1,N ²-Cyclic deoxyguanosine adducts and guanine adducts of 2-haloacroleins. Isolation, characterization, isomerization and stability

Abstract

The reaction of the mutagenic 2-haloacroleins, 2-fluoroacrolein, 2-chloroacrolein and 2-bromoacrolein, with nucleosides and 5′-mononucleotides was studied. We found two different regioisomers of 1,N ²-cyclic deoxyguanosine adducts of 2-chloroacrolein and 2-bromoacrolein: type A, the 6-hydroxy, 7-haloadduct in which the OH-substituent is vicinal to the N ²-atom of the guanine moiety and type B, the 8-hydroxy, 7-haloadduct in which the OH-group is adjacent to the N¹-atom of the guanine moiety. The major adducts were the trans pairs of diastereomers of type A and type B in which the 6,7-substituents as well as the 7,8-substituents are in the energetically favoured diaxial position of the newly formed tetrahydropyrimidine ring. In the case of the type A regioisomers, the cis pairs of diastereomers (traces with chloroacrolein and about 4% with bromoacrolein) were also found in which the halosubstituent probably takes the equatorial position. Due to the anomeric effect, the OH-group takes the axial position in both regioisomers. No cis isomers of the type B regioisomers could be isolated. Acid hydrolysis of the deoxyguanosine adducts released deoxyribose, and the respective guanine adducts were isolated and characterized. Besides the vicinal halo, hydroxy adducts, trace amounts of the corresponding dihydroxy adducts were formed by hydrolysis of the chlorine or bromine substituents. The dihydroxy compounds possess the same structures and conformations in the newly formed tetrahydropyrimidine ring as do the halo, hydroxy adducts. Under our conditions no adducts other than those with deoxyguanosine and guanine could be identified. We found, however, indication for the formation of deoxyadenosine adducts when using dimethylsulfoxide as a solvent. No adducts in substantical amounts could be isolated with fluoroacrolein due to its rapid polymerization.