title: Spin trapping of hydroperoxyl radical by a cyclic nitrone conjugated toβ-cyclodextrin: a computational study.
abstract: Spin trapping of hydroperoxyl radical (HOO.) by the amide-linked conjugate of 5-carbamoyl-5-methyl-1-pyrrolineN-oxide (AMPO) toβ-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 theβ-CD. When the HOO.addition product is formed, the most stable isomer has the nitroxyl (N1-O1) moiety pointing inside the cavity of theβ-CD. Thus, this "internal" conformation might protect the N1-O1moiety 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 theβ-CD). To optimize the reactivity of theβ-CD-AMPO conjugate, the effect of a spacer unit between the AMPO segment and theβ-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 bestβ-CD-AMPO conjugate for trapping of such reactive oxygen species and providing for the rational design of novel nitrones as spin traps.
authors.affiliation: Department of Chemistry, Ohio State University, 100 West 18th Avenue, Columbus, OH 43210, USA.
authors.forename: Xiaoguang
authors.initials: X
authors.lastname: Bao
authors.forename: Peng
authors.initials: P
authors.lastname: Tao
authors.forename: Frederick A
authors.initials: FA
authors.lastname: Villamena
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Hadad
keywords: Cyclodextrin; Electron paramagnetic resonance spectroscopy; Hydroperoxyl radical; Nitrone; Spin trapping