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Reactivity of Superoxide Radical Anion with Cyclic Nitrones:  Role of Intramolecular H-Bond and Electrostatic Effects

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journal contribution
posted on 04.07.2007, 00:00 by Frederick A. Villamena, Shijing Xia, John K. Merle, Robert Lauricella, Beatrice Tuccio, Christopher M. Hadad, Jay L. Zweier
Limitations exist among the commonly used cyclic nitrone spin traps for biological free radical detection using electron paramagnetic resonance (EPR) spectroscopy. The design of new spin traps for biological free radical detection and identification using EPR spectroscopy has been a major challenge due to the lack of systematic and rational approaches to their design. In this work, density functional theory (DFT) calculations and stopped-flow kinetics were employed to predict the reactivity of functionalized spin traps with superoxide radical anion (O2•-). Functional groups provide versatility and can potentially improve spin-trap reactivity, adduct stability, and target specificity. The effect of functional group substitution at the C-5 position of pyrroline N-oxides on spin-trap reactivity toward O2•- was computationally rationalized at the PCM/B3LYP/6-31+G(d,p)//B3LYP/6-31G(d) and PCM/mPW1K/6-31+G(d,p) levels of theory. Calculated free energies and rate constants for the reactivity of O2•- with model nitrones were found to correlate with the experimentally obtained rate constants using stopped-flow and EPR spectroscopic methods. New insights into the nucleophilic nature of O2•- addition to nitrones as well as the role of intramolecular hydrogen bonding of O2•- in facilitating this reaction are discussed. This study shows that using an N-monoalkylsubstituted amide or an ester as attached groups on the nitrone can be ideal in molecular tethering for improved spin-trapping properties and could pave the way for improved in vivo radical detection at the site of superoxide formation.

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