Alpha-diaminobutyric acid-linked hairpin polyamides.
A hairpin polyamide-chlorambucil conjugate linked by alpha-diaminobutyric acid (alpha-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 alpha-DABA and compare them to polyamides containing the standard gamma-DABA turn unit. The alpha-DABA hairpins have overall decreased binding affinities. However, alpha-DABA polyamide-chlorambucil conjugates are sequence-specific DNA alkylators with increased specificities. Affinity cleavage studies of alpha-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 alpha-DABA polyamide into the forward hairpin binding motif.
Farkas
Michelle E
ME
Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
Tsai
Sherry M
SM
Dervan
Peter B
PB
D000613:Aminobutyrates / Q000737:chemistry*; D001483:Base Sequence; D001665:Binding Sites; D004247:DNA / Q000737:chemistry; D004249:DNA Damage; D018983:DNA Footprinting / Q000379:methods; D019175:DNA Methylation; D008969:Molecular Sequence Data; D015394:Molecular Structure; D009757:Nylons / Q000138:chemical synthesis / Q000737:chemistry*; D010957:Plasmids / Q000737:chemistry; D013379:Substrate Specificity; D013696:Temperature
D000613:Aminobutyrates; D009757:Nylons; C005959:2,4-diaminobutyric acid; D004247:DNA