Journal of medicinal and pharmaceutical chemistry 2013-09-26

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, Peter B Dervan

Index: J. Med. Chem. 56(18) , 7449-57, (2013)

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Abstract

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.