Thermodynamic versus kinetic products of DNA alkylation as modeled by reaction of deoxyadenosine

Alkylating agents that react through highly electrophilic quinone methide i ntermediates often express a specificity for the weakly nucleophilic exocyc lic amines of deoxyguanosine (dG N-2) and deoxyadenosine (dA N-6) in DNA. I nvestigations now indicate that the most nucleophilic site of dA (N1) prefe rentially, but reversibly, conjugates to a model ortho-quinone methide. Ult imately, the thermodynamically stable dA N-6 isomer accumulates by trapping the quinone methide that is transiently regenerated from collapse of the d A N1 adduct. Alternative conversions of the dA N1 to the dA N-6 derivative by a Dimroth rearrangement or other intramolecular processes are not compet itive under neutral conditions, as demonstrated by studies with [6-N-15]dA. Both a model quinone methide precursor and its dA NI adduct yield a simila r profile of deoxynucleoside products when treated with an equimolar mixtur e of dC, dA, dG, and T. Consequently, the most readily observed products of DNA modification resulting from reversible reactions may reflect thermodyn amic rather than kinetic selectivity.