Nucleobases, Nucleosides and Nucleotides - Free-Radical-Induced DNA Damage and Its Repair - page 255

10.5
Reactions with Alkyl and Thiyl Radicals

The question as to the reactions of alkyl radicals with nucleobases is a very im-
portant one. For example, -hydroxyalkyl radicals, generated in the reaction

of reactive free-radicals with alcohols, are capable of inactivating biologically
active DNA (Nabben et al. 1983). Moreover, alkyl-type radicals are formed when
reactive radicals such as • OH and H • add to the nucleobases or abstract an H
atom from the sugar moiety of DNA. Thus, in principle, these DNA radicals thus
generated could add to a neighboring nucleobase if the rate of reaction is suf-
ficiently high and steric conditions allow the reaction to proceed. In DNA, this
kind of reaction may lead to an intramolecular cross-link, e.g. by forming a small
loop. Furthermore, DNA histone cross-linking may occur if a protein-derived
radical would add to one of the DNA bases. Mechanistically, one has to clearly
distinguish such addition reactions from the trivial case, where two base radi-
cals or a base radical and a protein radical recombine. This trivial case is well
documented (Yamamoto 1973; Grachev et al. 1983, 1986; Dizdaroglu and Simic
1984a,b; Dizdaroglu and Simic 1985a,b; Simic and Dizdaroglu 1985; Karam et al.
1986; Gajewski et al. 1988; Margolis et al. 1988; Dizdaroglu and Gajewski 1989;
Dizdaroglu et al. 1989; Gajewski and Dizdaroglu 1990; Gajewski et al. 1990).
A case in point is the combination of a Thy • OH-adduct with a tyrosine-de-
rived phenoxyl radical [reaction (186); Simic and Dizdaroglu 1985].

α

Apparently, the phenoxyl radical reacts also at carbon [reaction (187); the typi-
cal site for self-termination; Jin et al. 1993, 1995]. The resulting product under-
goes an H-shift and eliminates water [reactions (188) and (189)]. The first step is
certainly very fast and is expected to occur on the sub-ms time scale (cf. Capponi