In this paper, quaternary 8-（1-acylethene-l-yl）-13-methylcoptisine chlorides targeting thioredoxin reductases （TrxRs） were designed to test the growth inhibitory activity against human cancer cell lines and the ef...In this paper, quaternary 8-（1-acylethene-l-yl）-13-methylcoptisine chlorides targeting thioredoxin reductases （TrxRs） were designed to test the growth inhibitory activity against human cancer cell lines and the effect on viability of the normal intestinal epithelial cell-6 （IEC-6） in vitro and to evaluate structure-activity relationship （SAR）. The introduced α, β-unsaturated ketone groups at C-8 consisting of n-alkanoyls possessing five to ten carbons or aroyls or cyclohexylcarbonyl increased the tested activity against the target cancer cell lines. By and large, this type of improvement was increasingly graced by the elongation of the aliphatic chain of the n-alkanoyls in the range of less than ten carbon atoms. The relatively more polar l-acylethene-l-yls displayed no effect on improving the activity. All the explored aroyls showed significant effect on improving the activity of the target compounds against the tested cancer cell lines with no SAR being observed, The findings of this study suggested that oil]water partition coefficient of the test compounds was one of the key factors impacting the target activity against the tested cancer cell lines. At the concentration of 10 μmol/L, except for the compounds with n-all（anoyls possessing seven or more carbons or with α-naphthoyl, none of the other compounds displayed obvious cytotoxicity on normal IEC-6 cell when co-incubated. The survival rate of IEC-6 cell ranged from 75% to 100% for the noncytotoxic compounds.展开更多
基金supported by grants from the National Natural Science Foundation of China(No. 81373269)CAMS Innovation Fund for Medical Sciences(No. 2016-12M-1-010)National Science and Technology Project of China(No.2017ZX09305008002)
文摘In this paper, quaternary 8-（1-acylethene-l-yl）-13-methylcoptisine chlorides targeting thioredoxin reductases （TrxRs） were designed to test the growth inhibitory activity against human cancer cell lines and the effect on viability of the normal intestinal epithelial cell-6 （IEC-6） in vitro and to evaluate structure-activity relationship （SAR）. The introduced α, β-unsaturated ketone groups at C-8 consisting of n-alkanoyls possessing five to ten carbons or aroyls or cyclohexylcarbonyl increased the tested activity against the target cancer cell lines. By and large, this type of improvement was increasingly graced by the elongation of the aliphatic chain of the n-alkanoyls in the range of less than ten carbon atoms. The relatively more polar l-acylethene-l-yls displayed no effect on improving the activity. All the explored aroyls showed significant effect on improving the activity of the target compounds against the tested cancer cell lines with no SAR being observed, The findings of this study suggested that oil]water partition coefficient of the test compounds was one of the key factors impacting the target activity against the tested cancer cell lines. At the concentration of 10 μmol/L, except for the compounds with n-all（anoyls possessing seven or more carbons or with α-naphthoyl, none of the other compounds displayed obvious cytotoxicity on normal IEC-6 cell when co-incubated. The survival rate of IEC-6 cell ranged from 75% to 100% for the noncytotoxic compounds.
