Superoxide Radical Anion Adduct of 5,5-Dimethyl-1-pyrroline N-Oxide. 6. Redox Properties

Abstract

Cyclic nitrones have been employed for decades as spin trapping reagents for the detection and identification of transient radicals, and have been employed as pharmacological agent against ROS-mediated toxicity. The short half-life of the nitrone-superoxide adducts limits the application of nitrones in biological millieu, and therefore investigaton of the redox properties of the superoxide adducts is important. Moreover, computational investigation of the redox properties of the nitrones and their corresponding spin adducts may provide new insights into the nature of their pharmacological activity against ROS-induced toxicity. In general, electron-withdrawing group substitution at the C-5 position results in higher EAs and IPs making these substituted nitrones more susceptible to reduction but more difficult to oxidize compared to DMPO. One-electron reduction and oxidation of nitrones both resulted in elongated N-C(2) bonds indicating the tendency of radical anion and cation forms of nitrone to undergo ring-opening. The EAs and IPs of various O(2)(*-) adducts indicate that DEPMPO-O(2)H is the most difficult to reduce and oxidize compared to the O(2)(*-) adducts of DMPO, EMPO, and AMPO. In general, nitroxides gave higher EAs compared to nitrones making them more suceptible to reduction. One-electron oxidation of nitroxides leads to elongation of the N-C(2) bond but not for their reduction. The energetics of redox reaction of O(2)(*-) adducts was also explored. Results indicate that the reduction of O(2)(*-) adducts with O(2)(*-) is preferred followed by their oxidation by O(2) and then by O(2)(*-), but the maximum difference between these free energies of redox reactions in aqueous solution is only 0.21 kcal/mol. The preferred decomposition pathways for the one-electron oxidation and reduction of nitroxides was also explored, and formation of potentially biologically active products such as NO, H(2)O(2), and hydroxamic acid was predicted.