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

Silyl-protected phenol derivatives serve as convenient precursors for gener ating highly electrophilic quinone methide intermediates under biological c onditions. Reaction is initiated by addition of fluoride and has previously exhibited proficiency in DNA alkylation and cross-linking. This approach h as now been extended to the modification of duplex DNA through triplex reco gnition and fluoride-dependent quinone methide induction. Both oligonucleot ides of a model duplex were alkylated in a sequence specific manner by an o ligonucleotide conjugate that is consistent with triplex association. Optim um 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 mo dification varied from approximately 20% for the purine-rich strand to only 4% for the pyrimidine-rich strand. This surprising difference indicates th at the linker between the recognition and reactive elements may limit produ ctive interaction between the quinone methide and the reactive nucleophiles of DNA. Restricted orientation of this intermediate may also be responsibl e for the lack of target cross-linking at detectable levels. (C) 2001 Elsev ier Science Ltd. All rights reserved.