1,4-Diformyl-Piperazine Ferrostatin-1 衍生物作为新型铁氧化酶抑制剂的设计与合成。

IF 3.2 4区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Chemical Biology & Drug Design Pub Date : 2024-10-28 DOI:10.1111/cbdd.70000

Yi-Fan Zhang, Wei Guo, Hui Zheng, Nai-Yu Zhang, Hua-Long Ji, Ning Meng, Juan Zhang, Cheng-Shi Jiang

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引用次数: 0

摘要

本研究的重点是设计和合成新型 1,4-二甲酰基哌嗪基铁锈素-1（Fer-1）衍生物，并评估它们的抗铁锈色素沉着活性。合成的化合物在人脐血管内皮细胞（HUVECs）中表现出显著的抗铁细胞沉降活性，其中化合物 24 的效力最高。机理研究表明，化合物 24 能有效降低细胞内活性氧（ROS）水平，减轻线粒体损伤，并增强谷胱甘肽过氧化物酶 4（GPX4）的表达。此外，与对照化合物 Fer-1 和 JHL-12 相比，化合物 24 的溶解性和血浆稳定性都有所提高。这些发现表明，基于 1,4-二甲酰基哌嗪的 Fer-1 衍生物有望成为治疗与铁蛋白沉积相关的心血管疾病的药物。

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Design and Synthesis of 1,4-Diformyl-Piperazine Ferrostatin-1 Derivatives as Novel Ferroptosis Inhibitors

The present study focuses on the design and synthesis of novel 1,4-diformyl-piperazine-based ferrostatin-1 (Fer-1) derivatives, and their evaluation against ferroptosis activity. The synthesized compounds demonstrated significant anti-ferroptosis activity in human umbilical vascular endothelial cells (HUVECs), with Compound 24 showing the highest potency. Mechanistic studies revealed that Compound 24 effectively reduced intracellular reactive oxygen species (ROS) levels, mitigated mitochondrial damage, and enhanced glutathione peroxidase 4 (GPX4) expression. Additionally, Compound 24 exhibited improved solubility and plasma stability compared to control compounds, Fer-1 and JHL-12. These findings suggest that 1,4-diformyl-piperazine-based Fer-1 derivatives hold promise as therapeutic agents for ferroptosis-associated cardiovascular diseases.

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来源期刊

Chemical Biology & Drug Design 医学-生化与分子生物学

CiteScore

5.10

自引率

3.30%

发文量

164

审稿时长

4.4 months

期刊介绍： Chemical Biology & Drug Design is a peer-reviewed scientific journal that is dedicated to the advancement of innovative science, technology and medicine with a focus on the multidisciplinary fields of chemical biology and drug design. It is the aim of Chemical Biology & Drug Design to capture significant research and drug discovery that highlights new concepts, insight and new findings within the scope of chemical biology and drug design.