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Synthesis and Evaluation of Water-Soluble Prodrugs of Ursodeoxycholic Acid (UDCA), an Anti-apoptotic Bile Acid

Authors

  • Dr. Peter I. Dosa,

    Corresponding author
    1. Department of Medicinal Chemistry, Institute for Therapeutics Discovery and Development, University of Minnesota, 717 Delaware Street, Minneapolis, MN 55414 (USA)
    • Department of Medicinal Chemistry, Institute for Therapeutics Discovery and Development, University of Minnesota, 717 Delaware Street, Minneapolis, MN 55414 (USA)

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  • Dr. Tim Ward,

    1. Department of Medicinal Chemistry, Institute for Therapeutics Discovery and Development, University of Minnesota, 717 Delaware Street, Minneapolis, MN 55414 (USA)
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  • Dr. Rui E. Castro,

    1. Research Institute for Medicines and Pharmaceutical Sciences (iMed.UL), Faculty of Pharmacy, University of Lisbon, 1649-003 Lisbon (Portugal)
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  • Prof. Dr. Cecília M. P. Rodrigues,

    1. Research Institute for Medicines and Pharmaceutical Sciences (iMed.UL), Faculty of Pharmacy, University of Lisbon, 1649-003 Lisbon (Portugal)
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  • Prof. Dr. Clifford J. Steer

    1. Departments of Medicine and Genetics, Cell Biology, and Development, University of Minnesota, VFW Cancer Research Center, 406 Harvard Street, Minneapolis MN 55455 (USA)
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Abstract

Ursodeoxycholic acid (UDCA) is a bile acid with demonstrated anti-apoptotic activity in both in vitro and in vivo models. However, its utility is hampered by limited aqueous solubility. As such, water-soluble prodrugs of UDCA could have an advantage over the parent bile acid in indications where intravenous administration might be preferable, such as decreasing damage from stroke or acute kidney injury. Five phosphate prodrugs were synthesized, including one incorporating a novel phosphoryloxymethyl carboxylate (POMC) moiety. These prodrugs were highly water-soluble, but showed significant differences in chemical stability, with oxymethylphosphate prodrugs being the most unstable. In a series of NMR experiments, the POMC prodrug was bioactivated to UDCA by alkaline phosphatase (AP) faster than a prodrug containing a phosphate directly attached to the alcohol at the 3-position of UDCA. Both of these prodrugs showed significant anti-apoptotic activity in a series of in vitro assays, although the POMC prodrug required the addition of AP for activity, while the other compound was active without exogenous AP.

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