TY - JOUR
T1 - Synthesis and Evaluation of Water-Soluble Prodrugs of Ursodeoxycholic Acid (UDCA), an Anti-apoptotic Bile Acid
AU - Dosa, Peter I.
AU - Ward, Tim
AU - Castro, Rui E.
AU - Rodrigues, Cecília M.P.
AU - Steer, Clifford J.
PY - 2013/6
Y1 - 2013/6
N2 - 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.
AB - 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.
KW - Apoptosis
KW - Bile acids
KW - Phosphoryloxymethyl carboxylate
KW - Prodrugs
KW - Ursodeoxycholic acid
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U2 - 10.1002/cmdc.201300059
DO - 10.1002/cmdc.201300059
M3 - Article
C2 - 23640741
AN - SCOPUS:84878372256
SN - 1860-7179
VL - 8
SP - 1002
EP - 1011
JO - ChemMedChem
JF - ChemMedChem
IS - 6
ER -