Design, synthesis and structure-activity relationship of 2-(3',4',5'-trimethoxybenzoyl)-benzo[b]furan derivatives as a novel class of inhibitors of tubulin polymerization
Romagnoli, Romeo × Baraldi, Pier Giovanni Carrion, Maria Dora Cara, Carlota Lopez Cruz-Lopez, Olga Tolomeo, Manlio Grimaudo, Stefania Cristina, Antonietta Di Pipitone, Maria Rosaria Balzarini, Jan Zonta, Nicola Brancale, Andrea Hamel, Ernest #
The biological importance of microtubules in mitosis and cell division makes them an interesting target for the development of anticancer agents. Small molecules such as benzo[b]furans are attractive as inhibitors of tubulin polymerization. Thus, a new class of inhibitors of tubulin polymerization based on the 2-(3',4',5'-trimethoxybenzoyl)-benzo[b]furan molecular skeleton, with electron-donating (Me, OMe or OH) or electron-withdrawing (F, Cl and Br) substituents on the benzene ring, was synthesized and evaluated for antiproliferative activity, inhibition of tubulin polymerization and cell cycle effects. Adding a methyl group at the C-3 position resulted in increased activity. The most promising compound in this series was 2-(3',4',5'-trimethoxybenzoyl)-3-methyl-6-ethoxy-benzo[b]furan, which inhibits cancer cell growth at nanomolar concentrations and interacts strongly with tubulin by binding to the colchicine site.