The Catalytic Reaction of Nitroxides with Peroxyl Radicals and Its Relevance to Their Cytoprotective Properties

Abstract

Sterically-hindered nitroxides such as 2,2,6,6-tetramethylpiperidin- N-oxyl (TEMPO) have long been ascribed antioxidant activity that is thought to underlie their chemopreventive and anti-aging properties. However, the most commonly invoked reactions in this context-combination with an alkyl radical to give a redox inactive alkoxyamine or catalysis of superoxide dismutation-are unlikely to be relevant under (most) physiological conditions. Herein, we characterize the kinetics and mechanisms of the reactions of TEMPO, as well as an N-arylnitroxide and an N, N-diarylnitroxide, with alkylperoxyl radicals, the propagating species in lipid peroxidation. In each of aqueous solution and lipid bilayers, they are found to be significantly more reactive than Vitamin E, Nature's premier radical-trapping antioxidant (RTA). Inhibited autoxidations of THF in aqueous buffers reveal that nitroxides reduce peroxyl radicals by electron transfer with rate constants ( k ≈ 10 to >10 M s) that correlate with the standard potentials of the nitroxides ( E° ≈ 0.75-0.95 V vs NHE) and that this activity is catalytic in nitroxide. Regeneration of the nitroxide occurs by a two-step process involving hydride transfer from the substrate to the nitroxide-derived oxoammonium ion followed by H-atom transfer from the resultant hydroxylamine to a peroxyl radical. This reactivity extends from aqueous solution to phosphatidylcholine liposomes, where added NADPH can be used as a hydride donor to promote nitroxide recycling, as well as to cell culture, where the nitroxides are shown to be potent inhibitors of lipid peroxidation-associated cell death (ferroptosis). These insights have enabled the identification of the most potent nitroxide RTA and anti-ferroptotic agent yet described: phenoxazine- N-oxyl.

Electrochemical Azidooxygenation of Alkenes Mediated by a TEMPO–N3 Charge-Transfer Complex

“…In particular, we are interested in exploring the chemical space of the TEMPO + /TEMPO • redox couple because its application in synthetic contexts remains rare 13 when compared with TEMPO + /TEMPO − and TEMPO • /TEMPO − redox couples. Based on its reduction potential, TEMPO + is a stronger oxidant than TEMPO • itself (see Scheme 1) and can in principle engage nucleophiles that are less potent than main group organometallic compounds.…”

Organophotoredox‐Mediated Amide Synthesis by Coupling Alcohol and Amine through Aerobic Oxidation of Alcohol

“…This reaction happened because O 2 .− (HOO . ) may oxidize TEMPO to the N ‐oxoammonium cation, which can oxidize the alcohol and the intermediate hemiaminal . However, the use of PBN ( N ‐ tert ‐butyl‐α‐phenylnitrone) gave only 11 % of amide 1 .…”

“…Allylic alcoholc oupled successfully with ap rimary amine (Scheme 2, compound 27). Aliphatic alcohols were less favorable substrates for amide formations (Scheme 2, compounds [28][29][30].…”

“…This reaction happened because O 2 C À (HOOC)m ay oxidizeT EMPO to the N-oxoammonium cation,w hich can oxidizet he alcohol and the intermediate hemiaminal. [29] However,t he use of PBN (N-tertbutyl-a-phenylnitrone) gave only 11 %o fa mide 1.O nt he other hand, the coupling of benzyla lcohol and ap rimary amine (i.e., tert-butylamine)w as greatlyh indered by both TEMPO and PBN, providing only 19 and 14 %yield, respectively (SchemeS3, SupportingI nformation). These reactions indicate the involvement of radical species (O 2 C À and a-amino radical anion) in the photocatalytic amide formation.…”

Molecular Probes for Evaluation of Oxidative Stress by In Vivo EPR Spectroscopy and Imaging: State-of-the-Art and Limitations

“…In this case, the EPR signal appears along with nitroxide formation in the tissue following oxidation of the probe by RONS ( Figure 5). Far from being specific, oxidation occurs primarily upon reaction with a superoxide anion, peroxyl radicals, or peroxynitrite, whereas reaction with hydrogen peroxide is negligible, except in the presence of transition metal ions [46][47][48]. However, under aerobic conditions, lipophilic hydroxylamines are oxidized by cytochrome c oxidase in membranes, while hydrophilic hydroxylamines are not significantly oxidized by cells [49].…”