Design, Synthesis, in Vitro and in Vivo Anticancer and Antiangiogenic Activity of Novel 3-Arylamino Benzofuran Derivatives Targeting the Colchicine Site on Tubulin

A new series of compounds characterized by the presence of a 2-
methoxy/ethoxycarbonyl group, combined with either no substituent or a methoxy group at
each of the four possible positions of the benzene portion of the 3-(3’,4’,5’-
trimethoxyanilino)benzo[b]furan skeleton, were evaluated for antiproliferative activity against
cancer cells in culture, and, for selected, highly active compounds, inhibition of tubulin
polymerization, cell cycle effects and in vivo potency. The greatest antiproliferative activity
occurred with a methoxy group introduced at the C-6 position, the least with this substituent
at C-4. Thus far, the most promising compound in this series was 2-methoxycarbonyl-3-
(3’,4’,5’-trimethoxyanilino)-6-methoxybenzo[b]furan (3g), which inhibited cancer cell growth
at nanomolar concentrations (IC50’s, 0.3-27 nM), bound to the colchicine site of tubulin,
induced apoptosis and showed, both in vitro and in vivo, potent vascular disrupting properties
derived from the effect of this compound on vascular endothelial cells. Compound 3g had in
vivo antitumor activity in a murine model comparable to the activity obtained with
combretastatin A-4 phosphate.