Structural optimization and biological evaluation of ferrocene-appended RSL3 derivatives as potent ferroptosis inducers

IF 5.9 2区医学 Q1 CHEMISTRY, MEDICINAL

European Journal of Medicinal Chemistry Pub Date : 2025-09-16 DOI:10.1016/j.ejmech.2025.118162

Jing Wang , Hui Wang , Yunyun Liu , Xuejing Fan , Xiaomin Zhang , Dian Peng , Yong Wang

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Abstract

Ferroptosis inducers with novel chemical scaffolds are promising for overcoming cancer therapy resistance. In this study, we conducted structural optimization and biological evaluation of ferrocene-appended RSL3 derivatives as potent ferroptosis inducers for anticancer treatment. Through structure-activity relationship studies, compound A6 stands out with stronger antiproliferative ability (IC₅₀ ≈ 3–5 nM) and higher ferroptosis selectivity than RSL3. Mechanistic studies confirmed the dual-function role of ferrocene acting as both a structural scaffold to maintain the inhibition of GPX4 and a reactive oxygen species (ROS) generator to enhance the vulnerability to ferroptosis of cancer cells. Importantly, significant tumor shrinkage and optimal safety profile of A6 in xenograft model demonstrates its potential for treating aggressive cancers. This study of developing ferrocene-appended ferroptosis inducers via structural optimization expands the toolbox for metal-based therapies against oxidative stress-related pathologies.

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二茂铁附加RSL3衍生物作为强铁下垂诱导剂的结构优化和生物学评价

新型化学支架的铁下垂诱导剂有望克服癌症治疗耐药性。在这项研究中，我们对二茂铁附加的RSL3衍生物进行了结构优化和生物学评价，以作为有效的铁下垂诱导剂用于抗癌治疗。通过结构-活性关系研究，化合物A6比RSL3具有更强的抗增殖能力（IC50 ≈ 3 - nM）和更高的铁凋亡选择性。机制研究证实了二茂铁的双重功能作用，既可以作为结构支架维持对GPX4的抑制，又可以作为活性氧（ROS）的产生器增强癌细胞对铁凋亡的易感性。重要的是，在异种移植物模型中，显著的肿瘤缩小和最佳的安全性证明了A6治疗侵袭性癌症的潜力。这项通过结构优化开发二茂铁附加铁下垂诱导剂的研究扩展了金属基治疗氧化应激相关病理的工具箱。

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来源期刊

European Journal of Medicinal Chemistry 化学-医药化学

CiteScore

11.70

自引率

9.00%

发文量

863

审稿时长

29 days

期刊介绍： The European Journal of Medicinal Chemistry is a global journal that publishes studies on all aspects of medicinal chemistry. It provides a medium for publication of original papers and also welcomes critical review papers. A typical paper would report on the organic synthesis, characterization and pharmacological evaluation of compounds. Other topics of interest are drug design, QSAR, molecular modeling, drug-receptor interactions, molecular aspects of drug metabolism, prodrug synthesis and drug targeting. The journal expects manuscripts to present the rational for a study, provide insight into the design of compounds or understanding of mechanism, or clarify the targets.