化学
苯并呋喃
部分
立体化学
木脂素
生物活性
咖啡酸
细胞培养
微管蛋白
体外
生物化学
微管
遗传学
生物
细胞生物学
抗氧化剂
作者
Luc Pieters,Stefaan Van Dyck,Ming Gao,Ruoli Bai,Ernest Hamel,A. J. Vlietinck,Guy L. F. Lemière
摘要
A series of 19 related dihydrobenzofuran lignans and benzofurans was obtained by a biomimetic reaction sequence involving oxidative dimerization of p-coumaric, caffeic, or ferulic acid methyl esters, followed by derivatization reactions. All compounds were evaluated for potential anticancer activity in an in vitro human disease-oriented tumor cell line screening panel that consisted of 60 human tumor cell lines arranged in nine subpanels, representing diverse histologies. Leukemia and breast cancer cell lines were relatively more sensitive to these agents than were the other cell lines. Compounds 2c and 2d, but especially 2b (methyl (E)-3-[2-(3,4-dihydroxyphenyl)-7-hydroxy-3-methoxycarbonyl-2,3-dihydro-1-benzofuran-5-yl]prop-2-enoate), the dimerization product of caffeic acid methyl ester, containing a 3‘,4‘-dihydroxyphenyl moiety and a hydroxyl group in position 7 of the dihydrobenzofuran ring, showed promising activity. The average GI50 value (the molar drug concentration required for 50% growth inhibition) of 2b was 0.3 μM. Against three breast cancer cell lines, 2b had a GI50 value of <10 nM. Methylation, reduction of the double bond of the C3-side chain, reduction of the methoxycarbonyl functionalities to primary alcohols, or oxidation of the dihydrobenzofuran ring to a benzofuran system resulted in a decrease or loss of cytotoxic activity. Compound 2b inhibited mitosis at micromolar concentrations in cell culture through a relatively weak interaction at the colchicine binding site of tubulin. In vitro it inhibited tubulin polymerization by 50% at a concentration of 13 ± 1 μM. The 2R,3R-enantiomer of 2b was twice as active as the racemic mixture, while the 2S,3S-enantiomer had minimal activity as an inhibitor of tubulin polymerization. These dihydrobenzofuran lignans (2-phenyl-dihydrobenzofuran derivatives) constitute a new group of antimitotic and potential antitumor agents that inhibit tubulin polymerization.
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