Book of Abstracts: Albany 2005
Selective Alkylation of DNA through a Recognition-Dependent Process
Reactive intermediates described as quinone methides are generated during metabolism of various compounds ranging from food preservatives to anti-cancer drugs. These species are very transient and readily alkylate the most nucleophilic sites of DNA. Reaction is reversible, however, and the major adducts act as a reservoir for regenerating quinone methides over an extended period. The consequences of this reversibility are evident in the evolution of DNA products generated by a simple model quinone methide as well as quinone methides that have been conjugated to DNA binding ligands. In particular, oligodeoxynucleotide-quinone methide conjugates appear to form instrastrand adducts with all nucleotides except for T. Intrastrand reaction remains reversible and yet is not sensitive to trapping by external agents such as non-complementary DNA, thiols or ubiquitous water. The alternative interstrand reaction is only observed after association with complementary DNA. Once the self-adduct spontaneously regenerates the quinone methide, constraints on full nucleobase recognition are removed. Subsequent hybridization in turn inhibits reformation of the self-adduct and promotes alkylation of the chosen target sequence. This overall process represents a type of safety catch mechanism for delivering a highly reactive intermediate to a precise target and may ultimately provide a general approach to gene specific reactions in vivo.
Steven E. Rokita
Department of Chemistry and Biochemistry