Mechanism of reaction of beta-(aryloxy)acroleins with nucleosides

The mechanism of DNA adduct formation by acroleins substituted with good leaving groups in the beta-position was investigated using [3-2H]-3-(p-nitrophenoxy)acrolein (1). Reaction of 1 with guanosine at acidic pH produced 9-beta-D-ribofuranosylpyrimido[1,2-alpha]purin-10(3H)-one containing equal amounts of deuterium at both carbons 6 and 8, indicating that hydrolysis of 1 to beta-hydroxyacrolein (malondialdehyde) occurred prior to reaction with guanosine. In contrast, reaction of 1 with deoxyguanosine at neutral pH produced 9-(beta-D-2'-deoxyribofuranosyl)pyrimido[1,2-alpha]purin-10(3H)-one with deuterium selectively incorporated at position 8. This indicates that the pyrimido[1,2-alpha]purin-10(3H)-one adduct forms by 1,2-addition of the exocyclic amino group of deoxyguanosine to the aldehyde carbon of 1 followed by cyclization with the ring nitrogen. In concert with these observations, reaction of 1 with p-nitroaniline produced 3-[(p-nitrophenyl)amino]acrolein with deuterium exclusively in the aldehyde carbon. These observations define the chemical steps in DNA adduct formation by acroleins substituted at the beta-position with good leaving groups. In addition, they explain the relatively modest dependence of mutagenicity on leaving group ability in this series of compounds.