Dose Christian, Farkas Michelle E, Chenoweth David M, Dervan Peter B
Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California 91125, USA.
J Am Chem Soc. 2008 May 28;130(21):6859-66. doi: 10.1021/ja800888d. Epub 2008 May 7.
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.
报道了一类新型的带有β-氨基-γ-转角单元的吡咯-咪唑发夹型聚酰胺用于识别DNA小沟的特性。合成了一个包含（R）-和（S）-3,4-二氨基丁酸（β-氨基-γ-转角）的八个发夹的文库，并研究了这些分子对DNA双链体稳定性的影响，以便与母体γ-氨基丁酸（γ-转角）和标准的（R）-2,4-二氨基丁酸（α-氨基-γ-转角）连接的八环聚酰胺进行比较。对于某些但并非所有的序列组成，解链温度分析表明，相对于（R）-α-氨基-γ-转角，β-氨基-γ-转角的两种对映体形式都增加了聚酰胺的DNA结合亲和力。（R）-β-胺残基可能是构建发夹型聚酰胺缀合物的一个有吸引力的替代物。生物学试验表明，（R）-β-氨基-γ-转角发夹能够在细胞培养中抑制雄激素受体介导的基因表达，类似于带有标准（R）-α-氨基-γ-转角的发夹，由此我们推断它们具有细胞渗透性。
