Studies On The Design,Synthesis And Antitumor Activity Of Tetrahydroisoquinoline-Imidazolium Salt Hybrids

Cancer is one of the most lethal diseases and its incidence and mortality rates have been increasing in recent years.The situation is not optimistic.Therefore,medicinal chemists have been committed to finding and developing new anticancer drugs.The research shows that natural products and bioactive molecules containing structural skeleton of tetrahydroisoquinoline,tetrahydroquinolines or imidazole have significant antitumor activity.Base on the research of our group in recent years,a series of tetrahydroisoquinoline/tetrahydroquinolines-imidazolium salt hybrids was synthesized by molecular hybrid methods and evaluated in vitro against a panel of human tumor cell lines.The aim of this research was to find lead compounds for antitumor drugs with further research value.The thesis was divided into two chapters:In the first chapter,the recent research of biological activities of tetrahydroisoquinolines,tetrahydroquinolines and imidazoles were reviewed.In the secondchapter,thedesign,synthesisandantitumoractivityof tetrahydroisoquinoline-imidazolium salt hybrids were studied.Forty-six new tetrahydroisoquinoline/tetrahydroquinoline-imidazolium salt hybrids were prepared and evaluated in vitro against a panel of human tumor cell lines.The results showed that compounds e27 with the IC₅₀ values of 4.95,5.63,8.36,5.22,8.75?M and e39with the IC₅₀ values of 1.40,4.83,5.23,0.79,1.77?M displayed significant inhibitory activity in vitro against five tumor cells line,Leukemia cells?HL-60?,liver cancer?SMMC-7721?,lung cancer?A549?,breast cancer?MCF-7?and colon cancer?SW480?,respectively.Compound e24 had a good growth inhibition effect against HL-60,SMMC-7721,A549 and MCF-7 tumor cells,with the IC₅₀ values of 6.45,14.62,12.34,7.97?M.Notably,compounds e29,e35,e36 showed inhibitory activity selectively against MCF-7 cells line with IC₅₀ values lower than 1.00?M?0.76-0.79?M?,with 12-13 folds lower than control drug DDP.In summary,a series of tetrahydroisoquinoline/tetrahydroquinoline-imidazolium salt hybrids was synthesized.Among them,several imidazole salt hybrids showed excellent antitumor activity and especially exhibited inhibitory activity selectively against MCF-7 cells line.The future work will be focused on the structural modification,structure-activity relationship and mechanism,which will provide a scientific basis for the discovery of lead compounds for antitumor drugs.