Nitroxides—Metal-Independent SOD Mimics

Nitroxides are the most important metal-independent superoxide dismutase mimics. They act as antioxidants mainly by reacting with superoxide. Nitroxides are low molecular weight, cell membrane permeable, and relatively stable radicals. The SOD-mimic activities of nitroxides are catalytic processes in which nitroxides and their oxidized form exchange among themselves without depletion of nitroxides. Many experiments have confirmed that such SOD-mimic activities of nitroxides play a prime role in preventing biological free radical damage. Introduction The ability of superoxide dismutase (SOD) to catalyze superoxide ( O2 ) dismutation was first discovered by McCord and Fridovich in 1969. It is believed that it protects cells from O2 toxicity [1]. The catalytic dismutation of O2 by SOD involves alternate reduction and oxidation of the transition metal ion in a “ ping-pong”-like mechanism [2]. Increasing intracellular levels of SOD or administering exogenous SOD can lessen inflammation, decrease ischemia-induced reperfusion injury, decrease damage from tumor necrosis factor, and mitigate J. Luo Nitroxides-SOD mimics 3 the damage caused by rheumatoid arthritis [3]. However, native SOD has a few drawbacks in its use. The main problems are due to its short half life, which is about 10 minutes, and its inability to penetrate into the cells because of its larger molecular weight and also inability to reach lipophilic regions. Hence, compounds with SOD-like activity with low molecular weight, biological stability, and membrane permeability are being sought. SOD mimics In order that a compound with a high SOD-like activity would be able to mimic SOD in vivo, it is required that: 1. It should be non-toxic. 2. It should have a long metabolic half life. 3. It should have a high cell permeability. 4. It should be relatively stable to cell metabolism, which means that SOD mimics should have a high stability constant [3]. 5. Its reduced form should not be reoxidized by oxygen or H2O2. 6. It should have a reduction potential of -0.16 V < E < 0.89 V, be nonimmunogenic and active within the physiological pH range. 7. It should not form ternary complexes with the cell components, or alternatively, the ternary complexes should retain most of above mentioned properties. 8. It should be able to be directed preferentially either to a lipophilic or hydrophobic regions according to the demand [4]. J. Luo Nitroxides-SOD mimics 4 These requirements suggest that finding a SOD mimic to operate in vivo will not be an easy task.