Studies On Design,Synthesis And Antitumor Activity Of Tetrahydrobenzodifuran-imidazolium Salt Hybrids

According to WHO report in 2011,cancer causes more deaths than coronary heart disease and stroke,which shows that the burden of cancer will continue to increase in the next decades.Therefore,the discovery and search of new anticancer drugs have received extensive attention.Medicinal chemists have found that natural products and their derivatives with dihydrobenzofuran,tetrahydrobenzodifuran or imidazole moieties exhibit a wide range of remarkable biological activities,especially antitumor activity.In this thesis,a series of novel tetrahydrobenzofuran-imidazolium salt hybrids were designed and synthesized to explore their antitumor activity of tetrahydrobenzodifuran-imidazole hybrids with the ultimate aim of developing potent antitumor agents.This thesis consists of two chapters.The first chapter reviewed the biological activity and synthetic strategy of natural products and their derivatives with dihydrobenzofuran and tetrahydrobenzodifuran.The biological activities of imidazoles also were reviewed.In the second chapter,forty-there novel tetrahydrobenzofuran-imidazolium salt hybrids were designed and synthesized,and their cytotoxicity were evaluateded in vitro against a panel of human lines.The study showed that most of the compounds had significant cytotoxic activity compared to the positive control cisplatin(DDP).Notably,compound b42 was found to be the most potent derivative against five human tumor cell lines investigated with IC50 values below 4.34 ?M,and exhibited inhibitory activity selectively against SMMC-7721,A549 and SW480 cell lines compared with DDP.Meanwhile,compound b37 was more selective to MCF-7 cell lines with IC50 value 8.4-fold lower than DDP.Study on the antitumor mechanism showed that compound b37 could induce cell cycle G1 phase arrest and apoptosis in SMMC-7721 cells.In general,forty-there novel imidazolium compounds were designed and synthesized,and the cytotoxicity activity showed that some compounds had significant antitumor activity.On the basis of this work,we will carry out further analysis of structure-activity relationship and the structural modification of tetrahydrobenzofuran-imidazolium salt,and carry out further studies on the pharmacological mechanism to lay the foundations for the discovery of potent antitumor agents.