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

Peter I. Dosa, Tim Ward, Rui E. Castro, Cecília M.P. Rodrigues, Clifford J. Steer

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

Abstract

Ursodeoxycholic acid (UDCA) is a bile acid with demonstrated anti-apoptotic activity in both invitro and invivo 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 invitro assays, although the POMC prodrug required the addition of AP for activity, while the other compound was active without exogenous AP.

Original languageEnglish (US)
Pages (from-to)1002-1011
Number of pages10
JournalChemMedChem
Volume8
Issue number6
DOIs
StatePublished - Jun 1 2013

Keywords

  • Apoptosis
  • Bile acids
  • Phosphoryloxymethyl carboxylate
  • Prodrugs
  • Ursodeoxycholic acid

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