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Animal Toxicity of Hairpin Pyrrole-Imidazole Polyamides Varies with the Turn Unit

Yang, Fei and Nickols, Nicholas G. and Li, Benjamin C. and Szablowski, Jerzy O. and Hamilton, Shari R. and Meier, Jordan L. and Wang, Chieh-Mei and Dervan, Peter B. (2013) Animal Toxicity of Hairpin Pyrrole-Imidazole Polyamides Varies with the Turn Unit. Journal of Medicinal Chemistry, 56 (18). pp. 7449-7457. ISSN 0022-2623. PMCID PMC3788622. doi:10.1021/jm401100s.

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A hairpin pyrrole-imidazole polyamide (1) targeted to the androgen receptor consensus half-site was found to exert antitumor effects against prostate cancer xenografts. A previous animal study showed that 1, which has a chiral amine at the α-position of the γ-aminobutyric acid turn (γ-turn), did not exhibit toxicity at doses less than 10 mg/kg. In the same study, a polyamide with an acetamide at the β-position of the γ-turn resulted in animal morbidity at 2.3 mg/kg. To identify structural motifs that cause animal toxicity, we synthesized polyamides 1–4 with variations at the α- and β-positions in the γ-turn. Weight loss, histopathology, and serum chemistry were analyzed in mice post-treatment. While serum concentration was similar for all four polyamides after injection, dose-limiting liver toxicity was only observed for three polyamides. Polyamide 3, with an α-acetamide, caused no significant evidence of rodent toxicity and retains activity against LNCaP xenografts.

Item Type:Article
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URLURL TypeDescription Information CentralArticle
Szablowski, Jerzy O.0000-0001-7851-5408
Dervan, Peter B.0000-0001-8852-7306
Additional Information:© 2013 American Chemical Society. ACS AuthorChoice. Received: July 19, 2013. Publication Date (Web): September 9, 2013. This work was supported in part by the National Institutes of Health (Grant GM27681), Sanofi, and the Prostate Cancer Foundation. The authors thank Janet Baer and Gwen E. Williams for helpful discussions. The authors also thank the IDEXX-RADIL team for assistance with serum analysis. Author Contributions: F.Y. and N.G.N contributed equally. F.Y., N.G.N., and P.B.D. designed the experiments. F.Y. and N.G.N. conducted animal experiments. B.C.L. and J.W. synthesized the compounds. J.O.S. conducted liver uptake experiments. S.R.H. performed histopathology analysis. F.Y. and N.G.N. performed cytotoxicity, comet, and ELISA experiments. F.Y. conducted confocal experiments. N.G.N. conducted RT-qPCR experimnts. J.L.M. ran thermal denaturation experiments. F.Y., N.G.N., J.O.S., S.R.H., J.L.M., and P.B.D. analyzed data. F.Y., N.G.N., and P.B.D. wrote the paper. The authors declare no competing financial interest.
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Prostate Cancer FoundationUNSPECIFIED
Issue or Number:18
PubMed Central ID:PMC3788622
Record Number:CaltechAUTHORS:20140225-100138273
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Official Citation:Animal Toxicity of Hairpin Pyrrole-Imidazole Polyamides Varies with the Turn Unit Fei Yang, Nicholas G. Nickols, Benjamin C. Li, Jerzy O. Szablowski, Shari R. Hamilton, Jordan L. Meier, Chieh-Mei Wang, and Peter B. Dervan Journal of Medicinal Chemistry 2013 56 (18), 7449-7457 DOI: 10.1021/jm401100s
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:43976
Deposited By: Ruth Sustaita
Deposited On:25 Feb 2014 18:18
Last Modified:10 Nov 2021 16:46

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