Regioisomeric synthesis and characteristics of the α-hydroxy-1,N²-propanodeoxyguanosine

Acrolein, a known mutagen, undergoes reaction in vitro under physiological conditions with both 2′-deoxyguanosine and native DNA to give rise to exocyclic adducts of the 5,6,7,8-tetrahydropyrimido[1,2-a]purine-10(3H)-one class having a hydroxyl group at either the 6 or the 8 position (these positions are respectively designated α and γ when referring to the 1,N²-(propano-bridge). Previously, we have shown that the 8-hydroxy derivative has very low mutagenicity probably because, in double-stranded DNA, this residue exists in the open-chain aldehydic form [N²-(3-oxopropyl)-2′-deoxyguanosine] (5). To continue our investigation in this area, we needed ample supplies of the 6-hydroxy isomers. This current paper describes high-yield simple methods for the synthesis in bulk of the 6-hydroxy and the 6-methoxy exocyclic adducts 1 and 3 and a new efficient synthesis of 1,N²-(prop-1,3-diyl)-2′-deoxyguanosine (4), previously used as a chemically stable model in studying the physico-biological implications of 1,N² exocyclic adduction to dG.