Design, synthesis, and bioevaluation of 1-pyrrolo[3,2-]pyridine derivatives as colchicine-binding site inhibitors with potent anticancer activities.

A new series of 1-pyrrolo[3,2-]pyridine derivatives were designed and synthesised as colchicine-binding site inhibitors. Preliminary biological evaluations showed that most of the target compounds displayed moderate to excellent antitumor activities against three cancer cell lines (HeLa, SGC-7901, and MCF-7) . Among them, exhibited the most potent activities against three cancer cell lines with IC values ranging from 0.12 to 0.21 μM. Tubulin polymerisation experiments indicated that potently inhibited tubulin polymerisation at concentrations of 3 μM and 5 μM, and immunostaining assays revealed that remarkably disrupted tubulin microtubule dynamics at a concentration of 0.12 μM. Furthermore, cell cycle studies and cell apoptosis analyses demonstrated that at concentrations of 0.12 μM, 0.24 μM, and 0.36 μM significantly caused G2/M phase cell cycle arrest and apoptosis. The results of molecular modelling studies suggested that interacts with tubulin by forming hydrogen bonds with colchicine sites Thrα179 and Asnβ349. In addition, the prediction of physicochemical properties disclosed that conformed well to the Lipinski's rule of five.