Design, synthesis and biological evaluation of 1,2,3-triazole benzothiazole derivatives as tubulin polymerization inhibitors with potent anti-esophageal cancer activities.

Autor: Wu BW; School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450001, China., Huang WJ; School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450001, China., Liu YH; School of Pharmaceutical Sciences, Institute of Drug Discovery & Development, Key Laboratory of Advanced Drug Preparation Technologies (Ministry of Education), Zhengzhou University, Zhengzhou, 450001, China., Liu QG; School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450001, China., Song J; School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450001, China., Hu T; School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450001, China., Chen P; School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450001, China. Electronic address: zzdx_chenping@zzu.edu.cn., Zhang SY; School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450001, China; State Key Laboratory of Esophageal Cancer Prevention &Treatment, Zhengzhou 450001, China. Electronic address: saiyangz@zzu.edu.cn.
Jazyk: angličtina
Zdroj: European journal of medicinal chemistry [Eur J Med Chem] 2024 Feb 05; Vol. 265, pp. 116118. Date of Electronic Publication: 2024 Jan 03.
DOI: 10.1016/j.ejmech.2023.116118
Abstrakt: In this work, we utilized the molecular hybridization strategy to design and synthesize novel 1,2,3-triazole benzothiazole derivatives K1-26. The antiproliferative activities against MGC-803, Kyse30 and HCT-116 cells were explored, and their structure-activity relationship were preliminarily conducted and summarized. Among them, compound K18, exhibited the strongest proliferation inhibitory activity, with esophageal cancer cells Kyse30 and EC-109 being the most sensitive to its effects (IC 50 values were 0.042 and 0.038 μM, respectively). Compound K18 effectively inhibited tubulin polymerization (IC 50  = 0.446 μM), thereby hindering tubulin polymerize into filamentous microtubules in Kyse30 and EC-109 cells. Additionally, compound K18 induced the degradation of oncogenic protein YAP via the UPS pathway. Based on these dual molecular-level effects, compound K18 could induce G2/M phase arrest and cell apoptosis in Kyse30 and EC-109 cells, as well as regulate the expression levels of cell cycle and apoptosis-related proteins. In summary, our findings highlight a novel 1,2,3-triazole benzothiazole derivative K18, which possesses significant potential for treating esophageal cancers.
Competing Interests: Declaration of competing interest There is no conflict of interest about this article to declare.
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Databáze: MEDLINE
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