Synthesis and biological evaluation of dihydrobenzofuran lignans and related compounds as potential antitumor agents that inhibit tubulin polymerization

A series of 19 related dihydrobenzofuran lignans and benzofurans was obtain ed by a biomimetic reaction sequence involving oxidative dimerization of p- coumaric, caffeic, or ferulic acid methyl esters, followed by derivatizatio n 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, represe nting diverse histologies. Leukemia and breast cancer cell lines were relat ively more sensitive to these agents than were the other cell lines. Compou nds 2c and 2d, but especially 2b (methyl (E)-3-[2-(3,4-dihydroxyphenyl)-7-h ydroxy-3-methoxycarbonyl-2,3-dihydro-1-benzofuran-5-yl]prop-2-enoate), the dimerization product of caffeic acid methyl ester, containing a 3',4'-dihyd roxyphenyl moiety and a hydroxyl group in position 7 of the dihydrobenzofur an ring, showed promising activity. The average GI(50) value (the molar dru g concentration required for 50% growth inhibition) of 2b was 0.3 mu M. Aga inst three breast cancer cell Lines, 2b had a GI(50) value of <10 nhl. Meth ylation, reduction of the double bond of the C-3-side chain, reduction of t he methoxycarbonyl functionalities to primary alcohols, or oxidation of the dihydrobenzofuran ring to a benzofuran system resulted in a decrease or lo ss of cytotoxic activity. Compound 2b inhibited mitosis at micromolar conce ntrations in cell culture through a relatively weak interaction at the colc hicine binding site of tubulin. In vitro it inhibited tubulin polymerizatio n by 50% at a concentration of 13 +/- 1 mu M. The 2R,3R-enantiomer of 2b wa s twice as active as the racemic mixture, while the 2S,3S-enantiomer had mi nimal activity as an inhibitor of tubulin polymerization. These dihydrobenz ofuran lignans (2-phenyl-dihydrobenzofuran derivatives) constitute a new gr oup of antimitotic and potential antitumor agents that inhibit tubulin poly merization.