Design,Synthesis And Anti-Hepatocellular Carcinoma Activity Of Evodiamine Derivatives

Hepatocellular carcinoma（HCC）,the most hackneyed primary hepatic carcinoma,is now considered as one of the most pervasive and fatal malignant tumors with increasing incidence by year.At present,the first-line small molecule targeted therapeutic drugs for advanced HCC are extremely finite,and it is badly in need of developing novel therapeutic drugs.Evodiamine,a tryptamine indole alkaloid,is isolated from Evodia rutaecarpa,which has been identified as Top1 inhibitor and show numerous biological activities comprising antitumor.When our research group optimized the structure of evodiamine in the early stage,it was found that the activity was better when phenyl was introduced at N14 position,fluorine atom was introduced at the N14-phenyl group meta-position,and substituent was introduced at the 10-position of A ring and the 3-position of E ring at the same time,but no candidate compound with good anti-HCC activity in vitro and in vivo was obtained.Therefore,based on previous studies,23 disubstituted derivatives of evodiamine on N14-phenyl or E-ring were designed and synthesized in order to obtain highly active compounds.The indagation on structure-activity relationship proved the compounds F-3 and F-4 had the best activity when meta-position of N14-phenyl group was substituted by fluorine atom,1,3-difluoro disubstituted on E-ring and 10-position of A-ring was synergistically substituted by hydroxyl or acetyl.At the same time,these two compounds performed double inhibition against Top1/Top2,and the cytotoxicity to normal liver cells was low,so compounds F-3 and F-4 were optimized for subsequent biological activity evaluation on HCC cell lines Huh7 and SK-Hep-1.In vitro antiproliferative studies showed that two compounds significantly suppressed the proliferation of Huh7(IC₅₀=0.05μM or 0.04μM,respectively)and SK-Hep-1(IC₅₀=0.07μM or 0.06μM,respectively).In addition,F-3 and F-4 could inhibit cell invasion and migration,block cell cycle to G2/M stage,induce apoptosis,inhibit the activation of HSC-T6 and reduce the secretion of Col-1 to delay the progress of liver fibrosis.Most importantly,compound F-4 inhibited tumor growth more significantly than the positive drug sorafenib in vivo,whose tumor inhibition rate was60.3%.In short,compound F-4 has excellent potential to be a candidate for therapy of hepatocellular carcinoma,and the study also provides ideas for developing novel and efficient evodiamine derivatives.