A general method for the synthesis of the N²- and N⁶- carcinogenic amine adducts of 2'-deoxyguanosine and 2'-deoxyadenosine

A number of simple arylamino compounds (Figure 1) are well-established as pro-carcinogenic agents. Metabolic activation leads to a series of unstable N-hydroxy derivatives that on solvolysis, give nitrenium ions. The latter, which are regarded as the primary mutagenic/carcinogenic agents attack DNA to give a variety of adducts. Principal among these are the C-8 arylamination products of 2'-deoxyguanosine (dG) and the N²-and N⁶-(2- acetylamino)arylation adducts of dG and 2'-deoxyadenosine (dA), respectively. The latter types of adducts have received little biological attention because synthetic methods for their preparation have been lacking. We now describe a general high-yield method for the synthesis of both of these types of N- arylated 2'-deoxynucleosides. The key step is a Buchwald-Hartwig coupling reaction between an appropriately protected derivative of dG or dA (1 and 7, respectively) and an o-nitroaryl bromide or triflate (2a-e). Subsequent reduction, acetylation, and deprotection of the N²-adducts (3b-e) of dG and of the N⁶-adduct (8c) of dA then gives the desired adducts 6b-e (overall yield 70-88%) and 11 (overall yield 43%), respectively.