Pyrimidine peroxyl radicals

The reduction of pyrimidine peroxyl radicals by 02 is not an efficient process since the rate constant of the reaction has been estimated to be 6 x 10 ... 

In aqueous solution, intercalated Hoechst 3342 protects DNA against strand breakage beyond OH-scavenging (quenching diameter by Hoechst 3-4 bp Adhikary et al. 1997a). Besides, intercalated Hoechst reacts with OH-induced DNA on the ms time scale. The Hoechst-reactive damaged DNA sites are likely the oxidizing radicals A and G and pyrimidine peroxyl radicals (Table 12.17 for further pulse radiolysis studies on Hoechst in aqueous solution see Adhikary et al. 2000). 

Deprotonation provides the necessary electron push to kick out the electron pair joining C(6) with the nitrobenzene oxygen. If, however, N(l) is alkylated (as with the nucleosides and nucleotides), OH catalysis is much less efficient since it now proceeds by deprotonation from N(3) (with the uracils) or from the amino group at C(4) (with the cytosines). In these cases the area of deprotonation is separated from the reaction site by a (hydroxy)methylene group which means that the increase in electron density that results from deprotonation at N(3) is transferable to the reaction site only through the carbon skeleton (inductive effect), which is of course inefficient as compared to the electron-pair donation from N(l) (mesomeric effect) [26]. Reaction 15 is a 1 1 model for the catalytic effect of OH on the heterolysis of peroxyl radicals from pyrimidine-6-yl radicals (see Sect. 2.4). 

Razskazovskii Y, Sevilla MD (1996) Reactions of sulphonyl peroxyl radicals with DNA and its components hydrogen abstraction from the sugar backbone versus addition to pyrimidine double bonds. Int J Radiat Biol 69 75-87... 

Schuchmann MN, Naumov S, Schuchmann H-P, von Sonntag J, von Sonntag C (2005) 4-Amino-3Ff-pyrimidin-2-one ("isocytosine") is a short-lived non-radical intermediate formed in the pulse radiolysis of cytosine in aqueous solution. Radiat Phys Chem 72 243-250 Schulte-Frohlinde D, Hildenbrand K (1989) Electron spin resonance studies of the reactions of OH and SO4 radicals with DNA, polynucleotides and single base model compounds. In Minisci F (ed) Free radicals in synthesis and biology. Kluwer, Dordrecht, pp 335-359 Schulte-Frohlinde D, Behrens G, Onal A (1986) Lifetime of peroxyl radicals of poly(U), poly(A) and single- and double-stranded DNA and the rate of their reaction with thiols. Int J Radiat Biol 50 103-110... 

The most detailed information as to the decay of nucleobase peroxyl radicals may be obtained from a study on uracil. The limited space here does not allow for the discussion of details, but some aspects are shown in reactions (41)-(47). With the pyrimidine nucle-obases, isopyrimidines are typical intermediates in these and other oxidation reactions cf. reaction (41). For their chemistry see Ref. 2. 

In considering the reactivity of pyrimidine bases with the hydroxyl radical, it is evident that the simple ring structure favours the addition of oxygen after hydroxyl radical attack at either the C5 or C6 position [35,40]. For example, from the C5 radical adduct, the resultant 5-hydroxy, 6-peroxyl radical adduct may subsequently eliminate O7 after reaction with water to yield thymine glycol [35, 40]. In the absence of oxygen, reduction of either 5-OH or 6-OH adduct radicals, followed by protonation yields the corresponding hydroxy, hydropyrimidine shown below in Scheme 5. Reduction of the thymine-OH radical adduct also occurs to yield 5-hydroxy-5-methylhydantoin [37]. 

The OH-adduct radicals of the pyrimidines react with oxygen at close to diffusion-controlled rates, yielding the corresponding peroxyl radicals. In basic solutions, but also in neutral solutions provided that these peroxyl radicals have a sufficiently long lifetime, the C(5)-OH,C(6)-peroxyl radicals can undergo superoxide elimination after deprotonation at N(l) [reactions (26) and (27)]... 

In acid solutions, but also in neutral solutions at high steady-state radical concentrations, the superoxide elimination becomes too slow compared with the bimolecular decay of these peroxyl radicals [reactions (28)-(31)]. This leads to a very different product distribution, as seen in Table 5. There is evidence that in their bimolecular decay peroxyl radicals can give rise to the formation of oxyl radicals which may undergo fragmentation (see, e.g., [37, 38]) [e.g., reaction (30)], leading to products with the pyrimidine cycle destroyed (e.g., l-N-formyl-5-hydroxyhydantoin. Other pyrimidine-ring cleavage reactions are conceivable but at present not supported by product data). 

However, if non-tertiary, oxyl radicals in aqueous solution are capable of undergoing a rapid 1,2-H-shift [44-46] [reaction (34)] in competition with fragmentation. Then after addition of oxygen, superoxide is eliminated [reaction (36)]. Thus under these conditions also, superoxide radicals are likely intermediates which are expected to react with peroxyl radiceds, reducing them to the corresponding hydroperoxides. These are abundant, though somewhat unstable, products in the radiolysis of air-saturated pyrimidine solutions. They are considered to be important precursors of the pyrimidine glycols observed under various conditions [1]. 

Similar to the OH radical, the H-atom acts as an electrophilic radical, and in its additions to C=C double bonds it has a preference for the electron-richer site. Thus, in the pyrimidine series an addition to the C(5)-position is the preferred reaction [cf. reaction (52) and Table 7]. The same kind of radical is formed by H-atom abstraction from 5,6-dihydropyrimidines [c/. reaction (54)][50], as can be inferred from the data compiled in Table 8. Regarding the behaviour of the H-atom-adduct peroxyl radicals one would start from the dihydropyrimidines while it would be impractical to study it in the pyrimidine system. 

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