DNA Minor‐Groove Recognition by 3‐Methylthiophene/Pyrrole Pair

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‐1 H ‐pyrrole ( Py ), 1‐methyl‐1 H ‐imidazole ( Im ), and 3‐hydroxy‐1‐methyl‐1 H ‐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 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 five‐membered ring 1‐methyl‐1 H ‐pyrrole‐2‐carboxamide scaffold for DNA recognition.