Hydroxyl radical reaction with nucleobases

Radicals can react with bases via hydrogen atom abstraction or, more commonly, by addition to the pi bonds in the heterocyclic nucleobases (Scheme 8.1). These reactions have been extensively studied in the context of hydroxyl radical (HO ), which is generated by y-radiolysis of water. When DNA is exposed to the hydroxyl radical, approximately 80% of the reactions occur at the bases. Many base damage products arising from the reaction hydroxyl radical with DNA have been characterized (Fig. 8.2). ... 

Among the species produced upon radiolysis of water, hydroxyl radical ( OH) is the most reactive. Indeed, its reaction rate with the four bases and related nucleosides is diffusion-controlled. The main reactive sites of hydroxyl radicals on nucleobases are the double-bonds of the heterocycles. Accordingly, addition of OH at the C8 position of adenine and guanine yields the corresponding reducing 8-hydroxy-7,8-dihydropurin-7-yl radical (Fig. 2). Oxidation of this intermediate leads to the formation of related 8-hydroxypurines that are in dynamic equilibrium with their more stable 8-oxo-7,8-dihydropurine tautomeric form. Competitive reduction of the latter purine radical gives rise to imidazole ring opened compounds the... 

The observation of 4 -hydroxylated abasic site 23 allowed to propose the mechanism summarized in Fig. 7 in association to the observation of similar oxidation products previously characterized with Fe-bleomycin or neocarzi-nostatin (4,7). It results in the initial formation of a C4 radical 6 due to H4 abstraction by activated Cu(phen)2. Then a C4 -hydroxylated compound is probably formed. It allows the release of the nucleobase and the formation of 4 -hydroxylated abasic site 23 that is not associated to DNA cleavage. This site was trapped by the authors as a pyridazine after reaction with hydrazine followed by an enzymatic digestion to nucleosides. Oyushi and Sugiyama proposed that a C4 carbocation was involved as intermediate in the reaction, as for Cl -DNA oxidation performed by activated Cu(phen)2. This hypothesis needs, however, to be confirmed since other evolutions of the C4 radical 6, producing also C4 -hydroxylated site, have been proposed with other chemical nucleases (4). However, in the case of DNA oxidation by activated Cu(phen)2 this oxidation pathway seemed minor when compared to the pathway leading to the formation of phosphoglycolate fragment 11. 

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