Studies On The Design,Synthesis And Antitumor Activity Of Novel Matrine Derivatives

Matrine is the main active components of sophora flavescens.Besides the sophora flavescent contains many other kinds of chemicals such like sophocarpine,oxymatrine,oxysophocarpine,sophoridine,sophoramine and so on.Matrine has extensive biological activity,such as anti-inflammatory,antibacterial,antiviral,antitumor,analgesic,immunity regulation,cardiovascular system regulation and central nervous system regulation.These pharmacological activities showed good therapeutic effects in clinical applications and the matrine is made into many different kinds of pharmaceutican preparation.It is of great importance and challenging to do the structural modifications on matrine for the purpose of searching for new lead compound with high bioavailability and low toxicity.In our previous study,it is indicated that the physicochemical property and biological activity can be improved when introduce sulfur and hydrophobic groups in the structure of matrine.According to the structure-activity relationship of matrine,some hydrophobic functional groups,such as thiophenol group,benzoyl group,cinnamoyl group,benzyl group,disulfide generation of formic acid ester structure and piperazinyl group were introduced into matrine scaffold for the purpose of regulating the lipid-water partition coefficient and improving the pharmacological activity of the compound in order to search for new lead compound with better biological activity.Five series of new matrine derivatives were designed and synthesized.Using sophocarpine as the starting material,then introduce substituted thiophenol group to 13 site through Michael addition Reaction to get ? series of compounds.Using sophocarpine as the starting material,turn carbonyl group to thiocarbonyl group through sulfurization to get thiolsophocarpine,then introduce substituted thiophenol group to 13 site through Michael addition Reaction to get ? series of compounds.Using sophocarpine as the starting material,introduce disulfide generation of formic acid ester structure and piperazinyl group to 13 site through Michael addition Reaction to get the intermediate product S,then introduce substituted benzoyl group,substituted cinnamoyl group and substituted benzyl group to the intermediate product S through Amidation Reaction and Alkylation Reaction with substituted benzoic acid,substituted cinnamic acid and substituted benzyl bromide to get ?,? and ? series of compounds.All the 85 target compounds were firstly reported.The structures of them were confirmed through 1H NMR,13 C NMR and ESI-MS.All the target compounds were screened for the antitumor activity in vitro test against HCC-LM3 Human Hepatocarcinoma Cells.Preliminary pharmacological results of the experiments showed that almost all the target compounds exhibited a certain inhibitory activities to HCC-LM3 Human Hepatocarcinoma Cells,while a few others showed the opposite effect incredibly.Compounds ?14 and ?14 showed the strongest inhibitory activities towards HCC-LM3 Human Hepatocarcinoma Cells with the IC50 of 23.6 ?mol/L and 1.76 ?mol/L,respectively.This discovery provided new research direction for the structural modifications and had a certain significance to the study of searching for new antitumor drugs.