1,8-桉树脑衍生物的合成及其对顺铂诱导的HK-2细胞损伤的细胞保护作用评价

IF 3 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic & Medicinal Chemistry Pub Date : 2025-08-11 DOI:10.1016/j.bmc.2025.118347

Xinyao Pan , Xiaodan Wang , Yun Yang , Ziwei Le , Shiyu Wang , Yao Shen , Hongbo Dong , Kaifeng Lai , Congcong Lin , Chunjuan Yang , Huanjun Xu , Chunli Gan

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引用次数: 0

摘要

本研究通过对具有肾保护作用的天然产物1,8-桉叶脑（c0）进行结构修饰，合理设计合成18个衍生物，旨在发现治疗急性肾损伤（AKI）的新型先导化合物。初步体外筛选发现衍生物3c-2是最有希望的候选者。随后在顺铂损伤的HK-2细胞中进行的评估表明，3c-2通过减少活性氧（ROS）和丙二醛（MDA）的产生，以及增强超氧化物歧化酶（SOD）的活性，有效地减轻了顺铂诱导的氧化应激。结合线粒体膜电位（MMP）测量和基于流式细胞术的细胞凋亡实验的综合评价一致表明，化合物3c-2具有显著的细胞凋亡抑制作用，并能有效减轻顺铂诱导的HK-2肾小管上皮细胞的细胞毒性。分子对接和动力学模拟表明，3c-2与氧化应激和凋亡通路的关键调节因子PI3K之间存在稳定的结合，表明PI3K可能是3c-2的潜在治疗靶点。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

Synthesis of 1,8-cineole derivatives and evaluation of their cytoprotective effects against cisplatin-induced HK-2 cell injury

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Synthesis of 1,8-cineole derivatives and evaluation of their cytoprotective effects against cisplatin-induced HK-2 cell injury

This study aimed to discover novel lead compounds for acute kidney injury (AKI) treatment by rationally designing and synthesizing 18 derivatives through structural modifications of 1,8-cineole (c0), a nephroprotective natural product. Initial in vitro screening identified derivative 3c-2 as the most promising candidate. Subsequent evaluations in cisplatin-injured HK-2 cells demonstrated that 3c-2 effectively attenuated cisplatin-induced oxidative stress by reducing reactive oxygen species (ROS) and malondialdehyde (MDA) generation, and enhancing superoxide dismutase (SOD) activity. Comprehensive evaluations combining mitochondrial membrane potential (MMP) measurements and flow cytometry-based apoptosis assays consistently demonstrated that compound 3c-2 possessed a significant inhibitory effect on apoptosis and was effective in attenuating cisplatin-induced cytotoxicity in HK-2 renal tubular epithelial cells. Molecular docking and dynamics simulations indicated stable binding between 3c-2 and PI3K, a key regulator of oxidative stress and apoptosis pathways, suggesting PI3K as the potential therapeutic target of 3c-2.

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来源期刊

Bioorganic & Medicinal Chemistry 医学-生化与分子生物学

CiteScore

6.80

自引率

2.90%

发文量

413

审稿时长

17 days

期刊介绍： Bioorganic & Medicinal Chemistry provides an international forum for the publication of full original research papers and critical reviews on molecular interactions in key biological targets such as receptors, channels, enzymes, nucleotides, lipids and saccharides. The aim of the journal is to promote a better understanding at the molecular level of life processes, and living organisms, as well as the interaction of these with chemical agents. A special feature will be that colour illustrations will be reproduced at no charge to the author, provided that the Editor agrees that colour is essential to the information content of the illustration in question.