Reactivities of Superoxide and Hydroperoxyl Radicals with Disubstituted Cyclic Nitrones: A DFT Study
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- 作者：Shang-U Kim ; Frederick A. Villamena
- 刊名：The Journal of Physical Chemistry A
- 出版年：2012
- 出版时间：January 19, 2012
- 年：2012
- 卷：116
- 期：2
- 页码：886-898
- 全文大小：717K
- 年卷期：v.116,no.2(January 19, 2012)
- ISSN：1520-5215
文摘
The unique ability of nitrone spin traps to detect and characterize transient free radicals by electron paramagnetic resonance (EPR) spectroscopy has fueled the development of new spin traps with improved properties. Among a variety of free radicals in chemical and biological systems, superoxide radical anion (O2鈥⑩€?/sup>) plays a critical role as a precursor to other more oxidizing species such as hydroxyl radical (HO鈥?/sup>), peroxynitrite (ONOO鈥?/sup>), and hypochlorous acid (HOCl), and therefore the direct detection of O2鈥⑩€?/sup> is important. To overcome the limitations of conventional cyclic nitrones, that is, poor reactivity with O2鈥⑩€?/sup>, instability of the O2鈥⑩€?/sup> adduct, and poor cellular target specificity, synthesis of disubstituted nitrones has become attractive. Disubstituted nitrones offer advantages over the monosubstituted ones because they allow bifunctionalization of spin traps, therefore accommodating all the desired spin trap properties in one molecular design. However, because of the high number of possible disubstituted analogues as candidate, a systematic computational study is needed to find leads for the optimal spin trap design for biconjugation. In this paper, calculation of the energetics of O2鈥⑩€?/sup> and HO2鈥?/sup> adduct formation from various disubstituted nitrones at PCM/B3LYP/6-31+G(d,p)//B3LYP/6-31G(d) level of theory was performed to determine the most favorable disubstituted nitrones for this reaction. In addition, our results provided general trends of radical reactivity that is dependent upon but not exclusive to the charge densities of nitronyl-C, the position of substituents including stereoselectivities, and the presence of intramolecular H-bonding interaction. Unusually high exoergic 螖G298K,aq鈥檚 for O2鈥⑩€?/sup> and HO2鈥?/sup> adduct formation were predicted for (3S,5S)-5-methyl-3,5-bis(methylcarbamoyl)-1-pyrroline N-oxide (11-cis) and (4S,5S)-5-dimethoxyphosphoryl-5-methyl-4-ethoxycarbonyl-1-pyrroline N-oxide (29-trans) with 螖G298K,aq = 鈭?.3 and 鈭?.4 kcal/mol, respectively, which are the most exoergic 螖G298K,aq observed thus far for any nitrone at the level of theory employed in this study.