Unveiling Benzoxazole-Substituted Thiazolyl-Pyrazole Derivatives Inducing Apoptosis by Targeting β-Tubulin and Caspase-3

IF 3.4 4区 医学 Q2 CHEMISTRY, MEDICINAL
ChemMedChem Pub Date : 2025-07-28 DOI:10.1002/cmdc.202500320
Burak Kuzu, Mustafa Cakir, Eda Acikgoz, Mehmet Abdullah Alagoz
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引用次数: 0

Abstract

In the present study, the biological activities of novel compounds (BP-1 to BP-6), designed as antitubulin agents, were systematically evaluated, with a particular focus on their effects on the triple-negative breast cancer cell line MDA-MB-231 and non-cancerous cell line MCF-10A. BP-2 and BP-6 demonstrated micromolar-range antiproliferative activity against MDA-MB-231 cancer cells, with IC50 values of 8 and 4 µM, respectively, comparable to nocodazole (3 µM), and showed selective cytotoxicity over normal MCF-10A cells, with selectivity indices of approximately 3.3 and 8. In vitro analyses revealed that BP-2 and more notably BP-6 significantly inhibited cell proliferation in a time- and dose-dependent manner, disrupted microtubule organization through the downregulation of β-tubulin expression, and induced apoptosis, as evidenced by increased levels of Cleaved Caspase-3 and distinct apoptotic morphological changes. Among the tested compounds, BP-6 exhibited the most potent antiproliferative and proapoptotic activity, with an IC50 value close to that of NOC. Molecular docking supported these findings by showing strong binding affinities of BP-6 to both β-tubulin and Caspase-3, indicating a dual-targeted mechanism. Furthermore, molecular dynamics simulations confirmed the stable binding and dynamic integrity of BP-6 within both β-Tubulin and Caspase-3 targets, underscoring its potential as a robust candidate for anticancer drug development.

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揭示苯并恶唑取代噻唑吡唑衍生物通过靶向β-微管蛋白和Caspase-3诱导细胞凋亡。
本研究系统评价了新型抗微管蛋白化合物(BP-1 ~ BP-6)的生物学活性,重点研究了它们对三阴性乳腺癌细胞系MDA-MB-231和非癌细胞系MCF-10A的影响。BP-2和BP-6对MDA-MB-231癌细胞表现出微摩尔范围的抗增殖活性,ic50值分别为8和4µM,与nocodazole(3µM)相当,并且对正常MCF-10A细胞表现出选择性细胞毒性,选择性指数约为3.3和8。体外分析显示,BP-2和BP-6以时间和剂量依赖的方式显著抑制细胞增殖,通过下调β-微管蛋白表达破坏微管组织,诱导细胞凋亡,Cleaved Caspase-3水平升高,凋亡形态学改变明显。结果表明,BP-6具有较强的抗增殖和促凋亡活性,ic50值与NOC相近。分子对接显示BP-6与β-微管蛋白和Caspase-3具有较强的结合亲和力,表明BP-6具有双靶向机制,支持了这些发现。此外,分子动力学模拟证实了BP-6在β-微管蛋白和Caspase-3靶点内的稳定结合和动态完整性,强调了BP-6作为抗癌药物开发的强大候选者的潜力。
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来源期刊
ChemMedChem
ChemMedChem 医学-药学
CiteScore
6.70
自引率
2.90%
发文量
280
审稿时长
1 months
期刊介绍: Quality research. Outstanding publications. With an impact factor of 3.124 (2019), ChemMedChem is a top journal for research at the interface of chemistry, biology and medicine. It is published on behalf of Chemistry Europe, an association of 16 European chemical societies. ChemMedChem publishes primary as well as critical secondary and tertiary information from authors across and for the world. Its mission is to integrate the wide and flourishing field of medicinal and pharmaceutical sciences, ranging from drug design and discovery to drug development and delivery, from molecular modeling to combinatorial chemistry, from target validation to lead generation and ADMET studies. ChemMedChem typically covers topics on small molecules, therapeutic macromolecules, peptides, peptidomimetics, and aptamers, protein-drug conjugates, nucleic acid therapies, and beginning 2017, nanomedicine, particularly 1) targeted nanodelivery, 2) theranostic nanoparticles, and 3) nanodrugs. Contents ChemMedChem publishes an attractive mixture of: Full Papers and Communications Reviews and Minireviews Patent Reviews Highlights and Concepts Book and Multimedia Reviews.
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