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Discovery of novel coumarin-based derivatives as inhibitors of tubulin polymerization targeting the colchicine binding site with potent anti-gastric cancer activities.
- Source :
-
European journal of medicinal chemistry [Eur J Med Chem] 2024 Feb 05; Vol. 265, pp. 116079. Date of Electronic Publication: 2023 Dec 22. - Publication Year :
- 2024
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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 <subscript>50</subscript>  = 0.034 μM), HCT-116 (IC <subscript>50</subscript>  = 0.081 μM) and KYSE30 cells (IC <subscript>50</subscript>  = 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.<br />Competing Interests: Declaration of competing interest There is no conflict of interest about this article to declare.<br /> (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)
- 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
Subjects
Details
- Language :
- English
- ISSN :
- 1768-3254
- Volume :
- 265
- Database :
- MEDLINE
- Journal :
- European journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 38150962
- Full Text :
- https://doi.org/10.1016/j.ejmech.2023.116079