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) 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 α-TOH. Live cell imaging established that cytoprotection was associated with suppression of (phospho)lipid peroxidation. These results highlight 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.
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http://dx.doi.org/10.1021/jacs.0c06379 | DOI Listing |
ACS Omega
October 2023
Xheme, Inc.,, 100 Carlson Ave, Newton, Massachusetts 02459, United States.
The use of nanomaterials as inhibitors of the autoxidation of organic materials is attracting tremendous interest in petrochemistry, food storage, and biomedical applications. Metal oxide materials and CeO in particular represent one of the most investigated inorganic materials with promising radical trapping and antioxidant abilities. However, despite the importance, examples of the CeO material's ability to retard the autoxidation of organic substrates are still lacking, together with a plausible chemical mechanism for radical trapping.
View Article and Find Full Text PDFJ Am Chem Soc
August 2020
Department of Chemistry and Biomolecular Sciences, University of Ottawa, Ottawa, ON K1N 6N5, Canada.
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.
View Article and Find Full Text PDFChem Sci
July 2018
Department of Chemistry and Biomolecular Sciences , University of Ottawa, Ottawa , Ontario , Canada K1N 6N5 . Email:
Nitroxides are putative intermediates in the accepted reaction mechanisms of the diarylamine and hindered amine antioxidants that are universally added to preserve synthetic and natural hydrocarbon-based materials. New methodology which enables monitoring of hydrocarbon autoxidations at low rates of radical generation has revealed that diarylnitroxides and hindered nitroxides are far better inhibitors of unsaturated hydrocarbon autoxidation than their precursor amines, implying intervention of a different mechanism. Experimental and computational investigations suggest that the nitroxides catalyze the cross-dismutation of hydroperoxyl and alkylperoxyl radicals to yield O and a hydroperoxide, thereby halting the autoxidation chain reaction.
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