Synthesis And Antitumor Activity Of Podophyllotoxin Derivatives

Objective Cancer is a serious threat to human health and life has become the number one cause of death of human beings.The clinical treatment of cancer based on comprehensive treatment,but chemical treatment is one of the main treatments.The research of cancer chemotherapy drug has made great progress.Cancer patient survival time was significantly prolonged and the cure rate also was gradually improved.However.there are many problems,for example,more and more serious clinical multidrug resistance(MDR)is the important reason for the failure of chemotherapy.It is a major problem in cancer chemotherapy need to be resolved.Looking for efficiency and low toxicity,effective multi-drug resistant tumor anticancer drugs has become a hot topic in the field of anticancer drug research.This topic is using the anti-tumor effect of podophyllotoxin as raw materials for the preparation of a series of derivatives of the structural modification to filter efficiency and low toxicity of the compounds.Content According to drug design flattening principle,we introduced the benzene ring,indole substituents,as well as a number of active small molecule heterocyclic in C-4 position on the basis of podophyllotoxin nucleus.Methods In recent years,our group has been engaged in the transformation of podophyllotoxin and has synthesized a large number of high activity podophyllotoxin derivatives.On the basis of the analysis of podophyllotoxin SAR,we designed and synthesized four series of podophyllotoxin derivatives:5-substituted indole-3-deoxypodophyllotoxin derivatives were synthesized by podophyllotoxin and indoles.Amines podophyllotoxin derivatives were synthesised by aldehydes reacting with 4?-amino-desoxypodophyllotoxin or 4'-demethyl desoxypodophyllotoxin.N-methyl amine podophyllotoxin derivatives were synthesized by methylation of amine podophyllotoxin derivatives.Use the MTT assay to test anti-tumor activity of all the target compounds on Hela cells.MCF-7 cells.KB cells.K562 cells and K562/A02 cell.Results We Synthesis four series of 57 target compounds,all these target compounds were not reported by previous literature.Their structures were confirmed by 1H-NMR,13C-NMR.HR-ESI-MS and melting point determination analysis.MTT assay was used to filter the anti-tumor activity of these compounds in vitro.The test results show that all the target compounds had varying degrees of totoxic activity in vitro.Most of the compounds had significant anti-MDR activity in vitro.Conclusion According to test results,we preliminarily analyzed and summarized the structure-activity relationship of four series of compounds,it will settle the basis for our further research.