Hairpin versus extended DNA binding of a substituted β-alanine linked polyamide

A series of α-substituted β-alanine (β*) linked polyamides (DbaPyPyPy-β*-PyPyPy) were prepared and examined. This resulted in the observation that while most substituents disrupt DNA binding, (R)-α-methoxy-β-alanine (β(R)-OMe) maintains strong binding affinity and preferentially adopts a hairpin versus extended binding mode, providing an alternative hairpin linker to γ-aminobutyric acid (γ). A generalized variant of a fluorescent intercalator displacement assay conducted on a series of hairpin deoxyoligonucleotides containing a systematically varied A/T-rich binding site size was developed to distinguish between the extended binding of the parent β-alanine 1 (DbaPyPyPy-β-PyPyPy) and the hairpin binding of 3 (DbaPyPyPy-β(R)-OMe-PyPyPy).