Back to Search
Start Over
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 . Feb2024, Vol. 265, pN.PAG-N.PAG. 1p. - Publication Year :
- 2024
-
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 (IC 50 = 0.081 μM) and KYSE30 cells (IC 50 = 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. [Display omitted] • A series of novel coumarin-based derivatives were designed and synthesized. • Compound I-3 (MY-1442) exhibited potent inhibitory activities. • Compound I-3 (MY-1442) could inhibit tubulin polymerization by binding to the colchicine binding site. • Compound I-3 (MY-1442) was effective in the inhibition of MGC-803 cells Xenograft Model. [ABSTRACT FROM AUTHOR]
- Subjects :
- *COUMARINS
*BINDING sites
*TUBULINS
*COLCHICINE
*POLYMERIZATION
*MOLECULAR docking
Subjects
Details
- Language :
- English
- ISSN :
- 02235234
- Volume :
- 265
- Database :
- Academic Search Index
- Journal :
- European Journal of Medicinal Chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 174789287
- Full Text :
- https://doi.org/10.1016/j.ejmech.2023.116079