Novel Indoline Derivatives as Ferroptosis Inhibitors: Synthesis, Biological Evaluation, and Mechanistic Investigation

IF 3.4 4区 医学 Q2 CHEMISTRY, MEDICINAL
ChemMedChem Pub Date : 2025-08-18 DOI:10.1002/cmdc.202500487
Wen Shao, Yuanyuan Liu, Deling Jiang, Zhiyang Xing, Jiale Qiao, Man Liu, Xupeng Huang, Renyu Zhang, Yuying Fang, Wei Peng
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Abstract

Ferroptosis, a form of regulated cell death characterized by excessive lipid peroxidation, has been implicated in various neurological disorders. Ferrostatin-1 (Fer-1), a well-known ferroptosis inhibitor, exhibits therapeutic potential but suffers from poor metabolic stability, limiting its applications. In this study, a phenotype-based screening of an in-house compound library is conducted and a novel ferroptosis inhibitor, TJC-2-1, is identified. To optimize its inhibitory activity, a series of 35 indoline derivatives are synthesized and evaluated. Among them, compound 14 exhibits the most potent inhibition against erastin-induced (EC50 = 0.15 μM) and RSL3-induced (EC50 = 0.15 μM) ferroptosis in HT22 mouse hippocampal cells. Mechanistic investigations reveal that compound 14 functions as a novel radical-trapping antioxidant, exhibiting lipid peroxidation scavenging capacity comparable to that of Fer-1. Remarkably, compound 14 demonstrates significantly improved microsomal metabolic stability compared to Fer-1. These findings suggest that compound 14 has the potential to serve as a lead compound for ferroptosis-related diseases.

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新型吲哚啉衍生物作为铁下垂抑制剂:合成、生物学评价和机制研究。
铁下垂是一种以过度脂质过氧化为特征的调节细胞死亡形式,与各种神经系统疾病有关。铁抑素-1 (ferl -1)是一种众所周知的铁下垂抑制剂,具有治疗潜力,但代谢稳定性差,限制了其应用。在这项研究中,对内部化合物文库进行了基于表型的筛选,并鉴定出一种新的铁下垂抑制剂TJC-2-1。为了优化其抑制活性,合成了35个吲哚啉衍生物并对其进行了评价。其中化合物14对erastin诱导的(EC50 = 0.15 μM)和rsl3诱导的(EC50 = 0.15 μM) HT22小鼠海马细胞铁下垂的抑制作用最强。机制研究表明,化合物14作为一种新的自由基捕获抗氧化剂,具有与fe -1相当的脂质过氧化清除能力。值得注意的是,与fe -1相比,化合物14显著改善了微粒体代谢稳定性。这些发现提示化合物14有可能作为铁中毒相关疾病的先导化合物。
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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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