1. Discovery of novel coumarin-based derivatives as inhibitors of tubulin polymerization targeting the colchicine binding site with potent anti-gastric cancer activities.
- Author
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Tian XY, Zhang WX, Chen XY, Jia MQ, Zhang SY, Chen YF, Yuan S, Song J, and Li J
- Subjects
- Humans, Colchicine pharmacology, Tubulin metabolism, Tubulin Modulators chemistry, Molecular Docking Simulation, Polymerization, Cell Proliferation, Binding Sites, Coumarins pharmacology, Drug Screening Assays, Antitumor, Stomach Neoplasms drug therapy, Antineoplastic Agents pharmacology, Antineoplastic Agents chemistry
- Abstract
In this work, a series of novel coumarin-based derivatives were designed and synthesized as tubulin polymerization inhibitors targeting the colchicine binding site, and their antiproliferative activities against MGC-803, HCT-116 and KYSE30 cells were evaluated. Among them, the compound I-3 (MY-1442) bearing a 6-methoxy-1,2,3,4-tetrahydroquinoline group exhibited most potent inhibitory activities on MGC-803 (IC
50 = 0.034 μM), HCT-116 (IC50 = 0.081 μM) and KYSE30 cells (IC50 = 0.19 μM). Further mechanism studies demonstrated that compound I-3 (MY-1442) could directly bind to the colchicine binding site of β-tubulin to inhibit tubulin polymerization and microtubules at the cellular level. The results of molecular docking indicated there were well binding interactions between compound I-3 (MY-1442) and the colchicine binding site of β-tubulin. Compound I-3 (MY-1442) also exhibited effective anti-proliferation, pro-apoptosis, and anti-migration abilities against gastric cancer cells MGC-803. Additionally, compound I-3 (MY-1442) could regulate the expression of cell cycle- and apoptosis-related proteins. Importantly, compound I-3 (MY-1442) could significantly inhibit tumor growth in the MGC-803 xenograft tumor model with a TGI rate of 65.5 % at 30 mg/kg/day. Taken together, this work suggested that the coumarin skeleton exhibited great potential to be a key pharmacophore of tubulin polymerization inhibitors for the discovery of anticancer agents., Competing Interests: Declaration of competing interest There is no conflict of interest about this article to declare., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)- Published
- 2024
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