Antischistosomal versus Antiandrogenic Properties of Aryl Hydantoin Ro 13-3978

Chunkai Wang College of Pharmacy, University of Nebraska Medical Center, Omaha, Nebraska; Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, Tennessee; Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, Nebraska; Department of Medical Parasitology and Infection Biology, Swiss Tropical and Public Health Institute, and University of Basel, Basel, Switzerland

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Qingjie Zhao College of Pharmacy, University of Nebraska Medical Center, Omaha, Nebraska; Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, Tennessee; Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, Nebraska; Department of Medical Parasitology and Infection Biology, Swiss Tropical and Public Health Institute, and University of Basel, Basel, Switzerland

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Jaeki Min College of Pharmacy, University of Nebraska Medical Center, Omaha, Nebraska; Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, Tennessee; Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, Nebraska; Department of Medical Parasitology and Infection Biology, Swiss Tropical and Public Health Institute, and University of Basel, Basel, Switzerland

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Sakthivel Muniyan College of Pharmacy, University of Nebraska Medical Center, Omaha, Nebraska; Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, Tennessee; Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, Nebraska; Department of Medical Parasitology and Infection Biology, Swiss Tropical and Public Health Institute, and University of Basel, Basel, Switzerland

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Mireille Vargas College of Pharmacy, University of Nebraska Medical Center, Omaha, Nebraska; Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, Tennessee; Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, Nebraska; Department of Medical Parasitology and Infection Biology, Swiss Tropical and Public Health Institute, and University of Basel, Basel, Switzerland

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Xiaofang Wang College of Pharmacy, University of Nebraska Medical Center, Omaha, Nebraska; Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, Tennessee; Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, Nebraska; Department of Medical Parasitology and Infection Biology, Swiss Tropical and Public Health Institute, and University of Basel, Basel, Switzerland

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Yuxiang Dong College of Pharmacy, University of Nebraska Medical Center, Omaha, Nebraska; Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, Tennessee; Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, Nebraska; Department of Medical Parasitology and Infection Biology, Swiss Tropical and Public Health Institute, and University of Basel, Basel, Switzerland

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R. Kiplin Guy College of Pharmacy, University of Nebraska Medical Center, Omaha, Nebraska; Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, Tennessee; Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, Nebraska; Department of Medical Parasitology and Infection Biology, Swiss Tropical and Public Health Institute, and University of Basel, Basel, Switzerland

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Ming-Fong Lin College of Pharmacy, University of Nebraska Medical Center, Omaha, Nebraska; Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, Tennessee; Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, Nebraska; Department of Medical Parasitology and Infection Biology, Swiss Tropical and Public Health Institute, and University of Basel, Basel, Switzerland

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Jennifer Keiser College of Pharmacy, University of Nebraska Medical Center, Omaha, Nebraska; Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, Tennessee; Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, Nebraska; Department of Medical Parasitology and Infection Biology, Swiss Tropical and Public Health Institute, and University of Basel, Basel, Switzerland

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Jonathan L. Vennerstrom College of Pharmacy, University of Nebraska Medical Center, Omaha, Nebraska; Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, Tennessee; Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, Nebraska; Department of Medical Parasitology and Infection Biology, Swiss Tropical and Public Health Institute, and University of Basel, Basel, Switzerland

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In the early 1980s, the antischistosomal aryl hydantoin Ro 13-3978 (AH01), a close structural analogue of the androgen receptor antagonist nilutamide, was discovered. Administration of 100 mg/kg oral doses of AH01 to mice infected with adult and juvenile Schistosoma mansoni produced 95% and 64% total worm burden reductions, confirming its high activity against adult worms, and showing that AH01 is also effective against juvenile infections. AH01 had no measureable interaction with the androgen receptor in a ligand competition assay, but it did block dihydrotestosterone-induced cell proliferation in an androgen-dependent human prostate cancer cell line. For AH01, nilutamide, and three closely related aryl hydantoin derivatives, there was no correlation between antischistosomal activity and androgen receptor interaction.

Author Notes

* Address correspondence to Jonathan L. Vennerstrom, University of Nebraska Medical Center, College of Pharmacy, 986025 Nebraska Medical Center, Omaha, NE 68198-6025. E-mail: jvenners@unmc.edu

Financial support: This investigation received financial support from the NIH (R21 AI097802-02) and the Swiss National Science Foundation (PPOOP3-135170 and 320030-149310).

Authors' addresses: Chunkai Wang, Xiaofang Wang, Yuxiang Dong, and Jonathan L. Vennerstrom, Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE, E-mails: chunkai.wang@unmc.edu, xiaofangwang@unmc.edu, ydong@unmc.edu, and jvenners@unmc.edu. Qingjie Zhao, Department of Pathology, University of Michigan, Ann Arbor, MI, E-mail: chemwo@gmail.com. Jaeki Min and R. Kiplin Guy, Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, TN, E-mails: jaeki.min@stjude.org and kip.guy@stjude.org. Sakthivel Muniyan and Ming-Fong Lin, Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, NE, E-mails: s.muniyan@unmc.edu and mlin@unmc.edu. Mireille Vargas and Jennifer Keiser, Department of Medical Parasitology and Infection Biology, Swiss Tropical and Public Health Institute, Basel, Switzerland, E-mails: mireille.vargas@unibas.ch and jennifer.keiser@unibas.ch.

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