Regioselective synthesis of 1,N²-Etheno-2′-deoxyguanosine and its generation in oligomeric DNA

Chloroethylene oxide and chloroacetaldehyde, reactive intermediates derived from vinyl chloride, and the epoxy-hydroxy-alkanals, produced endogenously in the metabolism of polyunsaturated fatty acids, react with nucleic acid bases in DNA to form exocyclic etheno derivatives of 2′-deoxyadenosine, 2′-deoxyguanosine, and 2′-deoxycytidine. This paper describes an efficient method for the synthesis of the exocyclic 1,N²-etheno adduct of 2′-deoxyguanosine and its incorporation into DNA oligomers using automated synthesis techniques. The synthesis was initiated by a high-yield alkylation of N²-protected 2′-deoxyguanosine at the 1-position with 1,2-diacetoxy-3-bromopropane. The product was converted to the 5′-O-dimethoxytrityl-3′-O-phosphoramidite using published techniques and incorporated site specifically into DNA oligomers with 99% coupling efficiency. Ring closure to yield the 6-hydroxyethano derivative was accomplished by oxidation with sodium periodate, and facile dehydration then afforded DNA oligomers containing 1,N²-etheno-2′-deoxyguanosine. All oligomers were characterized fully by physicochemical methods.