Water-Soluble Cholesteryl-Containing Phosphorothioate Monogalactosides: Synthesis, Properties, and Use in Lowering Blood Cholesterol by Directing Plasma Lipoproteins to the Liver

Article abstract of DOI:10.1021/jm00107a024

The synthesis of several monogalactoside-terminated phosphorothiolated cholesteryl derivatives is described.Monogalactosyl derivatives are coupled by phosphorothiolation to cholesterol by using ethylene glycol units as hydrophilic spacer moieties.The resulting compounds are easily soluble in water.Upon addition of such solutions to human serum (to 2mM final concentration) the compounds are readily incorporated into lipoproteins.Isolated low-density lipoprotein (LDL) and high-density lipoprotein (HDL), preloaded with the compounds, are rapidly cleared from the circulation by the liver.The hepatic association is blocked by N-acetylgalactosamine, which indicates that galactose-specific recognition sites are responsible for the increased liver uptake.The plasma clearance and hepatic uptake of LDL loaded with the compounds is substantially higher (about 2-fold) than clearance and uptake of HDL containing the compounds.The selectivity of the effects of monogalactoside-terminated phosphorothiolated cholesteryl derivatives on the in vivo behavior of LDL as compared to that of HDL indicates that these compounds might be used to lower specifically LDL levels in patients with a high LDL-cholesterol level.