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Spin trapping of hydroperoxyl radical by a cyclic nitrone conjugated to ?-cyclodextrin: a computational study.

ABSTRACT: Spin trapping of hydroperoxyl radical (HOO.) by the amide-linked conjugate of 5-carbamoyl-5-methyl-1-pyrroline N-oxide (AMPO) to ?-cyclodextrin (?-CD) was studied computationally using a two-layered ONIOM method. From a conformational perspective, the "internal" conformation of 5R-?-CD-AMPO is more favored than the "external" conformation in which the nitrone is located outside of the cavity of the ?-CD. When the HOO. addition product is formed, the most stable isomer has the nitroxyl (N1-O1) moiety pointing inside the cavity of the ?-CD. Thus, this "internal" conformation might protect the N1-O1 moiety of the resulting spin adduct from access by reducing agents, thereby improving the lifetime of the radical adduct. The computed energetic barrier for HOO. addition to the 5R-?-CD-AMPO is 8.7 kcal/mol, which is marginally smaller than spin trapping by the non-conjugated AMPO (that is, without the ?-CD). To optimize the reactivity of the ?-CD-AMPO conjugate, the effect of a spacer unit between the AMPO segment and the ?-CD moiety with varying methylene units, (CH2) n (n = 1, 2, 3), on the energetics of HOO. addition was evaluated. The structure with only one methylene spacer (n = 1) appears to be optimal as determined by the smaller activation barrier (6.2 kcal/mol) for HOO. addition to the nitrone moiety. Compared with very time-consuming quantum mechanical methods, the ONIOM method appears to offer significant advantages for evaluation of the best ?-CD-AMPO conjugate for trapping of such reactive oxygen species and providing for the rational design of novel nitrones as spin traps.

SUBMITTER: Bao X

PROVIDER: S-EPMC3621576 | biostudies-literature | 2012 Jul

REPOSITORIES: biostudies-literature

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Spin trapping of hydroperoxyl radical by a cyclic nitrone conjugated to β-cyclodextrin: a computational study.

Bao Xiaoguang X Tao Peng P Villamena Frederick A FA Hadad Christopher M CM

Theoretical chemistry accounts 20120701

Spin trapping of hydroperoxyl radical (HOO.) by the amide-linked conjugate of 5-carbamoyl-5-methyl-1-pyrroline N-oxide (AMPO) to β-cyclodextrin (β-CD) was studied computationally using a two-layered ONIOM method. From a conformational perspective, the "internal" conformation of 5R-β-CD-AMPO is more favored than the "external" conformation in which the nitrone is located outside of the cavity of the β-CD. When the HOO. addition produ ...[more]

PMID: 23585725

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Project description: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 (O(2)(•-)) plays a critical role as a precursor to other more oxidizing species such as hydroxyl radical (HO(•)), peroxynitrite (ONOO(-)), and hypochlorous acid (HOCl), and therefore the direct detection of O(2)(•-) is important. To overcome the limitations of conventional cyclic nitrones, that is, poor reactivity with O(2)(•-), instability of the O(2)(•-) 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 O(2)(•-) and HO(2)(•) 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 ?G(298K,aq)'s for O(2)(•-) and HO(2)(•) 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 ?G(298K,aq) = -3.3 and -9.4 kcal/mol, respectively, which are the most exoergic ?G(298K,aq) observed thus far for any nitrone at the level of theory employed in this study.

Project description:Recently, we showed that peroxynitrite (ONOO(-)) reacts directly and rapidly with aromatic and aliphatic boronic acids (k ? 10(6) M(-1)s(-1)). Product analyses and substrate consumption data indicated that ONOO(-) reacts stoichiometrically with boronates, yielding the corresponding phenols as the major product (?85-90%), and the remaining products (10-15%) were proposed to originate from free radical intermediates (phenyl and phenoxyl radicals). Here, we investigated in detail the minor, free radical pathway of boronate reaction with ONOO(-). The electron paramagnetic resonance (EPR) spin-trapping technique was used to characterize the free radical intermediates formed from the reaction between boronates and ONOO(-). Using 2-methyl-2-nitrosopropane (MNP) and 5-diethoxyphosphoryl-5-methyl-1-pyrroline-N-oxide (DEPMPO) spin traps, phenyl radicals were trapped and detected. Although phenoxyl radicals were not detected, the positive effects of molecular oxygen, and inhibitory effects of hydrogen atom donors (acetonitrile, and 2-propanol) and general radical scavengers (GSH, NADH, ascorbic acid, and tyrosine) on the formation of phenoxyl radical-derived nitrated product, suggest that the phenoxyl radical was formed as the secondary species. We propose that the initial step of the reaction involves the addition of ONOO(-) to the boron atom in boronates. The anionic intermediate undergoes both heterolytic (major pathway) and homolytic (minor pathway) cleavage of the peroxy (O-O) bond to form phenol and nitrite as a major product (via a nonradical mechanism), or a radical pair PhB(OH)(2)O(•-)···(•)NO(2) as a minor product. It is conceivable that phenyl radicals are formed by the fragmentation of the PhB(OH)(2)O(•-) radical anion. According to the DFT quantum mechanical calculations, the energy barrier for the dissociation of PhB(OH)(2)O(•-) radical anion to form phenyl radical is only a few kcal/mol, suggesting rapid and spontaneous fragmentation of the PhB(OH)(2)O(•-) radical anion in aqueous media. Biological implications of the minor free radical pathway are discussed in the context of ONOO(-) detection, using the boronate probes.

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Spin trapping of hydroperoxyl radical by a cyclic nitrone conjugated to ?-cyclodextrin: a computational study.

Publications

Spin trapping of hydroperoxyl radical by a cyclic nitrone conjugated to <i>β</i>-cyclodextrin: a computational study.

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