Design,synthesis And Antitumor Evaluation Of Novel C-Met Kinase Inhibitors

c-Met tyrosine kinase is one of the important members of the tyrosine kinase receptor family and the high-affinity receptor for hepatocyte growth factor.HGF/c-Met signaling pathway abnormality,c-Met protein mutation or amplification is found in many cancers.c-Met is an important node of HGF/c-Met signaling pathway.This pathway plays an important role in the occurrence,development and metastasis of various cancers and interacts with other pathways.Small molecular c-Met kinase inhibitors can not only regulate the HGF-Met signal transduction pathway,but also effect on other transduction pathways simultaneously.At present,the structures of c-Met kinase inhibitors are relatively simple.The piperidine ring is oxidized by body.Its metabolite inhibits liver cell P450 enzyme system,causing great side effects on liver and kidney.Therefore,it is of great significance to research and develop c-Met kinase inhibitors with novel and diverse structures.In this study,based on the fragment-based drug design method,and the structure of existing c-Met kinase inhibitors.Aromatic,triazole and acylhydrazine fragments were used for fragment growth to obtain compound skeletons.Then virtual screening was added in drug design.A series of new types of compounds were synthesized and evaluated in vitro antitumor activity studies.A total of 31 target compounds of two structure types were designed and synthesized,including?E?-N'-benzylidenehydrazide compounds and 2-?4-phenyl-1H-1,2,3-triazol-1-yl?acetic acid compounds,all compounds have not been reported in the literature.The structures of all the target compounds were confirmed by MS?¹H-NMR and ¹³C NMR.In addition to showing good c-Met inhibitory activity,the target compounds also exhibit inhibitory activities at other targets,which provides a good idea for the design of new multi-target c-Met inhibitors.Target compound A-01(c-Met IC₅₀=1.70nM),A-02(c-Met IC₅₀=0.37 n M),A-06(c-Met IC₅₀=1.19 n M),A-09(c-Met IC₅₀=1.73 nM),B-02(c-Met IC₅₀=3.41 n M;VEGFR-2 IC₅₀=25.34 nM)and C-02(c-Met IC₅₀=2.1 n M)showed excellent dual target inhibitory activity and is worthy of further study.