Design,Synthesis And Biological Evaluation Of Novel C-Met And Multi-target Tyrosine Kinase Inhibitors

Receptor tyrosine kinase(RTKs)is currently the focus of research on anti-tumor drugs.Among them,c-Met tyrosine kinase is a highly promising biomolecular target.At present,two c-Met inhibitors have been launched and several new chemical entities are in clinical research.In addition,the tumorigenesis and development mechanisms are complex.The development of multi-target and multi-pathway tyrosine kinase inhibitors to combat drug resistance and relapse during the course of cancer therapy represents the future direction of the development of anti-cancer drugs.Multi-targeted tyrosine kinase inhibitors act on several tumor related targets,which could overcome the resistance problem of single target.It is worth to design,syhthesis and evaluate the activity of c-Met and multi-targeted tyrosine kinase inhibitors.1?Rational design of novel compounds1)Novel c-Met inhibitors were designed based on the preliminary work of research group and pharmacophores of type II c-Met inhibitors.Using compounds SIPI7224and SIPI7228 as lead compound respectively,new compounds of series A and B were designed by bioisosterism and R-group replacement,enzyme-inhibitory activities were evaluated,and structure-activity relationship was analysised preliminary.2)Based on the design idea of multi-targeted tyrosine kinase inhibition,structure feature of reported compounds and active fragments of tyrosine kinase inhibitors were used to design new chemical entities,and the reasonability of designation was verified through pharmacology activities.2?Sythesis of new compoundsConvenient synthetic routes were developed to sythesize 19 c-Met inhibitors and24 multi-target tyrosine kinase inhibitors based on retrosynthetic analysis.The chemical structures were comfirmed by MS and ~1H NMR spectroscopy.Reaction conditions of key steps were studied to increase conversion rate and product purity.3?In vitro activity of new compounds1)Anti-tumor activity of c-Met inhibitorsNew compounds in two series all displayed c-Met enzyme-inhibitory activity(0.1?M).In series A,compound SIPI8090 showed great activity(c-Met Inhibition=82.5%),which was significantly better than lead compound SIPI7224.In series B,compound SIPI8092 showed great activity(c-Met Inhibition=70.3%),which was significantly better than SIPI7228.The results of anti-tumor activity verified the reasonability of design idea.In vitro anti-tumor cell proliferation experiments showed that the anti-proliferative activity of compounds SIPI8071,SIPI8072 and SIPI8089 on A549 cells and SNU-5 cells was comparable to that of Carbozantinib.2)Anti-tumor activity of multi-target tyrosine kinase inhibitorsBased on references,EGFR,KDR and c-Met high expression tumor cell lines were selected to test anti-proliferative activities of series C.And then compound SIPI6931with better anti-proliferative activity was selected for EGFR,VEGFR(KDR)and HGFR(c-Met)of three kinases inhibitory activity assay.The results of in vitro experiments showed that the anti-proliferative activity and kinase inhibitory activity of the series C compounds were generally weak,suggesting that the activity of these compounds need to be further confirmed and the design concept need to be further improved.In summary,a total of 43 new compounds were designed and synthesized in this thesis.The present work enriches the existing structural types of c-Met and multi-target tyrosine kinase inhibitors,providing references for further design of high active compounds.The compounds SIPI8090 and SIPI8092 display great c-Met enzyme inhibitory activity in vitro and deserve further study.