The Reactivity of 2,5-Diaminoimidazolone Base Modification Towards Aliphatic Primary Amino Derivatives: Nucleophilic Substitution at C5 as a Potential Source of Abasic Sites in Oxidatively Damaged DNA

Document Type


Publication Date



N5-deoxyribosyl derivatives of 2,5-diaminoimidazolone formed by oxidative damage to the guanine bases in 2-deoxyguanosine and highly polymerized DNA readily undergo nucleophilic substitution at C5 in reaction with primary amines in neutral aqueous solutions at 37–70 °C, as it was found in a kinetic study using reverse-phase HPLC. The reaction of 2-amino-5-[(2′-deoxy-β-D-erythro-pentofuranosyl)amino]-4H-imidazol-4-one (dIz) with excess of ethanolamine, alanine and γ-aminobutyric acid (0.2–1 M) is a pseudo-first-order process that proceeds with 45–80 % yields depending on the nature of the amine, its concentration, and the reaction temperature. In the case of ethanolamine, the corresponding bimolecular rate constant has a pre-exponential factor and activation energy of 1.1 × 105 s−1 and 47 kJ mol−1, respectively. The reaction is highly competitive with the previously described hydrolysis of dIz into 2,2-diamino-4-[(2-deoxy-β-D-erythro-pentofuranosyl)amino]-5(2H)-oxazolone under biologically relevant conditions. A similar reaction with the same lesion in polymeric DNA results in the release of a low-molecular-weight analog of dIz, presumably producing an abasic site as the second reaction product. Kinetic characteristics of this process make it a potentially important source of abasic sites in oxidatively damaged DNA, formed through the reaction of 2,5-diaminoimidazolone lesions with naturally abundant DNA-affinic amines and proteins. The release of low-molecular-weight analogs of dIz can potentially be employed for quantification of imidazolone lesions in oxidized DNA. The half-life of imidazolone lesions in double-stranded DNA evaluated using this approach was found to be 154 min at 37 °C.