Structure−Activity Relationship of Cyclic Nitroxides as SOD Mimics and Scavengers of Nitrogen Dioxide and Carbonate Radicals

• Published in: The journal of physical chemistry. A, Molecules, spectroscopy, kinetics, environment, & general theory Vol. 110; no. 10; pp. 3679 - 3685
• Main Authors: Goldstein, Sara, Samuni, Amram, Hideg, Kalman, Merenyi, Gabor
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 16.03.2006
• Subjects: Antioxidants - metabolism; Carbonates - chemistry; Carbonates - metabolism; Cyclic N-Oxides - chemistry; Cyclic N-Oxides - metabolism; electron-spin-resonance; Free Radical Scavengers - metabolism; Free Radicals - metabolism; Hydrogen-Ion Concentration; Kinetics; Molecular Mimicry; nitric-oxide; Nitrogen Dioxide - metabolism; outer-sphere; Oxazoles - chemistry; Oxazoles - metabolism; Oxidation-Reduction; oxidative damage; oxoammonium cation; Piperidines - chemistry; Piperidines - metabolism; Pulse Radiolysis; Pyrrolidines - chemistry; Pyrrolidines - metabolism; rat-heart; Structure-Activity Relationship; superoxide; Superoxide Dismutase - metabolism; Superoxides - metabolism; tempol
• ISSN: 1089-5639; 1520-5215; 1520-5215
• DOI: 10.1021/jp056869r

Synthetic nitroxide antioxidants attenuate oxidative damage in various experimental models. Their protective effect reportedly depends on ring size and ring substituents and is greater for nitroxides having lower oxidation potential. The present study focuses on the kinetics and mechanisms of the reactions of piperidine, pyrrolidine and oxazolidine nitroxides with HO2 •/O2 •-, •NO2 and CO3 •- radicals, which are key intermediates in many inflammatory and degenerative diseases. It is demonstrated that nitroxides are the most efficient scavengers of •NO2 at physiological pH (k = (3−9) × 108 M-1 s-1) and among the most effective metal-independent scavengers of CO3 •- radicals (k = (2 − 6) × 108 M-1 s-1). Their reactivity toward HO2 •, though not toward •NO2 and CO3 •-, depends on the nature of the ring side-chain and particularly on the ring-size. All nitroxide derivatives react slowly with O2 •- and are relatively inefficient SOD mimics at physiological pH. Even piperidine nitroxides, having the highest SOD-like activity, demonstrate a catalytic activity of about 1000-fold lower than that of native SOD at pH 7.4. The present results do not indicate any correlation between the kinetics of HO2 •/O2 •-, •NO2 and CO3 •- removal by nitroxides and their protective activity against biological oxidative stress and emphasize the importance of target-oriented nitroxides, i.e., interaction between the biological target and specific nitroxides.