Potent Ferroptosis Inhibitors Can Catalyze the Cross-Dismutation of Phospholipid-Derived Peroxyl Radicals and Hydroperoxyl Radicals.

Journal of the American Chemical Society
Jia-Fei PoonDerek A Pratt

Abstract

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 operates in phospholipid bilayers and cell culture. Interestingly, only nitroxides that were efficiently converted to amines in situ were effective, with their activity paralleling the stability of the incipient aminyl radicals. The ether-linked diarylamine phenoxazine, one of the most potent RTAs known, was particularly effective as a cross-dismutation catalyst. In contrast, phenolic RTAs such as α-tocopherol (α-TOH), the most potent form of vitamin E, were 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 cotreated with phenoxazine (or its nitroxide) and a superoxid...Continue Reading

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Citations

Nov 21, 2020·Cell Metabolism·Jiashuo Zheng, Marcus Conrad
Apr 16, 2021·Journal of Medicinal Chemistry·Elisa SassettiLuca Laraia
May 10, 2021·Chemistry and Physics of Lipids·E M PlissO T Kasaikina
May 27, 2021·Chemical Society Reviews·Julian Helberg, Derek A Pratt

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