一种新型噻唑-磺酰胺杂化分子，作为一种有前景的双靶点微管蛋白/碳酸酐酶IX抑制剂，具有抗癌活性。
A novel thiazole-sulfonamide hybrid molecule as a promising dual tubulin/carbonic anhydrase IX inhibitor with anticancer activity.
作者信息
Khasawneh Hussam Elddin Nabeih, Ali Elryah I, Elmagzoub Ranya Mohammed, Al-Aouadi Raed Fanoukh Aboqader, Almagharbeh Wesam Taher, Alotaibi Ghallab, Bräse Stefan, Alkhammash Abdullah
机构信息
Chemical Engineering Department, Al-Huson University College, Al-Balqa' Applied University, Al-Salt, Jordan.
Department of Medical Laboratory Technology, College of Applied Medical Sciences, Northern Border University, Arar, Saudi Arabia.
出版信息
Front Chem. 2025 Jun 26;13:1606848. doi: 10.3389/fchem.2025.1606848. eCollection 2025.
INTRODUCTION
Multitargeted anticancer agents can overcome resistance by simultaneously modulating key pathways. This study reports a novel thiazole -chalcone/sulfonamide hybrid (compound 7) designed to inhibit both tubulin polymerization and carbonic anhydrase IX (CA IX).
METHODS
Compound 7 was synthesized through a five-step sequence and characterized by NMR and elemental analysis. Its cytotoxicity was assessed against cancer (HT-29, A549, 786-O, MCF-7) and normal (WI-38) cell lines. Tubulin polymerization and CA isoform inhibition (I, II, IX, XII) were evaluated. Apoptosis induction was confirmed by measuring p53, Bax, Bcl-2, and caspases 3 and 9. Molecular docking, ADMET, and DFT studies supported mechanistic insights.
RESULTS AND DISCUSSION
Compound 7 showed potent activity against HT-29 cells (IC = 0.98 μM) and low toxicity toward WI-38 cells. It inhibited tubulin polymerization (IC = 2.72 μM) and selectively targeted CA IX (IC = 0.021 μM) and CA XII, while sparing CA I and II. Apoptotic effects were confirmed by increased p53 and Bax, reduced Bcl-2, and activation of caspases. Docking studies revealed key interactions within the colchicine-binding site of tubulin and CA IX's zinc-binding pocket. ADMET and DFT results supported its drug-like properties and electronic suitability. These findings suggest that compound 7 is a promising lead for dual-targeted anticancer therapy with selective cytotoxicity and mechanistic efficacy.
引言
多靶点抗癌药物可通过同时调节关键信号通路来克服耐药性。本研究报道了一种新型噻唑 - 查耳酮/磺酰胺杂合物（化合物7），其设计目的是同时抑制微管蛋白聚合和碳酸酐酶IX（CA IX）。
方法
通过五步合成法制备化合物7，并通过核磁共振（NMR）和元素分析对其进行表征。评估了其对癌细胞系（HT - 29、A549、786 - O、MCF - 7）和正常细胞系（WI - 38）的细胞毒性。评估了微管蛋白聚合以及CA同工型抑制（I、II、IX、XII）情况。通过检测p53、Bax、Bcl - 2以及半胱天冬酶3和9来确认凋亡诱导情况。分子对接、药物代谢动力学/药物毒性预测（ADMET）和密度泛函理论（DFT）研究为作用机制提供了深入见解。
结果与讨论
化合物7对HT - 29细胞显示出强效活性（IC = 0.98 μM），对WI - 38细胞毒性较低。它抑制微管蛋白聚合（IC = 2.72 μM），并选择性靶向CA IX（IC = 0.021 μM）和CA XII，而对CA I和II无影响。p53和Bax增加、Bcl - 2减少以及半胱天冬酶的激活证实了其凋亡作用。对接研究揭示了在微管蛋白的秋水仙碱结合位点和CA IX的锌结合口袋内的关键相互作用。ADMET和DFT结果支持了其类药物性质和电子适宜性。这些发现表明化合物7是双靶点抗癌治疗的一个有前景的先导化合物，具有选择性细胞毒性和作用机制有效性。
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