Pyrimido[1,2-alpha]purin-10(3H)-one: A reactive electrophile in the genome

Malondialdehyde and base propenal react with deoxyguanosine residues in DNA to form an exocyclic adduct, pyrimido[1,2-alpha ]purin-10(3H)-one (1), tha t has been detected at high levels in genomic DNA of healthy humans. Previo us studies have shown that tris(hydroxymethyl)-aminomethane adds to 1 at el evated pH, forming an enaminoimine (2), but it is uncertain whether 1 react s directly or hydrolyzes under basic conditions to N-2-(3-oxo-1-propenyl)de oxyguanosine (3) prior to amine addition. We report that 1 reacts at neutra l pH with hydroxylamines to form oximes. The rate of reaction of 1 with hyd roxylamines at pH 7 is at least 150 times faster than the rate of hydrolysi s of 1 to 3. Thus, 1 is directly reactive to nucleophiles. These observatio ns indicate that 1 is an electrophile in the human genome that may react wi th cellular nucleophiles to form novel cross-linked adducts.