Intramolecular Hydrogen Atom Transfer Enables Hydroperoxyl Radical Formation during the Peroxidation of Unsaturated Lipids

Lipid peroxidation (autoxidation) is among the most well-studied free radical chain reactions and drives a cell death modality (ferroptosis) implicated in neurodegeneration and the damage resulting from reperfusion of ischemic tissue following stroke or organ transplant. In a recent study of structure-reactivity-potency relationships in phenoxazines─the most potent ferroptosis inhibitors yet identified─we found that electron-poor derivatives were able to trap more lipidperoxyl radicals than electron-neutral or electron-rich derivatives despite having lower inherent reactivity toward them. Herein, we report the results of our investigations to understand the basis for these surprising observations. Mechanistic and computational studies reveal a hitherto uncharacterized reaction in the context of lipid peroxidation: polyunsaturated fatty acid (PUFA)-derived peroxyl radicals can undergo an intramolecular H-atom transfer (HAT)/elimination sequence to form hydroperoxyl radicals. The hydroperoxyl radicals can then regenerate phenoxazines from their corresponding aminyl radicals, enabling them to trap additional lipidperoxyl radicals. Moreover, we show that lipid alcohols, such as farnesol and detoxification products of PUFA- and cholesterol-derived hydroperoxides, undergo similar chemistry, thereby converting chain-carrying lipidperoxyl radicals into hydroperoxyl radicals and retarding the propagation of lipid peroxidation. Ferroptosis inhibitors that can engage hydroperoxyl as a stoichiometric reductant are shown to have higher-than-expected potency, suggesting that this could be harnessed in the design of ferroptosis-targeting therapeutic candidates.