Redox factors in the antioxidant activity of nitroxides toward DNA guanyl and 2-deoxyribose-peroxyl radicals

A series of eight nitroxide compounds (four substituted piperidines, three pyrrolidines and one oxo-piperidine) are found to undergo electron transfer to 2'-deoxyribose-peroxyl and the guanyl radical. One-electron oxidation potentials of the nitroxides to oxoammonium cations (oxoammonium reduction potential), <i>E</i>^0', have been measured against a common redox indicator, chlorpromazine, and found to span the range 751 ± 15 mV to 973 ± 15 mV. Fast chemical reduction of the 2'-deoxyribose-peroxyl radical to the hydroperoxide, generated by <b>^•</b>OH radical attack on 2-deoxyribose, dR, in oxygenated aqueous solution, is a redox-dependent reaction, with rate constants of 0.8-3.5 x 10⁷ M^-1 s^-1. The guanyl radicals, produced upon one-electron oxidation of 2'-deoxyguanosine monophosphate, dG, by the selenite radical, SeO₃<b>^•</b>^-, react with the nitroxides in a redox-independent reaction with diffusion rate constants of 1-2 x 10⁸ M^-1 s^-1. These findings represent a possible antioxidant role for nitroxides in the fast chemical repair of DNA radicals, which is supported by an <i>in vitro</i> strand break study using a plasmid.