preliminary bioactivity evaluation of the target compounds at the enzyme level and cellular level revealed compounds Y5-19,Y6-15,Y6-16 and Y6-19 with favorable activity and selectivity,where compound Y6-16 showed the highest enzyme inhibitory activity(IC50=12.82 nM)and optimal selectivity index(SI=153.12),significantly better than the activity(IC50=41.71 nM)and selectivity(SI=37.40)of the lead compound.In addition,the IC50 of Y6-16 was less than 10 μM against six types of tumor cells,namely Hela,SiHa,C33a,SK-OV-3,HCT116 and A549.The preliminary in vivo anti-tumor activity assay in mice showed that Y6-16 had significant anti-tumor proliferation effects.The discovery of Y6-16 provides a reference for the development of selective inhibitors of PARP-1.