Animal Toxicity of Hairpin Pyrrole-Imidazole Polyamides Varies with the Turn Unit
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- 作者：Fei Yang ; Nicholas G. Nickols ; Benjamin C. Li ; Jerzy O. Szablowski ; Shari R. Hamilton ; Jordan L. Meier ; Chieh-Mei Wang ; Peter B. Dervan
- 刊名：Journal of Medicinal Chemistry
- 出版年：2013
- 出版时间：September 26, 2013
- 年：2013
- 卷：56
- 期：18
- 页码：7449-7457
- 全文大小：515K
- 年卷期：v.56,no.18(September 26, 2013)
- ISSN：1520-4804
文摘
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 伪-position of the 纬-aminobutyric acid turn (纬-turn), did not exhibit toxicity at doses less than 10 mg/kg. In the same study, a polyamide with an acetamide at the 尾-position of the 纬-turn resulted in animal morbidity at 2.3 mg/kg. To identify structural motifs that cause animal toxicity, we synthesized polyamides 1鈥?b>4 with variations at the 伪- and 尾-positions in the 纬-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 伪-acetamide, caused no significant evidence of rodent toxicity and retains activity against LNCaP xenografts.