Design, synthesis, in vitro, and in vivo anticancer and antiangiogenic activity of novel 3-arylaminobenzofuran derivatives targeting the colchicine site on tubulin

Journal of Medicinal Chemistry
Romeo RomagnoliGiampietro Viola

Abstract

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 values of 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.

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Citations

Jun 28, 2016·Journal of Medicinal Chemistry·María-Jesús Pérez-PérezSandra Liekens
Nov 10, 2016·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Souvik BanerjeeDuane D Miller
Mar 21, 2017·Bioorganic & Medicinal Chemistry Letters·Guo-Xue HeGui-Fa Su
Jun 10, 2020·Organic & Biomolecular Chemistry·Wu ZhangWanxiang Zhao
Nov 18, 2018·Frontiers in Oncology·Priscila Fabiana RodriguesRoberto Ronca
Jan 8, 2021·Organic & Biomolecular Chemistry·Roberta BortolozziGiampietro Viola
Dec 16, 2020·International Journal of Molecular Sciences·Arianna GiacominiRoberto Ronca
Feb 8, 2021·European Journal of Medicinal Chemistry·Romeo RomagnoliRoberta Bortolozzi

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