Next generation hairpin polyamides with (R)-3,4-diaminobutyric acid turn unit.
The characterization of a new class of pyrrole-imidazole hairpin polyamides with beta-amino-gamma-turn units for recognition of the DNA minor groove is reported. A library of eight hairpins containing ( R)- and ( S)-3,4-diaminobutyric acid (beta-amino-gamma-turn) has been synthesized, and the impact of the molecules on DNA-duplex stabilization was studied for comparison with the parent gamma-aminobutyric acid (gamma-turn) and standard ( R)-2,4-diaminobutyric acid (alpha-amino-gamma-turn)-linked eight-ring polyamides. For some, but not all, sequence compositions, melting temperature analyses have revealed that both enantiomeric forms of the beta-amino-gamma-turn increase the DNA-binding affinity of polyamides relative to the ( R)-alpha-amino-gamma-turn. The ( R)-beta-amine residue may be an attractive alternative for constructing hairpin polyamide conjugates. Biological assays have shown that ( R)-beta-amino-gamma-turn hairpins are able to inhibit androgen receptor-mediated gene expression in cell culture similar to hairpins bearing the standard ( R)-alpha-amino-gamma-turn, from which we infer they are cell-permeable.
Dose
Christian
C
Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California 91125, USA.
Farkas
Michelle E
ME
Chenoweth
David M
DM
Dervan
Peter B
PB
D000107:Acetylation; D000613:Aminobutyrates / Q000737:chemistry*; D004247:DNA / Q000737:chemistry*; D007093:Imidazoles / Q000737:chemistry; D008958:Models, Molecular; D008968:Molecular Conformation; D009690:Nucleic Acid Conformation; D009757:Nylons / Q000737:chemistry*; D011758:Pyrroles / Q000737:chemistry; D013379:Substrate Specificity
D000613:Aminobutyrates; D007093:Imidazoles; D009757:Nylons; D011758:Pyrroles; D004247:DNA