Sequence-specific delivery of a quinone methide intermediate to the major groove of DNA

Silyl-protected phenol derivatives serve as convenient precursors for generating highly electrophilic quinone methide intermediates under biological conditions. Reaction is initiated by addition of fluoride and has previously exhibited proficiency in DNA alkylation and cross-linking. This approach has now been extended to the modification of duplex DNA through triplex recognition and fluoride-dependent quinone methide induction. Both oligonucleotides of a model duplex were alkylated in a sequence specific manner by an oligonucleotide conjugate that is consistent with triplex association. Optimum reaction required the presence of the two complementary target sequences and a pH of below 6.5. In addition, one guanine in each strand adjacent to the triplex region was the predominant site of alkylation. The yield of modification varied from approximately 20% for the purine-rich strand to only 4% for the pyrimidine-rich strand. This surprising difference indicates that the linker between the recognition and reactive elements may limit productive interaction between the quinone methide and the reactive nucleophiles of DNA. Restricted orientation of this intermediate may also be responsible for the lack of target cross-linking at detectable levels.