α-Diaminobutyric acid-linked hairpin polyamides

Abstract

A hairpin polyamide-chlorambucil conjugate linked by α-diaminobutyric acid (α-DABA) has been shown to have interesting biological properties in cellular and small animal models. Remarkably, this new class of hairpin polyamides has not been previously characterized with regard to energetics and sequence specificity. Herein we present a series of pyrrole-imidazole hairpin polyamides linked by α-DABA and compare them to polyamides containing the standard γ-DABA turn unit. The α-DABA hairpins have overall decreased binding affinities. However, α-DABA polyamide-chlorambucil conjugates are sequence-specific DNA alkylators with increased specificities. Affinity cleavage studies of α-DABA polyamide-EDTA conjugates confirmed their preference for binding DNA in a forward hairpin conformation. In contrast, an unsubstituted glycine-linked polyamide prefers to bind in an extended binding mode. Thus, substitution on the turn unit locks the α-DABA polyamide into the forward hairpin binding motif.