2. Academic Validation
  3. Discovery of novel coumarin-based derivatives as inhibitors of tubulin polymerization targeting the colchicine binding site with potent anti-gastric cancer activities

Discovery of novel coumarin-based derivatives as inhibitors of tubulin polymerization targeting the colchicine binding site with potent anti-gastric cancer activities

  • Eur J Med Chem. 2023 Dec 22:265:116079. doi: 10.1016/j.ejmech.2023.116079.
Xin-Yi Tian 1,  Wei-Xin Zhang 2,  Xiao-Yu Chen 2,  Mei-Qi Jia 1,  Sai-Yang Zhang 3,  Yi-Fan Chen 1,  Shuo Yuan 4,  Jian Song 5,  Jia Li 6
Affiliations

Affiliations

  • 1 School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450001, China.
  • 2 School of Pharmaceutical Sciences, Institute of Drug Discovery & Development, Key Laboratory of Advanced Drug Preparation Technologies (Ministry of Education), Zhengzhou University, Zhengzhou, 450001, China.
  • 3 School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450001, China; State Key Laboratory of Esophageal Cancer Prevention &Treatment, Zhengzhou University, Zhengzhou, 450001, China.
  • 4 Children's Hospital Affiliated of Zhengzhou University, Henan Children's Hospital, Zhengzhou Children's Hospital, Zhengzhou, 450018, China.
  • 5 School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450001, China. Electronic address: [email protected].
  • 6 Department of Integrated Chinese and Western Medicine, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, 450008, China. Electronic address: [email protected].
PMID: 38150962 DOI: 10.1016/j.ejmech.2023.116079
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 (IC50 = 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.

Keywords

Antiproliferative activities; Colchicine binding site; Coumarin; Tubulin.

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