Res. Chem. Intermed.
, Vol. 32, No. 7, pp. 625–635 (2006)
Also available online - www.vsppub.com
Alkyl radical adducts of aromatic N-oxides
as hydrogen-abstracting agents: the reactivity
-dioxide–methyl radical adduct
and DAVID M. CLOSE
Department of Physics, Astronomy and Geology, Box 70652, East Tennessee State University,
Johnson City, TN 37614, USA
Received 24 August 2005; accepted 6 January 2006
Abstract—An O-methylated analog of protonated phenazine-di-N-oxide radical anion abstracts
hydrogen from primary and secondary alcohols in a slow (k
< 500 M
) bimolecular reaction.
No kinetic evidence has been found for the unimolecular release of free methoxyl radicals through
the homolytic N
OMe bond cleavage in these species. DFT calculations at the UB3LYP 6-31G(d)
level indicate that protonated and O-alkylated radical anions of pyrazine, quinoxaline and phenazine
di-N-oxides are close analogues of aromatic nitroxyl radicals with the highest spin density localized
on the oxygen and nitrogen of the nitrone moiety.
Keywords: Aromatic N-oxides; radical adducts; hydrogen abstraction; spin density.
Free radical DNA damage mediated by aromatic N-oxides has been extensively
investigated in the past decade. Most detailed studies have been performed on the
mechanism of reductively activated DNA cleavage by the antitumor agent 3-amino-
1,2,4-benzotriazine-1,4-dioxide (also known as TPZ, tirapazamine, SR4233, WIN
59075 and triazone). The DNA damage is believed to be inﬂicted by protonated
radical-anions of the drug, generated through enzymatic reduction. It has also been
suggested that N-oxides can be reduced by DNA-based free radicals originating
from other sources . This process transforms DNA radicals into permanent
lesions and generates the one-electron reduced form of the drug which, in turn, may
inﬂict further DNA damage. It has been shown experimentally that deoxyribose C1
radicals in model oligonucleotides are oxidized by TPZ into 2
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