Design, synthesis and biological evaluation of novel 2-phenyl-4,5,6,7-tetrahydro-1H-indole derivatives as potential anticancer agents and tubulin polymerization inhibitors

A new series of 2-phenyl-4,5,6,7-tetrahydro-1H-indole derivatives as tubulin polymerization inhibitors were synthesized and evaluated for the anti-proliferative activities. All newly prepared compounds were tested for their antiproliferative activity in vitro on the human breast cancer cell line (MCF-7) and human lung adenocarcinoma cell line (A549). Among them, compound 7b with a 4-methoxyl substituent at the phenylhydrazone moiety exhibited the most potent anticancer activity against MCF-7 and A549 with IC50 values of 1.77 +/- 0.37 and 3.75 +/- 0.11 lM, respectively. Interestingly, 7b displayed significant selectivity in inhibiting cancer cells over LO2 (normal human liver cells). Further mechanism studies revealed that 7b significantly arrested cell cycle at G2/M phase and induced apoptosis in a dose-dependent manner. Additionally, 7b effectively inhibited tubulin polymerization with an inhibitory manner similar to that of colchicine. Furthermore, molecular docking study suggested that 7b had high binding affinities for the colchi cine binding pocket of tubulin. Hence, this study demonstrates for the first time that tetrahydroindole can be used as a functional group for the design and development of new tubulin polymerization inhibitors. (C) 2021 The Author(s). Published by Elsevier B.V. on behalf of King Saud University.

Automated summary

A series of new 2-phenyl-4,5,6,7-tetrahydro-1H-indole derivatives were synthesized and evaluated for their anti-proliferative activities, with one compound showing the most potent anticancer activity against breast cancer and lung cancer cells while sparing normal liver cells. Mechanism studies revealed that the compound arrested cell cycle and induced apoptosis, and effectively inhibited tubulin polymerization with an inhibitory mechanism similar to colchicine. Molecular docking studies indicated high binding affinities for the colchicine binding pocket of tubulin, suggesting potential as new tubulin polymerization inhibitors.