Design, synthesis, and biological evaluation of cyclic-indole derivatives as anti-tumor agents via the inhibition of tubulin polymerization

This study revealed a new attractive cyclic-indole scaffold for the discovery of mitosis-targeting anti-tumour agents. Among all of the synthesized derivatives, compound 20 displayed the most potent anti-proliferative activity (with IC₅₀ values of 22-56 nM against seven Cancer cell lines) and tubulin polymerization inhibition (IC₅₀ = 0.15 ± 0.07 μM), which were much better than those of the reference compound Combretastain A-4 (CA-4). High selectivity ratios (9.68-7.61) of compound 20 toward human normal cells and Cancer cells were also observed. Immunofluorescence assay elucidated that compound 20 disrupted the intracellular microtubule network and interfered with cell mitosis. Cellular mechanism studies demonstrated that compound 20 arrested the cell cycle at the G₂/M phase and induced Apoptosis in a time- and dose-dependent manner. In summary, compound 20 deserves consideration for in vivo anti-tumour evaluation in further studies.

Antiproliferative activity; Apoptosis; Cell cycle arrest; Cyclic-indole derivatives; Tubulin polymerization inhibitor.