Phenoxazine: A Privileged Scaffold for Radical-Trapping Antioxidants

Abstract

Diphenylamines are widely used to protect petroleum-derived products from autoxidation. Their efficacy as radical-trapping antioxidants (RTAs) relies on a balance of fast H-atom transfer kinetics and stability to one-electron oxidation by peroxidic species. Both H-atom transfer and one-electron oxidation are enhanced by substitution with electron-donating substituents, such as the S-atom in phenothiazines, another important class of RTA. Herein we report the results of our investigations of the RTA activity of the structurally related, but essentially ignored, phenoxazines. We find that the H-atom transfer reactivity of substituted phenoxazines follows an excellent Evans-Polanyi correlation spanning k = 4.5 × 10 M s and N-H BDE = 77.4 kcal mol for 3-CN,7-NO-phenoxazine to k = 6.6 × 10 M s and N-H BDE = 71.8 kcal mol for 3,7-(OMe)-phenoxazine (37 °C). The reactivity of the latter compound is the greatest of any RTA ever reported and is likely to represent a reaction without an enthalpic barrier since log A for this reaction is likely ∼8.5. The very high reactivity of most of the phenoxazines studied required the determination of their kinetic parameters by inhibited autoxidations in the presence of a very strong H-bonding cosolvent (DMSO), which slowed the observed rates by up to 2 orders of magnitude by dynamically reducing the equilibrium concentration of (free) phenoxazine as an H-atom donor. Despite their remarkably high reactivity toward peroxyl radicals, the phenoxazines were found to be comparatively stable to one-electron oxidation relative to diphenylamines and phenothiazines (E° ranging from 0.59 to 1.38 V vs NHE). Thus, phenoxazines with comparable oxidative stability to commonly used diphenylamine and phenothiazine RTAs had significantly greater reactivity (by up to 2 orders of magnitude). Computations suggest that this remarkable balance in H-atom transfer kinetics and stability to one-electron oxidation results from the ability of the bridging oxygen atom in phenoxazine to serve as both a π-electron donor to stabilize the aminyl radical and σ-electron acceptor to destabilize the aminyl radical cation. Perhaps most excitingly, phenoxazines have "non-classical" RTA activity, where they trap >2 peroxyl radicals each, at ambient temperatures.

Ommochromes in invertebrates: biochemistry and cell biology

“…It occurs because the electronic delocalisation of the phenoxazine chromophore is increased in H 2 ‐xanthommatin, leading to greater stabilisation by resonance of the oxonium ion (O + ) (Schäfer & Geyer, ). Recent studies suggested that these redox and related antiradical behaviours allow phenoxazine‐based compounds to buffer oxidative stress (Romero & Martínez, ; Farmer et al, ; Shah, Margison & Pratt, ). The theoretical basis of this putative biological role was modelled using computational and quantum chemistry, as well as in biological assays.…”

“…Interestingly, this antiradical property was directly linked to the N–H bond of phenoxazine/phenothiazine rings (Fig. C) (Farmer et al, ), meaning that only reduced ommochromes could act as potent antiradicals and antioxidants in cells. This result is consistent with in silico measurements of hydrogen‐donor capacities of ommochromes (Fig.…”

Reactions of the Lipid Hydroperoxides With Aminic Antioxidants: The Influence of Stereoelectronic and Resonance Effects on Hydrogen Atom Transfer

“…Additionally, the stability to one-electron oxidation is another determine factor for the potency of antioxidants (Farmer et al, 2017). Thus, we will elaborately discuss the types involved in reactivity to H-atom transfer and stability to one-electron oxidation of aminic RTAs in the following context.…”

N10‐carbonyl‐substituted phenothiazines inhibiting lipid peroxidation and associated nitric oxide consumption powerfully protect brain tissue against oxidative stress

“…If we draw the structure of DT‐PTZ‐C as the tautomer (Figure ), then it is apparent that further stabilization of the radical cation or the radical form is possible. In the case of molecules such as phenols and enolates, the most facile reaction available is the HAT (Jovanovic, Steenken, Boone, & Simic, ) and has also been invoked to explain the antioxidant activity of phenoxazines (Farmer et al., ). It is clear that defining the mechanism of action of DT‐PTZ‐C will require further research, which is beyond the scope of this study.…”

“…Moosmann et al reported that three structurally similar compounds phenothiazine, phenoxazine, and iminostilbene had IC 50 's of 20-75 nM in their experimental paradigms. Separate studies on the radical trapping activity of unsubstituted N-10 phenoxazines demonstrated an ability to trap more two or more peroxyl radicals indicating the potential for this group of compounds (Farmer, Haidasz, Griesser, & Pratt, 2017;Lucarini et al, 1999).…”