Animal toxicity of hairpin pyrrole-imidazole polyamides varies with the turn unit.

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 ?-position of the ?-aminobutyric acid turn (?-turn), did not exhibit toxicity at doses less than 10 mg/kg. In the same study, a polyamide with an acetamide at the ?-position of the ?-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 ?- and ?-positions in the ?-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 ?-acetamide, caused no significant evidence of rodent toxicity and retains activity against LNCaP xenografts.

SUBMITTER: Yang F 

PROVIDER: S-EPMC3788622 | biostudies-literature | 2013 Sep

REPOSITORIES: biostudies-literature