LAUSR

Nitroxides were recently shown to catalyze the cross-dismutation of alkylperoxyl and hydroperoxyl radicals, making them uniquely effective radical-trapping antioxidants (RTAs) in unsaturated hydrocarbons where both species are formed. Given the abundance of unsaturated lipids in biological membranes, the continuous generation of hydroperoxyl (superoxide) as a byproduct of aerobic respiration and the demonstrated cytoprotective properties of some nitroxides, we probed if cross-dismutation can operate in phospholipid bilayers and cell culture. Interestingly, only nitroxides which were efficiently con-verted to amines in situ were found to be effective - with their activity paralleling the stability of the incipient aminyl radi-cals. The ether-linked diarylamine phenoxazine, one of the most potent RTAs known, was particularly effective as a cross-dismutation catalyst. The recycling of phenolic RTAs - exemplified by -tocopherol (-TOH), the most potent form of Vitamin E - was found to be inefficient due to the preference for the combination of hydroperoxyl and phenoxyl radicals over H-atom transfer between them. Experiments carried out in mouse embryonic fibroblasts corroborated these findings. Cells co-treated with phenoxazine (or its nitroxide) and a superoxide source were better protected from ferroptosis than those treated with phenoxazine (or its nitroxide) alone. No such synergy was observed for cells treated with -TOH. Live cell im-aging established that cytoprotection was associated with suppression of (phospho)lipid peroxidation. This demonstrates the remarkable capacity for select amines to act as effective phase-transfer catalysts for a reducing equivalent (an H-atom), such that a water-soluble 'reactive oxygen species' can be used to quench a lipid-soluble one.