Design,Synthesis And Mechanism Exploration Of Novel Lead Compound Based On A Scaffold Of Piperidine Ring Fused To Thiophene Against Ovarian Cancer

Ovarian cancer is one of the most common malignant tumor in the female reproductive system,as well as the most deadly in all kinds of gynecological cancer.75% of patients with ovarian cancer are confirmed in stage III and IV,the 5-year survival rate is only 25%.Statistics show that 80% of patients with advanced ovarian cancer will have a relapse accompanied by severe drug resistance,which is one of the important causes of death of patients.Therefore,it has great significance on the development of new small-molecule candidate drugs for the treatment of ovarian cancer.At the same time,the research shows,the STAT3 pathway is closely related to ovarian cancer,it promotes proliferation,inhibits apoptosis,induces the formation of blood vessels,and helps tumours evade immune system,and also has close relationship with ovarian cancer drug resistance.So,we are committed to developing new smallmolecule drugs for ovarian cancer,which can target the STAT3 signaling pathway.Our laboratory found compound 106,whose binding effect with STAT3 protein was obvious.Therefore,the compound 106 was reconstructed in the early stage.Based on previous work,we made a comprehensive analysis of the dominant structure and the group.Meanwhile,considering the steric hindrance,electronic effect,and reference to the structure of existing STAT3 inhibitors,etc.,we designed five aspects of chemical modification,including the exploration of original nucleus,the exploration of the connection part,and substituent exploration and so on,then we got a series of new molecule compounds.Through bioactive screening,including: Anti-ovarian cancer proliferation activity,inhibition mechanism in the cell and animal experiment,etc.,we found compound Z7 showed great activity in vivo or in vitro experiments,promising to be a potential STAT3 inhibitor for ovarian cancer.