Deamination and Dimroth Rearrangement of Deoxyadenosine-Styrene Oxide Adducts in Dna

In reactions between styrene oxide and the ring nitrogen at the 1-position of deoxyadenosine, the epoxide is opened at both the alpha-(benzylic) and beta-carbons. The 1-substituted nucleosides formed are unstable and subsequently undergo either Dimroth rearrangement to give N-6-substituted deoxyadenosines or deamination to give 1-substituted deoxyinosines. alpha N-6-Substituted compounds are also formed from direct reaction at the exocyclic nitrogen. Kinetic experiments revealed that relative rates of deamination of 1-substituted deoxyadenosine-styrene oxides and 1-substituted adenosine-styrene oxides were similar. However, the rate of Dimroth rearrangement in beta 1-substituted adenosine-styrene oxides was similar to 2.3-fold greater than that of beta 1-substituted deoxyadenosine-styrene oxides and similar to 1.5-fold greater in alpha 1-substituted adenosine-styrene oxides relative to alpha 1-substituted deoxyadenosine-styrene oxides. Analysis of the products formed from reactions of styrene oxide with [H-3]deoxyadenosine and [H-3]deoxyadenosine incorporated into native and denatured DNA showed that; the double-helical DNA structure reduced the levels of adducts formed 5-fold relative to denatured DNA but did not present a complete barrier to formation of either N-6-substituted deoxyadenosine- or 1-substituted deoxyinosine-styrene oxide adducts in native DNA. Additionally, in denatured and native DNA the product distributions were altered in favor of formation of beta 1-substituted deoxyinosine-styrene oxide adducts with respect to reactions of the nucleoside. The ratio of retained to inverted configuration of alpha N-6-substituted products was higher in DNA than in nucleoside reactions. These experiments indicate that in addition to the N-6-position, the ring nitrogen at the 1-position of deoxyadenosine is available, to some extent, for reaction in native DNA. In styrene oxide-DNA reactions, formation of 1-substituted adenines can lead to deaminated products where both Watson-Crick hydrogen-bonding sites are disrupted. [References: 32]

See More