A series of novel 3,5-diaryl-1H-pyrazolo[3,4-b]pyridines as tubulin polymerization inhibitors targeting the colchicine site were designed via ring tethering strategy, which was supported by conformational analysis. The general, chemically unstable and rotational linker, carbanyl group, was locked by 1H-pyrazolo[3,4-b]pyridine to avoid carbonyl reduction and restrict the instability of molecular conformation caused by the rotation of the carbon-carbon single bond beside carbonyl group. All of target compounds were synthesized and evaluated for their antiproliferative activities against three human cancer lines (SGC-7901, A549 and HeLa) by MTT assay. Most of these compounds showed prominent in vitro potency and the most potent compound in this scaffold 13d (SGC-7901: IC50 = 13 nM) could significantly inhibit tubulin polymerization and strongly disrupt cytoskeleton. The results of molecular modeling study revealed that 13d interacts with tubulin by binding to the colchicine site.
Keywords: Colchicine site; Conformational analysis; Pyrazolo[3,4-b]pyridine; Ring tethering.
Copyright © 2018. Published by Elsevier Masson SAS.