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J Am Chem Soc. 2009 May 27;131(20):7182-8. doi: 10.1021/ja901309z.

Cyclic pyrrole-imidazole polyamides targeted to the androgen response element.

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  • 1Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California 91125, USA.

Abstract

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 gamma-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.

PMID:
19413319
[PubMed - indexed for MEDLINE]
PMCID:
PMC2689155
Free PMC Article

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