Reactions of 2,6-dimethyl-1,3-dioxane-4-ol (aldoxane) with deoxyguanosine and DNA

In a recent study, we identified several new DNA adducts of the carcinogen acetaldehyde, including N-2-(2,6-dimethyl-1,3-dioxan-4-yl)deoxyguanosine (N -2-aldoxane-dG, 2). Our goal in this study was to investigate further the f ormation of 2 by allowing 2,6-dimethyl-1,3-dioxane-4-ol (aldoxane, 5) to re act with dG and DNA. Aldoxane is readily formed by trimerization of acetald ehyde. The reaction of aldoxane with dG and DNA produced diastereomers of N -2-aldoxane-dG (2) as observed in the reactions of acetaldehyde with dG and DNA, supporting the intermediacy of aldoxane in their formation. Unexpecte dly, however, an array of other adducts was formed in these reactions, incl uding 3-(2-deoxyribos-1-yl)-5,6,7,8-tetrahydro-8-hydroxy-6-methylpyrimido [ 1,2-a]purine-10(3H)one (3), 2-amino-7,8-dihydro-8-hydroxy-6-methyl-3H-pyrro lo[2,1-f]purine-4(6H)one (13), N-2-(3-hydroxybutylidene)dG (9), N-2-[(2-hyd roxypropyl)-6-methyl-1,3-dioxane-4-yl]dG (14), and N-2-ethylidene-dG (1). A dduct 1 was the major product and was found to be quite stable in DNA. The adducts result from a cascade of aldehydes, e.g., 2-butenal (crotonaldehyde , 12), 3-hydroxybutanal (7) and its dimer (2-hydroxypropyl)-6-methyl-1,3-di oxane-4-ol (paraldol, 6), and acetaldehyde, produced from aldoxane under th e reaction conditions. The reactions of aldoxane with dG and DNA were compa red with those of paraldol. The paraldol reactions gave products resulting from reactions of dG and DNA with paraldol, 3-hydroxybutanal, and crotonald ehyde (adducts 3, 13, and 9) but the products of the aldoxane and acetaldeh yde reactions (adducts I and 2) were not observed, indicating that paraldol is more stable under the reaction conditions than is aldoxane. The results of this study provide new insights about the formation of DNA adducts from aldehydes via condensation products of the latter.