The Fate of C5′ Radicals of Purine Nucleosides under Oxidative Conditions

Abstract

The factors that influence the reactivity of C5' radicals in purine moieties under aerobic conditions are unknown not only in DNA, but also in simple nucleosides. 5',8-Cyclopurine lesions are the result of a rapid C5' radical attack to the purine moieties before the reaction with oxygen. These well-known lesions among the DNA modifications were suppressed by the presence of molecular oxygen in solution. Here we elucidate the chemistry of three purine-substituted C5' radicals (i.e., 2'-deoxyadenosin-5'-yl, 2'-deoxyinosin-5'-yl, and 2'-deoxyguanosin-5'-yl) under oxidative conditions using gamma-radiolysis coupled with product studies. 2'-Deoxyadenosin-5'-yl and 2'-deoxyinosin-5'-yl radicals were selectively generated by the reaction of hydrated electrons (e(aq)(-)) with 8-bromo-2'-deoxyadenosine and 8-bromo-2'-deoxyinosine followed by a rapid radical translocation from the C8 to the C5' position. Trapping these two C5' radicals with Fe(CN)6(3-) gave corresponding hydrated 5'-aldehydes in good yields that were isolated and fully characterized. When an oxygen concentration in the range of 13-266 microM (typical oxygenated tissues) is used, the hydrated 5'-aldehyde is accompanied by the 5',8-cyclopurine nucleoside. The formation of 5',8-cyclopurines is relevant in all experiments, and the yields increased with decreasing O2 concentration. The reaction of HO(*) radicals with 2'-deoxyadenosine and 2'-deoxyguanosine under normoxic conditions was also investigated. The minor path of C5' radicals formation was found to be ca. 10% by quantifying the hydrated 5'-aldehyde in both experiments. Rate constants for the reactions of the 2'-deoxyadenosin-5'-yl with cysteine and glutathione in water were determined by pulse radiolysis to be (2.1 +/- 0.5) x 10(7) and (4.9 +/- 0.6) x 10(7) M(-1) s(-1) at 22 degrees C, respectively.

New Insights into the Reaction Paths of Hydroxyl Radicals with 2′-Deoxyguanosine

“…6 In this work we considered for comparison the 8-substituted guanosines. The spectral changes obtained from the pulse irradiation of a N 2 O-saturated unbuffered aqueous solutions of 1 mM 8-(2-hydroxypropan-2-yl)guanosine (7) or 8-bromoguanosine (8) are shown in Figures 1 and 2. The behavior in both cases was very similar to the analogous reaction of guanosine.…”

“…The consumption of 1b was accompanied by the formation of two main products, identified as guanine and the hydrated 5 0 -aldehyde 5. 8 The majority of cyclonucleosides (4) were replaced by hydrated 5 0 -aldehyde 5 (∼8%), which suggests that the oxygen concentration would be high enough to trap most of the C5 0 radicals prior to cyclization, whereas guanine (free base) is formed via well-known pathways of C1 0 , C3 0 and C4 0 sugar radicals trapped by oxygen. 9 The above considerations at the nucleoside level are strictly connected to DNA lesions.…”

Free Radicals in Chemical Biology: from Chemical Behavior to Biomarker Development

“…10% by hydrogen abstraction from C5′ position. 7 Our chemical biology approach for the libraries of purine 5',8-cyclo-2'-deoxyribonucleosides (including labeled compounds) is illustrated in Figure 7, with the identification of these lesions in oligonucleotides as well as in DNA samples obtained from various sources such as, for example, treated under ionizing radiation conditions, as mimic of radical stress conditions.…”

“…We focused our interest on the smallest tandem lesions, which are purine Bio-inspired synthetic procedures of compounds 1-4 were developed starting from 8-bromopurine derivatives under or photolysis. 7,12 These procedures involve a radical cascade reaction that mimics the DNA damage mechanism of formation of 5',8-cdAdo and 5',8-cdGuo lesions. From biological perspectives, it was found that these lesions accumulate with aging in a tissue-specific manner (liver>kidney>brain), providing evidence that DNA repair mechanisms are inadequate to preserve the genetic material from these lesions.…”

Hydrogen atom abstraction reactions of the sugar moiety of 2′‐deoxyguanosine with an OH radical: A quantum chemical study

“…0 ,8-cyclopurine-2 0 -deoxynucleosides [1][2][3][4][5]. Radicals centered at each of the C1 0 , C2 0 , C3 0 , C4 0 , and C5 0 carbon atoms of the 2 0 -deoxyribose moiety of DNA have been observed experimentally [6][7][8] (see Fig.…”