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The Potency of Diarylamine Radical-Trapping Antioxidants as Inhibitors of Ferroptosis Underscores the Role of Autoxidation in the Mechanism of Cell Death
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 <i>gpx4</i> 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, <i>gpx4</i> deletion or GSH
depletion), compounds which possess good RTA activity in organic solution
(<i>k</i><sub>inh</sub> > 10<sup>5</sup> M<sup>–1</sup> s<sup>–1</sup>) and lipid bilayers (<i>k</i><sub>inh</sub> > 10<sup>4</sup> M<sup>–1</sup> s<sup>–1</sup>) 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, <i>gpx4</i> 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