The role of a quinone methide in the sequence specific alkylation of DNA

Article abstract of DOI:10.1021/ja00084a009

Oligonucleotide-naphthoquinone conjugates were prepared and examined for use as inducible, site-directed alkylating agents of DNA. Reaction was found to be sequence specific and under control of either biomimetic reduction or near-UV irradiation. Both conditions induced the formation of a transient and highly electrophilic intermediate consistent with a quinone methide. Enzymatic reduction of 5-((mesyloxy)methyl)- and 5-(bromomethyl)naphthoquinone derivatives produced cross-linking between a target and probe sequence, but the equivalent 5-(acetoxymethyl), 5-(hydroxymethyl) and 5-methyl analogues were predictably inactive. Conversely, irradiation of the 5-methylnaphthoquinone derivative produced cross-linking through a mechanism of photochemical enolization that was not available to the 6-methyl, 3-methyl, or unsubstituted analogues. Hydroxyl radical footprinting of the modified DNA demonstrated that guanine and cytosine were targets of alkylation.