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Published May 27, 2009 | Supplemental Material + Accepted Version
Journal Article Open

Cyclic pyrrole-imidazole polyamides targeted to the androgen response element

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.

Additional Information

© 2009 American Chemical Society. Published In Issue: May 27, 2009; Article ASAP: May 04, 2009; Received: February 19, 2009. This work was supported by the National Institutes of Health (GM27681). DMC is grateful for a Caltech Kanel predoctoral fellowship. DAH thanks the California Tobacco-Related Disease Research Program (16FT-0055) for a postdoctoral fellowship. JWP is grateful to the California Breast Cancer Research Program for a predoctoral fellowship. CD thanks the Alexander von Humboldt foundation for a postdoctoral research fellowship. The National Science Foundation Chemistry Research Instrumentation and Facilities Program (CHE-0541745) is acknowledged for providing the UPLC-MS instrument. The full ADMET report including experimental conditions can be accessed via the Dervan laboratory homepage at http://dervan.caltech.edu.

Attached Files

Accepted Version - nihms-115453.pdf

Supplemental Material - ja901309z_si_001.pdf

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