Cyclic pyrrole-imidazole polyamides targeted to the androgen response element

被引：0
|
作者：
Chenoweth, David M. [1 ]
Harki, Daniel A. [1 ]
Phillips, John W. [1 ]
Dose, Christian [1 ]
Dervan, Peter B. [1 ]
机构：
[1] Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA 91125, United States
来源：
Journal of the American Chemical Society | 2009年 / 131卷 / 20期
关键词：
Hairpin pyrrole-imidazole (Py-Im) polyamides are a class of cell-permeable DNA-binding small molecules that can disrupt transcription factor-DNA binding and regulate endogenous gene expression. The covalent linkage of antiparallel Py-Im ring pairs with an γ-amino acid turn unit affords the classical hairpin Py-Im polyamide structure. Closing the hairpin with a second turn unit yields a cyclic polyamide; a lesser-studied architecture mainly attributable to synthetic Inaccessibility. We have applied our methodology for solution-phase polyamide synthesis to cyclic polyamides with an Improved high-yield cyclization step. Cyclic 8-ring Py-Im polyamides 1-3 target the DNA sequence 5-WGWWCW-3; which corresponds to the androgen response element (ARE) bound by the androgen receptor transcription factor to modulate gene expression. We find that cyclic Py-Im polyamides 1-3 bind DNA with exceptionally high affinities and regulate the expression of AR target genes In cell culture studies; from which we Infer that the cycle Is cell permeable. © 2009 American Chemical Society;
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页码：7182 / 7188
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