Unexpected Acid Catalysis in Reactions of Peroxyl Radicals with Phenols

Valgimigli, Luca; Amorati, Riccardo; Petrucci, Silvia; Pedulli, Gian Franco; Hu, Di; Hanthorn, Jason J.; Pratt, Derek A.

doi:10.1002/anie.200903360

Cited by 66 publications

(81 citation statements)

References 27 publications

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“…50 Consistent with this small α 2 H value, the reactivity of Fer-1 and Lip-1 toward peroxyl radicals differed only by factors of 1.7 and 0.6 when measured in DMSO (an excellent H-bond accepting solvent) compared to chlorobenzene (see Supporting Information for details).…”

Section: Resultsmentioning

confidence: 58%

On the Mechanism of Cytoprotection by Ferrostatin-1 and Liproxstatin-1 and the Role of Lipid Peroxidation in Ferroptotic Cell Death

et al. 2017

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Ferroptosis is a form of regulated necrosis associated with the iron-dependent accumulation of lipid hydroperoxides that may play a key role in the pathogenesis of degenerative diseases in which lipid peroxidation has been implicated. High-throughput screening efforts have identified ferrostatin-1 (Fer-1) and liproxstatin-1 (Lip-1) as potent inhibitors of ferroptosis − an activity that has been ascribed to their ability to slow the accumulation of lipid hydroperoxides. Herein we demonstrate that this activity likely derives from their reactivity as radical-trapping antioxidants (RTAs) rather than their potency as inhibitors of lipoxygenases. Although inhibited autoxidations of styrene revealed that Fer-1 and Lip-1 react roughly 10-fold more slowly with peroxyl radicals than reactions of α-tocopherol (α-TOH), they were significantly more reactive than α-TOH in phosphatidylcholine lipid bilayers − consistent with the greater potency of Fer-1 and Lip-1 relative to α-TOH as inhibitors of ferroptosis. None of Fer-1, Lip-1, and α-TOH inhibited human 15-lipoxygenase-1 (15-LOX-1) overexpressed in HEK-293 cells when assayed at concentrations where they inhibited ferroptosis. These results stand in stark contrast to those obtained with a known 15-LOX-1 inhibitor (PD146176), which was able to inhibit the enzyme at concentrations where it was effective in inhibiting ferroptosis. Given the likelihood that Fer-1 and Lip-1 subvert ferroptosis by inhibiting lipid peroxidation as RTAs, we evaluated the antiferroptotic potential of 1,8-tetrahydronaphthyridinols (hereafter THNs): rationally designed radical-trapping antioxidants of unparalleled reactivity. We show for the first time that the inherent reactivity of the THNs translates to cell culture, where lipophilic THNs were similarly effective to Fer-1 and Lip-1 at subverting ferroptosis induced by either pharmacological or genetic inhibition of the hydroperoxide-detoxifying enzyme Gpx4 in mouse fibroblasts, and glutamate-induced death of mouse hippocampal cells. These results demonstrate that potent RTAs subvert ferroptosis and suggest that lipid peroxidation (autoxidation) may play a central role in the process.

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Section: Resultsmentioning

confidence: 58%

On the Mechanism of Cytoprotection by Ferrostatin-1 and Liproxstatin-1 and the Role of Lipid Peroxidation in Ferroptotic Cell Death

et al. 2017

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“…92 The phenomenon was shown to be general for half a dozen common phenolic antioxidants and both organic and mineral acids. The rate acceleration increases with the concentration of acid, but not the acid strength; it is largest for carboxylic acids, and requires a relatively polar solvent such as acetonitrile to be effective.…”

Section: Dpphmentioning

confidence: 99%

“…Mechanistic studies support a H-atom transfer mechanism as for phenols (k H /k D ∼ 3), 64,106 a negative reaction constant for Hammett-type correlation with σ + , 107,165 HBA solvents slow kinetics, 64,106,166 and theoretical calculations yield transition states consistent with a role for PCET in this process. 92 This development has prompted the study of lipid-soluble analogs of pyridinol 65 (which has the best balance of reactivity to peroxyl radicals and stability in air, and most closely resembles α-TOH) under more physiologically relevant conditions, for 80 Since the peroxidation of membrane lipids has been implicated in virtually all degenerative diseases, the potential for these compounds to…”

Section: Ho N H 62mentioning

confidence: 99%

Antioxidants in Chemistry and Biology

Valgimigli

Pratt

2012

Encyclopedia of Radicals in Chemistry, Biology and Materials

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109

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Antioxidants are omnipresent in nature and industry; they are used to slow down the autoxidative degradation of both organic tissues and petroleum‐derived products. Various mechanisms by which antioxidants can act are known, the most common of which are introduced here. Since autoxidation is a radical chain reaction, radical‐trapping antioxidants play a particularly important role; therefore, we will discuss these compounds in most detail. To introduce and develop central concepts relating to this topic, we present kinetic and thermodynamic data obtained for the reactions of phenols, the archetypical radical‐trapping antioxidants, with chain‐carrying peroxyl radicals, and describe the means to obtain these data. We then extend our discussion to other important classes of radical‐trapping antioxidants, beginning with the closely related polyphenols and newly developed pyridinol and pyrimidinol antioxidants, and then further to aromatic amines, organosulfur compounds, and their derivatives. We go on to touch upon the synergistic behavior in antioxidant combinations, and the effects of the medium on these interactions, and finally round things up with a few more important biological examples: ascorbate and β‐carotene. A few comments on the state of the field and areas requiring further research and development are included.

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“…[8] We have recently shown that their reactions are acceleratedi np olar organic solvents( MeCN or EtCN) containing protic acids, in which it was suggested that the reactions proceed by as tepwise mechanism involving rate-controlling ET to the protonated peroxyl radical. [11] Litwinienko and Ingold and also Foti and co-workersi ndependently showed that, in alcohols, acidic phenols are oxidisedb yt he 2,2-diphenylpicrylhydrazyl radical (DPPHC)a tamuch faster rate than expectedf rom an EPT (CPET), following as tepwise PT-ET pathwayn amed sequential protonl oss electron transfer (SPLET), which involves the solvent as proton acceptor. [12] The key role of the solvent as proton acceptor was also highlighted by SavØant and co-workersi nt he electrochemical oxidationo f phenolsinwater,although they described it as aCPET.…”

Section: Introductionmentioning

confidence: 99%

Peroxyl Radical Reactions in Water Solution: A Gym for Proton‐Coupled Electron‐Transfer Theories

Amorati

Baschieri

Morroni

et al. 2016

Chemistry A European J

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The reactions of alkylperoxyl radicals with phenols have remained difficult to investigate in water. We describe herein a simple and reliable method based on the inhibited autoxidation of water/THF mixtures, which we calibrated against pulse radiolysis. With this method we measured the rate constants kinh for the reactions of 2-tetrahydrofuranylperoxyl radicals with reference compounds: urate, ascorbate, ferrocenes, 2,2,5,7,8-pentamethyl-6-chromanol, Trolox, 6-hydroxy-2,5,7,8-tetramethylchroman-2-acetic acid, 2,6-di-tert-butyl-4-methoxyphenol, 4-methoxyphenol, catechol and 3,5-di-tert-butylcatechol. The role of pH was investigated: the value of kinh for Trolox and 4-methoxyphenol increased 11- and 50-fold from pH 2.1 to 12, respectively, which indicate the occurrence of a SPLET-like mechanism. H(D) kinetic isotope effects combined with pH and solvent effects suggest that different types of proton-coupled electron transfer (PCET) mechanisms are involved in water: less electron-rich phenols react at low pH by concerted electron-proton transfer (EPT) to the peroxyl radical, whereas more electron-rich phenols and phenoxide anions react by multi-site EPT in which water acts as proton relay.

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Unexpected Acid Catalysis in Reactions of Peroxyl Radicals with Phenols

Cited by 66 publications

References 27 publications

On the Mechanism of Cytoprotection by Ferrostatin-1 and Liproxstatin-1 and the Role of Lipid Peroxidation in Ferroptotic Cell Death

On the Mechanism of Cytoprotection by Ferrostatin-1 and Liproxstatin-1 and the Role of Lipid Peroxidation in Ferroptotic Cell Death

Antioxidants in Chemistry and Biology

Peroxyl Radical Reactions in Water Solution: A Gym for Proton‐Coupled Electron‐Transfer Theories

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