title: 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 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.
authors.affiliation: Division of Chemistry and Chemical Engineering, California Institute of Technology , Pasadena, California 91125, United States.
authors.forename: Fei
authors.initials: F
authors.lastname: Yang
authors.forename: Nicholas G
authors.initials: NG
authors.lastname: Nickols
authors.forename: Benjamin C
authors.initials: BC
authors.lastname: Li
authors.forename: Jerzy O
authors.initials: JO
authors.lastname: Szablowski
authors.forename: Shari R
authors.initials: SR
authors.lastname: Hamilton
authors.forename: Jordan L
authors.initials: JL
authors.lastname: Meier
authors.forename: Chieh-Mei
authors.initials: CM
authors.lastname: Wang
authors.forename: Peter B
authors.initials: PB
authors.lastname: Dervan
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology / Q000633:toxicity*; D001692:Biological Transport; D001835:Body Weight / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004355:Drug Stability; D006801:Humans; D007093:Imidazoles / Q000737:chemistry*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D009757:Nylons / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology / Q000633:toxicity*; D011758:Pyrroles / Q000737:chemistry*; D013329:Structure-Activity Relationship; D018675:Toxicity Tests; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D007093:Imidazoles; D009757:Nylons; D011758:Pyrroles; C029899:imidazole
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