Hairpin polyamides are synthetic oligomers, which fold and bind to specific DNA sequences in a programmable manner. Internal side-by-side pairings of the aromatic amino acid residues 1-methyl-1H-pyrrole (Py), 1-methyl-1H-imidazole (Im), and 3-hydroxy-1-methyl-1H-pyrrole (Hp) confer the ability to distinguish between all four Watson-Crick 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 S-atom to the minor groove, is paired with Py, it exhibits a modest threefold specificity for TA>AT 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 five-membered ring 1-methyl-1H-pyrrole-2-carboxamide scaffold for DNA recognition.
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