DNA Minor Groove Recognition by Multiple Thiophene/Pyrrole Pairs

Hairpin polyamides are synthetic oligomers that fold and bind to specific DNA sequences in a programmable manner. Internal side-by-side pairings of the aromatic amino acids N-methylpyrrole (Py), N-methylimidazole (Im), and Nmethylhydroxypyrrole (Hp) confer the ability to distinguish between all four WatsonCrick base pairs in the minor groove of B-form DNA. In a broad search to expand the heterocycle repertoire we found that when 3-methylthiophene (Tn), which presents a sulfur atom to the minor groove, is paired with Py, it exhibits a modest 3-fold specificity for T•A > A•T presumably by shape selective recognition. In this study we explore the scope and limitations of this lead by incorporating multiple Tn residues within a single hairpin polyamide. It was found that hairpin polyamides containing more that one Tn/Py pair exhibit lowered affinities and specificities for their match sites. It appears that little deviation is permissible from the parent 5-membered ring N-methylpyrrole-carboxamide scaffold for DNA recognition.