Deamination and Dimroth Rearrangement of Deoxyadenosine−Styrene Oxide Adducts in DNA

Abstract

In reactions between styrene oxide and the ring nitrogen at the 1-position of deoxyadenosine, the epoxide is opened at both the α- (benzylic) and β-carbons. The 1-substituted nucleosides formed are unstable and subsequently undergo either Dimroth rearrangement to give N⁶-substituted deoxyadenosines or deamination to give 1-substituted deoxyinosines. αN⁶-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 β1-substituted adenosine−styrene oxides was ∼2.3-fold greater than that of β1-substituted deoxyadenosine−styrene oxides and ∼1.5-fold greater in α1-substituted adenosine−styrene oxides relative to α1-substituted deoxyadenosine−styrene oxides. Analysis of the products formed from reactions of styrene oxide with [³H]deoxyadenosine and [³H]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 N⁶-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 β1-substituted deoxyinosine−styrene oxide adducts with respect to reactions of the nucleoside. The ratio of retained to inverted configuration of αN⁶-substituted products was higher in DNA than in nucleoside reactions. These experiments indicate that in addition to the N⁶-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.