Design,Synthesis,and Biological Activity Of C-Met Kinase Inhibitors

c-Mesenchymal-epithelial transition（c-Met）kinase is a unique RTK with pleiotropic properties.It has an influential role in cancer progression,tumorigenesis,and development of treatment resistance.Therefore,c-Met is a promising therapeutic target for various cancers.Broadly speaking,c-Met TKIs can be divided into type I,type II,and Type III.Because of the small molecule inhibitors targeting c-Met,type II small molecule inhibitors have better selectivity than type I inhibitors.At the same time,molecular docking studies have shown that type II small molecule inhibitors can extend to protein.The hydrophobic pocket of kinase forms a hydrophobic effect,thereby solving drug resistance caused by related mutations.Therefore,the main research target of this article is the type II small molecule inhibitor of the c-Met kinase.We designed and synthesized a series of N-sulfonyl amidine derivatives and evaluated their c-Met inhibitory effect and cytotoxic activity.First,through a fast,efficient,and convenient one-pot boiling reaction,the small target molecules are synthesized by selecting alkynes,amines,and azides as raw materials.In addition,a sulfonyl group is added to the target compound,and its function is to improve the selectivity of the target compound to c-Met.Subsequently,c-Met kinase inhibitory activity,and human lung cancer cells（A549）,human colorectal adenocarcinoma cells（HT-29）,human gastric cancer cells（SGC-7901）,and human triple-negative breast cancer cells（MDA-MB-231）was evaluated for their antiproliferative activity.The activity results showed that most of the target compounds showed moderate to high-efficiency inhibitory activity against c-Met and cancer cells.Among them,the target compounds had better inhibitory activity against HT-29 and SGC-7901 and had certain selectivity.Furthermore,four of the derivatives,3c-f,3c-d,3c-e,and3c-a,show highly effective activity on the c-Met kinase.Fortunately,compound3c-f(IC₅₀=1.99 n M)showed a potency equivalent to foretinib(IC₅₀=2.15 n M).The means that the compound 3c-f is a promising molecule in this series.In addition,molecular docking simulation revealed the binding mode of 3c-d and 3c-f to the active site of c-Met.In summary,this indicates that it can be used as a new lead molecule for the further discovery of selective type II c-Met inhibitors.