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Design, synthesis and mechanism study of coumarin-sulfonamide derivatives as carbonic anhydrase IX inhibitors with anticancer activity

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机构： [1]Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, the NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences and the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, China [2]State Key Laboratory of Quality Research in Chinese Medicine, School of Pharmacy, Macau University of Science and Technology, Taipa, Macau, China

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关键词： Coumarin-sulfonamide derivatives Carbonic anhydrase IX inhibitors Migration Invasion Action mechanism

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In this study, twenty-nine coumarin-3-sulfonamide derivatives, twenty-seven of which are original were designed and synthesized. Cytotoxicity assay indicated that most of these derivatives exhibited moderated to good potency against A549 cells. Among them, compound 8q showed potent inhibition against the four tested cancer cell lines, especially A549 cells with IC50 value of 6.01 ± 0.81 μM, and much lower cytotoxicity on the normal cells was observed compared to the reference compounds. Bioinformatics analysis revealed human carbonic anhydrase IX (CAIX) was highly expressed in lung adenocarcinoma (LUAD) and associated with poor prognosis. The inhibitory activity of compound 8q against CAIX was assessed by using molecular docking and molecular dynamics simulations, which revealed prominent interactions of both compound 8q and CAIX at the active site and their high affinity. The results of ELISA assays verified that compound 8q possessed strong inhibitory activity against CAIX and high subtype selectivity, and could also down-regulate the expression of CAIX in A549 cells. Furthermore, the significant inhibitory effects of compound 8q on the migration and invasion of A549 cells were also found. After treatment with compound 8q, intracellular reactive oxygen species (ROS) levels increased and mitochondrial membrane potential (MMP) decreased. Mechanistic investigation using western blotting revealed compound 8q exerted the anti-migrative and anti-invasive effects probably through mitochondria-mediated PI3K/AKT pathway by targeting CAIX. In summary, coumarin-3-sulfonamide derivatives were developed as potential and effective CAIX inhibitors, which were worthy of further investigation.Copyright © 2024 Elsevier B.V. All rights reserved.

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出版当年[2023]版：

大类 | 2 区医学

小类 | 1 区毒理学 2 区生化与分子生物学 2 区药学

最新[2025]版：

大类 | 2 区医学

小类 | 1 区毒理学 2 区生化与分子生物学 2 区药学

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第一作者机构： [1]Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, the NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences and the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, China

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