DNA adducts of bis-electrophiles

Covalent modification of DNA by both endogenous and exogenous chemicals, including bis-electrophiles, leads to the formation of DNA adducts. DNA damage is the primary step in chemical carcinogenesis resulting from inaccurate replication of these DNA adducts. We have improved upon reaction conditions enabling characterization of the bis-nucleosides formed from the reactions of dA, dC, and dG with the glyoxal adduct of dG (3-(2'-deoxy-beta-D-erythro-pentofuranosyl)-5,6,7-trihydro-6,7-dihydroxyimidazo[1,2- a]purin-9-one) by NMR and chemical techniques. We have also synthesized and examined the stability and polymerase bypass of distal hydroxyethano dG (6-hydroxy-3,5,6,7-tetrahydro-9H-imidazo[1,2-a]purin-9-one), an intermediate in the formation of the known mutagenic lesion, 1, N2-etheno dG.