Guanine (G) as the most oxidizable part of DNA is the major focus of studies of oxidation damage to DNA. The present study reports the first detailed characterization of G dimerization products potentially resulting from recombination of neutral G. radicals. Our research has discovered a novel type of products of G. dimerization, D1 and D2, formed as a result of one-electron oxidation of G derivatives. The mechanism of this dimerization remains elusive. The current presentation focuses on two aspects: 1. While there appears to be a tautomeric equilibrium between two forms of G., G(N1-H). or G(N2-H)., it remains unclear which intermediate participates in formation of D1 and D2. By methylation at the N1 or at the N2 positions, it was demonstrated by using reverse-phase HPLC and 1H-NMR analysis that hydrogens at the exocyclic N2 position are absolutely required for the D1 and D2 analogs to be produced, while hydrogen at the N1 position is not required. This proves the hypothesis that G(N2-H). is the major contributor to the pathway resulting in D1 and D2. 2. A proposed precursor to D1 generated by the recombination of the two G radicals is likely too unstable and hence cannot be isolated. We synthesized several stable 8-arylamino- or 8-alkylamino- substituted guanosine (Guo) compounds to create stable structural analogs of the D1 precursor and demonstrated by UV-Vis spectroscopy and 1H-NMR that one-electron oxidation of these analogs produces structural analogs of D1 and, upon further oxidation, D2. Importantly, the isolated analogs of D1 quantitatively converted into the D2 analogs. Isolated analogs of D2 were tested for the characteristic reaction with primary amines to form of 2-aminoimidozalones (AIz), in agreement with the mechanism typical of D2.

Mechanisms of formation of novel guanine-guanine cross-links as major end products during one-electron oxidation of guanine derivatives

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