Novel tubulin polymerization inhibitors based on the hybridization of coumarin and indole ring: Design, synthesis and bioactivities evaluation

In order to find the potent tubulin polymerization inhibitors as anticancer drugs, a series of novel coumarinindole derivatives were synthesized, and the bioactivity of these synthetic compounds was performed to elucidate the mechanism of anticancer activity. In vitro cell experiments indicated that among these compounds, 7a exhibited excellent inhibitory activities on MCF-7, A549 and HepG2 cells, having IC50 values ranging from 1.79 to 40.55 nanomolar, which was better than the positives cisplatin and colchicine. Tubulin polymerization inhibition assay found 7a could inhibit the polymerization of tubulin. Meanwhile, immunofluorescence staining of A549 cells showed that 7a targeted the tubulin to exert its anticancer activity. Additionally, compound 7a displayed significant inhibition of the wound-healing activity of A549 cells. The outcomes of flow cytometry demonstrated 7a could significantly halt the progression of the cell cycle during the G2/M phase and induce the apoptosis of A549 cells by reducing the mitochondrial membrane potential and increasing the level of ROS. Finally, molecular docking further demonstrated 7a could interact with tubulin. Collectively, the promising biological activity of 7a makes it valuable as further development of antitumor drugs.