Cyclic pyrrole-imidazole polyamides targeted to the androgen response element

David M. Chenoweth, Daniel A. Harki, John W. Phillips, Christian Dose, Peter B. Dervan

Research output: Contribution to journalArticlepeer-review

55 Scopus citations

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 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.

Original languageEnglish (US)
Pages (from-to)7182-7188
Number of pages7
JournalJournal of the American Chemical Society
Volume131
Issue number20
DOIs
StatePublished - May 27 2009

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