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 alpha- (benzylic) and beta-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. alphaN6-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 beta1-substituted adenosine-styrene oxides was approximately 2.3-fold greater than that of beta1-substituted deoxyadenosine-styrene oxides and approximately 1.5-fold greater in alpha1-substituted adenosine-styrene oxides relative to alpha1-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 beta1-substituted deoxyinosine-styrene oxide adducts with respect to reactions of the nucleoside. The ratio of retained to inverted configuration of alphaN6-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.

Studies of the Mechanisms of Adduction of 2‘-Deoxyadenosine with Styrene Oxide and Polycyclic Aromatic Hydrocarbon Dihydrodiol Epoxides

“…Analytical runs were performed on a 4.6 mm × 250 mm YMC-ODS-AQ column at a flow rate of 1.0 mL/min; preparative-scale isolations were carried out on a 10 mm × 250 mm YMC-ODS-AQ column at a flow rate of 3.0 mL/min. The structure and stereochemistry of the styrene oxide adducts were confirmed by independent syntheses from 6-chloropurine 2′-deoxyriboside and (R)-and (S)-2-amino-2-phenylethanol (9) for the R adducts and (R)-and (S)-2-amino-1-phenylethanol (10) for the adducts and also by comparison with literature values (6,11).…”

Identification and Characterization of 2′-Deoxyadenosine Adducts Formed by Isoprene Monoepoxides in Vitro

“…Studies with epoxides containing substituents capable of delocalizing positive charge by conjugation, such as styrene oxide and butadiene monoepoxide, show that direct alkylation of the N 6 -position of adenosine occurs mainly on the internal oxirane carbon, predominantly by a S N 1 mechanism (as reviewed in 36). In contrast, it was demonstrated that N 6 - dAdo adducts on the terminal oxirane carbon of styrene oxide were exclusively formed by Dimroth rearrangement of N1-dAdo adducts (40;54). …”

Synthesis and Characterization of Adducts Formed in the Reactions of Safrole 2′,3′‐Oxide with 2′‐Deoxyadenosine, Adenine, and Calf Thymus DNA

“…[17] We did not observe any ring opening adducts from the β attack of 2 or deamination of 4 to form an N1-inosine adduct, which has been reported in the reaction of styrene oxide with 2Ј-deoxyadenosine. [23][24][25] The lack of a phenyl or vinyl group on the α-carbon atom of an oxiran to stabilize the carbocation intermediate of an S N 1 reaction of 2 explains why no β attack and only γ attack adducts were observed; furthermore, the γ-position of 2 is sterically less hindered than the β-position. The secondary hydroxy group on the β-carbon atom of 4 cannot form an oxazolinium ring to facilitate the deamination process, therefore, the deamination product of 4 was not observed.…”

“…[17,[23][24][25] The transformation of 4 (an N1 adduct) to 5 (an N 6 adduct) by Dimroth rearrangement was monitored with a reversephase HPLC system, which showed that 4 had a half life of ca. 24 h in K 2 HPO 4 buffer solution at 37°C.…”