Spin trapping of hydroperoxyl radical by a cyclic nitrone conjugated to β-cyclodextrin: a computational study
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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 product is formed, the most stable isomer has the nitroxyl (N1–O1) moiety pointing inside the cavity of the β-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-β-CD-AMPO is 8.7 kcal/mol, which is marginally smaller than spin trapping by the non-conjugated AMPO (that is, without the β-CD). To optimize the reactivity of the β-CD-AMPO conjugate, the effect of a spacer unit between the AMPO segment and the β-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 β-CD-AMPO conjugate for trapping of such reactive oxygen species and providing for the rational design of novel nitrones as spin traps.
KeywordsNitrone Spin trapping Hydroperoxyl radical Electron paramagnetic resonance spectroscopy Cyclodextrin
Financial support from the National Institutes of Health (R01-HL081248) is acknowledged. The Ohio Supercomputer Center (OSC) provided generous computational support of this research. We thank Dr. Shubham Vyas for technical assistance.
The optimized structures of “internal” and “external” conformation of 5S-β-CD-AMPO, some other isomers of spin-adduct products, PES scans of the C2–Ob bond cleavage of 5R-β-CD-A-(CH2) n -MPO-HOO• (n = 1, 2, 3) and the corresponding reactant complex, TS and product structures are provided in the supporting information. Supplementary material 1 (AVI 3403 kb)
Supplementary material 2 (AVI 3586 kb)
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