2 '-deoxyguanosine reacts with a model quinone methide at multiple sites

Quinone methides and related intermediates have been implicated in a range of beneficial and detrimental processes in biology and effectively alkylate a variety of cellular components despite the ubiquitous presence of water. As a prerequisite to understanding the origins of their specificity, the m ajor products generated by DNA and its components with an unsubstituted ort ho quinone methide under aqueous conditions were recently characterized [Pa nde, P., Shearer, J., Yang, J., Greenberg, W. A., and Rokita, S. E. (1999) J. Am. Chem. Soc. 121, 6773-6779]. Investigations currently focus on the co mplete range of derivatives formed by deoxyguanosine (dG) and guanine resid ues in duplex DNA through product isolation and structure determination usi ng reversed-phase chromatography and a range of one and two-dimensional NMR techniques. Previous construction of a synthetic standard for dG alkylatio n is now shown to have yielded the Nl-linked adduct rather than the N-2-lin ked adduct. This later adduct has also now been characterized and confirmed to be the major product of reaction between the quinone methide and both d uplex DNA and dG under neutral conditions. An N7 adduct of guanine has addi tionally been identified under these conditions and appears to result from spontaneous deglycosylation of the corresponding N7 adduct of dG. A combina tion of steric and electronic properties of duplex DNA likely contribute to the enhanced selectivity of the quinone methide for its guanine N-2 positi on (7.8:3.2:1.0 for adducts of N-2:N7:N1) relative to that of dG (4.7:3.5:1 .0 for adducts of N-2:N7:N1).