A Linear Free-Energy Approach to the Study of Substituted Phenoxazines as a Potent Family of Radical Trapping Antioxidants

• Main Author: Farmer, Luke
• Other Authors: Pratt, Derek
• Format: Others
• Language: en
• Published: Université d'Ottawa / University of Ottawa 2018
• Subjects: antioxidant; phenoxazine
• Online Access: http://hdl.handle.net/10393/37722; http://dx.doi.org/10.20381/ruor-21986

Radical mediated autoxidation is a pervasive phenomenon in commercial (i.e. rubbers, fuels, lubricants, etc.) and biological contexts (i.e. lipid peroxidation associated with neurodegeneration, cancer, and aging), which can be strategically managed with radical-trapping antioxidants (RTAs). While various phenol and polyphenol RTAs have enjoyed much academic fanfare, particularly in biochemical circles, there are other RTA scaffolds that tend to be overlooked despite possessing rather promising activity. Among these seldom studied RTA scaffolds is that of the tricyclic aromatic amine phenoxazine. The inherent reactivity of phenoxazines as RTAs was explored using a quantitative linear free energy approach. A library of phenoxazines was synthesized and Hammett correlations developed between BDE/(log kinhPhCl)/Eo and the electrophilicity substituent parameters (Σ σp+) served to unambiguously demonstrate that phenoxazine RTAs collectively represent the most reactive family of RTAs yet reported. The high inherent reactivity of phenoxazine RTAs towards peroxyl radicals necessitated the co- development of an approach to enable the accurate prediction of kinhPhCl based on the inhibition rate constants measured in hydrogen-bond accepting solvent mixtures containing chlorobenzene, 1,4-dioxane, and/or dimethylsulfoxide. The catalytic antioxidant activity of phenoxazines was established in hexadecane autoxidations at elevated temperatures, where they demonstrated superior activity to industry standard alkylated diphenylamine (ADPA), but also an inferiority to phenothiazine. These results combined with amine/nitroxide monitoring experiments serve to re-emphasize some current design considerations for high-temperature RTAs while challenging others. Lastly the activity of these as inhibitors of lipid peroxidation was assessed in liposomes and mammalian cell culture. The kinetics of peroxyl radical-trapping of the various phenoxazines in phosphatidylcholine liposomes enabled the quantitation of H- bonding interactions to the phosphate head groups of the phospholipids on RTA activity – which diminish the kinetics by up to two orders of magnitude relative to non-H- bonding hydrocarbons. The potency of these phenoxazines to subvert ferroptosis corresponds well with their inhibition activity in liposomes which further affirms the role that non-enzymatic autoxidation plays in this form of cell death.