Design And Synthesis Of Derivatives Of Winolide A And The Synthesis Process Optimization Of Rotundine

At present,one of the most common malignant tumors in the world is liver cancer,which has no obvious clinical symptoms and progresses rapidly with poor prognosis.Therefore,liver cancer ranks second in the global mortality rate.In China,the incidence of liver cancer is extremely high,the number of patients in the world accounted for more than50%of the world’s population.Currently,the only first-line drugs available for patients with advanced liver cancer are levastinib and sorafenib,which are highly effective and can easily lead to drug resistance.Therefore,it is urgent to develop new and effective drugs for the treatment of liver cancerA key approach to drug discovery is to have new active molecules in naturally occurring substances.The experimental team of the author found Winolide A through screening natural substances,and found that it has A strong inhibitory effect on the active proliferation of liver cancer cells,and can effectively kill Hep G2,huh-7 and smmc-7721liver cancer cells.In this study,the Winolide A as a lead compound,in order to obtain a compound having a less toxic and can inhibit the activity of the proliferation of hepatoma cells.The main raw materials used in this study were 1,4-maleic glycol and propargylic acid.After the esterification reaction and the cyclization of enyne,a variety of new derivatives were obtained through the four reactions of oxidation and amidation.The structures of all the substances were verified by ¹³C-NMR,¹H-NMR and HR-MS.In addition,the reaction conditions for aniline condensation were further optimized,and the synthetic derivatives were studied.STAT3 and P53 were used as relevant targets for cancer-related signaling networks,and RAF protein with sorafenib as a ligand Targets are molecularly docked.It was found to have an effect on the RAF target,from which it can be preliminarily concluded that the target of the Winolide A derivative may be RAF.Finally,the proliferation inhibition activity of 20 Winolide A derivatives on Huh-7and Hep G2 liver cancer cells and the toxicity of normal liver cells L02 were studied.The most active derivative is S-2,which has IC50 values of 1.85μM and 1.19μM for Huh-7cells and Hep G2 cells.It is hoped that this study can provide more ideas and directions for finding more kinds of lead compounds with inhibitory effects on the activities of liver cancer cells,and also provide more references for the studies on other natural substances.At the same time,this article also studied the optimization of the route of semi-synthesis of rotundine,and improved the demethylation of berberine hydrochloride,so that the first step yield was more than 95%.