The Potency of Diarylamine Radical-Trapping Antioxidants as Inhibitors of Ferroptosis Underscores the Role of Autoxidation in the Mechanism of Cell Death

GPX4 自动氧化 脂质过氧化 程序性细胞死亡 化学 磷脂过氧化氢谷胱甘肽过氧化物酶 谷胱甘肽 抗氧化剂 生物化学 细胞生物学 细胞凋亡 谷胱甘肽过氧化物酶 生物
作者
Ron Shah,Kaitlyn D. Margison,Derek A. Pratt
出处
期刊:ACS Chemical Biology [American Chemical Society]
卷期号:12 (10): 2538-2545 被引量:119
标识
DOI:10.1021/acschembio.7b00730
摘要

Two aromatic amines (ferrostatin-1 and liproxstatin-1) were recently identified from high-throughput screening efforts to uncover potent inhibitors of ferroptosis, the necrotic-like cell death induced by inhibition of glutathione peroxidase 4 (GPX4), deletion of the corresponding gpx4 gene, or starvation of GPX4 of its reducing cosubstrate, glutathione (GSH). We have since demonstrated that these two aromatic amines are highly effective radical-trapping antioxidants (RTAs) in lipid bilayers, suggesting that they subvert ferroptosis by inhibiting lipid peroxidation (autoxidation) and, thus, that this process drives the execution of ferroptosis. Herein, we show that diarylamine RTAs used to protect petroleum-derived products from autoxidation can be potent inhibitors of ferroptosis. The diarylamines investigated include representative examples of additives to engine oils, greases and rubber (4,4'-dialkyldiphenylamines), core structures of dyes and pharmaceuticals (phenoxazines and phenothiazines), and aza-analogues of these three classes of compounds that we have recently shown can be modified to achieve much greater reactivity. We find that regardless of how ferroptosis is induced (GPX4 inhibition, gpx4 deletion or GSH depletion), compounds which possess good RTA activity in organic solution (kinh > 105 M-1 s-1) and lipid bilayers (kinh > 104 M-1 s-1) are generally potent inhibitors of ferroptosis (in mouse embryonic fibroblasts). Likewise, structural analogs that do not possess RTA activity are devoid of antiferroptotic activity. These results further support the argument that lipid peroxidation (autoxidation) plays a major role in the mechanism of cell death induced by either GPX4 inhibition, gpx4 deletion, or GSH depletion. Moreover, it offers clear direction that ongoing medicinal chemistry efforts on liproxstatin and ferrostatin derivatives, which have been proposed as lead compounds for the treatment and/or prevention of ischemia/reperfusion injury, renal failure, and neurodegeneration, can be widened to include other aminic RTAs. To aid in these efforts, some relevant structure-reactivity relationships are discussed.
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