Wf. Veldhuyzen et al., Thermodynamic versus kinetic products of DNA alkylation as modeled by reaction of deoxyadenosine, J AM CHEM S, 123(45), 2001, pp. 11126-11132
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.