Directing Quinone Methide-Dependent Alkylation and Cross-Linking of Nucleic Acids with Quaternary Amines.

Polyamine and polyammonium ion conjugates are often used to direct reagents to nucleic acids based on their strong electrostatic attraction to the phosphoribose backbone. Such nonspecific interactions do not typically alter the specificity of the attached reagent, but polyammonium ions dramatically redirected the specificity of a series of quinone methide precursors. Replacement of a relatively nonspecific intercalator based on acridine with a series of polyammonium ions resulted in a surprising change of DNA products.

Migratory ability of quinone methide-generating acridine conjugates in DNA.

The dynamic nature of nucleic acid alkylation by simple ortho quinone methides (QM) and their conjugates has provided numerous opportunities ranging from sequence selective targeting to bipedal walking in duplex DNA. To enhance the diffusion rate of adduct migration, one of two sites for QM generation was deleted from a bisQM conjugate of acridine to remove the covalent anchor to DNA that persists during QM regeneration. This conversion of a bisfunctional cross-linking agent to a monofunctional alkylating agent allowed adduct diffusion to traverse an extrahelical -TT- bulge that previously acted as a barrier for its bisfunctional analog.