一锅远距离合成产生的喹啉并三唑通过产生 ROS 促进 MCF-7 细胞凋亡

IF 3.5 3区医学 Q2 CHEMISTRY, MEDICINAL

ACS Medicinal Chemistry Letters Pub Date : 2024-10-15 DOI:10.1021/acsmedchemlett.4c0028910.1021/acsmedchemlett.4c00289

Joydip Mondal, Tiasha Dasgupta, Rakesh R. Panicker, Venkatraman Manickam, Arup Sinha and Akella Sivaramakrishna*,

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引用次数: 0

摘要

抑制血管内皮生长因子受体 2（VEGFR-2）可促进有效的抗血管生成和抗癌反应。在这方面，我们的研究重点是通过一锅伸缩法开发有效的药层，即基于喹啉的三唑衍生物 6a-j。其中，具有酰胺和氰基取代基的 6f 与 VEGFR-2 的结合能力最强，亲和力高达 -8.9 kcal/mol。此外，6f 和 6g（含酰胺基和溴基）由于含有活性氧化应激诱导剂，表现出广泛的抗癌活性，细胞毒性值分别为 10 ± 0.2 和 12 ± 0.6 μM。细胞凋亡分析表明，6f 和 6g 参与了线粒体损伤和线粒体膜电位损失（ΔΨm）。6f/6g在MCF-7中的细胞间定位显示，6g存在于细胞质中，同时ROS产生增加，MMP减少，这证明了6g靶向线粒体的能力。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

Promoting Apoptosis in MCF-7 Cells via ROS Generation by Quinolino-triazoles Derived from One-Pot Telescopic Synthesis

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Promoting Apoptosis in MCF-7 Cells via ROS Generation by Quinolino-triazoles Derived from One-Pot Telescopic Synthesis

Inhibition of vascular endothelial growth factor receptor 2 (VEGFR-2) facilitates potent antiangiogenic and anticancer responses. In this regard, the development of effective pharmacophores, i.e., quinoline-based triazole derivatives 6a–j, by a one-pot telescopic approach is our focus. Among all of them, 6f, possessing amide and cyanide substituents, displayed the highest binding ability with VEGFR-2, having high affinity of −8.9 kcal/mol. Further, 6f and 6g (containing amide and bromo groups) exhibited a wide spectrum of anticancer activities due to the presence of active oxidative stress inducers, with cytotoxicity values of 10 ± 0.2 and 12 ± 0.6 μM, respectively. Apoptosis analysis demonstrated the involvement of 6f and 6g in mitochondrial damage and the loss of mitochondrial membrane potential (ΔΨ_m). Intercellular localization of 6f/6g in MCF-7 revealed the presence of 6g in the cytoplasm along with an increase in ROS production and a reduction in MMP, proving the ability of 6g to target mitochondria.

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来源期刊

ACS Medicinal Chemistry Letters CHEMISTRY, MEDICINAL-

CiteScore

7.30

自引率

2.40%

发文量

328

审稿时长

1 months

期刊介绍： ACS Medicinal Chemistry Letters is interested in receiving manuscripts that discuss various aspects of medicinal chemistry. The journal will publish studies that pertain to a broad range of subject matter, including compound design and optimization, biological evaluation, drug delivery, imaging agents, and pharmacology of both small and large bioactive molecules. Specific areas include but are not limited to: Identification, synthesis, and optimization of lead biologically active molecules and drugs (small molecules and biologics) Biological characterization of new molecular entities in the context of drug discovery Computational, cheminformatics, and structural studies for the identification or SAR analysis of bioactive molecules, ligands and their targets, etc. Novel and improved methodologies, including radiation biochemistry, with broad application to medicinal chemistry Discovery technologies for biologically active molecules from both synthetic and natural (plant and other) sources Pharmacokinetic/pharmacodynamic studies that address mechanisms underlying drug disposition and response Pharmacogenetic and pharmacogenomic studies used to enhance drug design and the translation of medicinal chemistry into the clinic Mechanistic drug metabolism and regulation of metabolic enzyme gene expression Chemistry patents relevant to the medicinal chemistry field.