Design,Synthesis And Antitumor Activity Of Evodiamine Derivatives Containing Trimethoxyphenyl

Designing and synthesizing a evodiamine derivative that can inhibit tumor vascularity and inhibit glycolysis of tumor cells by inhibiting tubulin and HIF-1α.Methods:The evodiamine derivatives were obtained through seven steps using aniline,salicylic acid and 3,4,5-trimethoxybenzoic acid as raw materials.Finally,18 compounds are obtained.Their structures were characterized by ¹H NMR and MS.The anti-proliferative activities of those evodiamine derivatives were tested by cytotoxicity assay on five tumor cell lines.Further,the cell scratch test and the colony test were used to determine the antitumor activity;and the effect of the compound on the apoptosis and cell cycle of the tumor cells was examined by flow cytometry.The lactic acid kit is used to detect whether the compound can reduce the production of cellular lactic acid,and the binding of the compound to tubulin is analyzed by molecular docking.Results:A series of evodiamine derivatives were successfully synthesized and identified.10-methoxy-13-（3,4,5-trimethoxybenzoyl）-7,8,13,13btetrahydro-5H-benzo[5’,6’][1,3]Pyrazino[3’,2’:1,2]pyrido[3,4-b]i-ndole-5-one（12h）showed the best antitumor activity against gastric cancer cell HGC-27(IC₅₀=3.3±1.5μmol/L),and the cytotoxicity of GES-1 in normal gastric gland cells was found to be non-toxic for 12h.It was shown by cell colony and scratch test that compound 12h can inhibit the growth and migration ability of HGC-27 cells.At the same time,we examined the effect of compound 12h on the apoptosis and cycle of HGC-27 cells by flow cytometry,and found that it can induce apoptosis and block G2/M phase to inhibit cancer cell proliferation.The lactic acid content of HGC-27 cells treated with compound 12h was significantly decreased in a dose-dependent manner compared with the control group.Finally,we simulated the binding of compound 12h to tubulin by computer.The results showed that 12h might be an effective tubulin inhibitor.