Design,Synthesis And Anti-tumor Activity Of Silybin Derivatives Based On CDK Protein Target

Natural products have always been a hot topic of anti-tumor drugs due to their diversity of biochemical structures,selectivity to target proteins and low biological toxicity and side effects.Silybin(Silybin)is a flavonoid lignin compound,which has the effect of protecting the liver and anti-hepatotoxicity.At the same time,silybin also has anti-cancer effect.It is used for prostate adenocarcinoma,estrogen dependence and estrogen.Treatment of non-dependent breast cancer,cervical cancer,colon cancer,etc.CDK(Cyclin-dependentkinases functiom)is a cyclin-dependent kinase involved in cell cycle regulation.Research now shows that CDK plays a different role in the regulation of the cell cycle.Therefore,CDK is a very important protein in the research process of anti-tumor drugs.In order to improve the water solubility of silibinin,a new class of silibinin derivatives was rationally designed and synthesized using computer-aided drug design methods using silibinin as the parent compound.In this paper,computer molecular docking technology is used to simulate the molecular docking of CDK inhibitor Abemaciclib and CDK target protein(5L2S),analyze its interaction mode with CDK target protein,and determine the key chemical fragments of its action on CDK target protein.The results show that Abemaciclib binds to the amino acid residues of the CDK target protein through hydrogen bonds,hydrophobic bonds and van der Waals forces,and its amino linking arm binds to the key amino acid residue ASP145 of the CDK4/6 target protein.The nitrogen on the five-membered ring Combines with amino acid residue GLY165.A series of 11 new silibinin derivatives were designed and synthesized by introducing amino groups into the C ring of silibinin and further synthesizing amides.The target compound is obtained by column chromatography separation technology,and the structure characterization of the target compound is determined by hydrogen nuclear magnetic spectrum.By studying the binding mode of the target compound and the CDK target protein,the results show that the series of silybin derivatives produce hydrogen bonding with key amino acid residues of the target protein,and the binding energy is significantly better than silibinin.In this test,the synthesized silybin derivatives were subjected to the in vitro tumor cell suppression test of MCF-7 human adenocarcinoma cells and Hep G-2 human liver cancer cells by the MTT method.The experimental results show that the inhibitory activity of the tested compounds on two kinds of tumor cells is significantly stronger than that of silibinin.Among them,compounds 2 and 3 show strong inhibitory effects on MCF-7 breast cancer cells and Hep G-2 liver cancer cells,which is worthwhile further research.