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

• Published in: European journal of medicinal chemistry 2024-02, Vol.265, p.116118-116118, Article 116118
• Main Authors: Wu, Bo-Wen, Huang, Wen-Jing, Liu, Yun-He, Liu, Qiu-Ge, Song, Jian, Hu, Tao, Chen, Ping, Zhang, Sai-Yang
• Format: Article
• Language: English
• Subjects: 1,2,3-Triazole; Antineoplastic Agents; Antiproliferative activities; Benzothiazole; Benzothiazoles - pharmacology; Cell Line, Tumor; Cell Proliferation; Drug Screening Assays, Antitumor; Esophageal cancer; Esophageal Neoplasms - drug therapy; gamma-Globulins; Humans; Melphalan; Molecular Structure; Polymerization; Structure-Activity Relationship; Triazoles - pharmacology; Tubulin; Tubulin - metabolism; Tubulin Modulators
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2023.116118

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 (IC50 values were 0.042 and 0.038 μM, respectively). Compound K18 effectively inhibited tubulin polymerization (IC50 = 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. [Display omitted] •Compound K18 showed low nanomolar IC50 values of 0.042 and 0.038 μM against Kyse30 and EC-109 cells.•Compound K18 inhibited tubulin polymerization (EC50 = 0.445 μM).•Compound K18 induced YAP degradation.•Compound K18 induced the G2/M phase arrest and apoptosis in Kyse30 and EC-109 cells.