Modifications at the C-Terminus To Improve Pyrrole−Imidazole Polyamide Activity in Cell Culture
- Creators
- Jacobs, Claire S.
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Dervan, Peter B.
Abstract
Pyrrole−imidazole (Py-Im) hairpin polyamides are a class of small molecule DNA minor groove binding compounds that have been shown to modulate endogenous gene expression in cell culture. Gene regulation by polyamides requires efficient cellular uptake and nuclear localization properties for candidate compounds. To further optimize Py-Im polyamides for enhanced potency in cell culture, a focused library of polyamides possessing various modifications at the C-terminus was synthesized and tested. Comparison of polyamide biological activity in two cell lines revealed tolerance for structural modifications and agreement in activity trends between cell lines. The use of an oxime linkage between the polyamide and an aromatic functionality on the C-terminus resulted in a ~20-fold increase in the potency of polyamides targeted to the androgen response element (ARE) in LNCaP cells by measuring AR-activated PSA expression.
Additional Information
© 2009 American Chemical Society. Received February 28, 2009. Publication Date (Web): July 2, 2009. We thank the National Institutes of Health for support (Grant GM051747), Dr. Giovanni Melillo for U251 cells, and Dr. Daniel Harki for providing tert-butyl 3-aminopropoxycarbamate, tert-butyl 3-(aminooxy)propylcarbamate, and 11 and for help with the manuscript.Attached Files
Accepted Version - nihms130150.pdf
Supplemental Material - Jacobs2009p6650J_Med_Chem_supp.pdf
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Additional details
- PMCID
- PMC2788682
- Eprint ID
- 17052
- DOI
- 10.1021/jm900256f
- Resolver ID
- CaltechAUTHORS:20100104-140118463
- GM-051747
- NIH
- Created
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2010-01-06Created from EPrint's datestamp field
- Updated
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2021-11-08Created from EPrint's last_modified field