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J Biol Chem, Vol. 274, Issue 21, 14662-14669, May 21, 1999
From the Division of Nephrology, Department of Internal Medicine,
University of Michigan Medical Center, Ann Arbor, Michigan 48109
Previous work has led to the identification of
inhibitors of glucosylceramide synthase, the enzyme catalyzing the
first glycosylation step in the synthesis of glucosylceramide-based
glycosphingolipids. These inhibitors have two identified sites of
action: the inhibition of glucosylceramide synthase, resulting in the
depletion of cellular glycosphingolipids, and the inhibition of
1-O-acylceramide synthase, resulting in the elevation of
cell ceramide levels. A new series of glucosylceramide synthase
inhibitors based on substitutions in the phenyl ring of a parent
compound, 1-phenyl-2-palmitoylamino-3-pyrrolidino-1-propanol (P4), was
made. For substitutions of single functional groups, the potency of
these inhibitors in blocking glucosylceramide synthase was primarily
dependent upon the hydrophobic and electronic properties of the
substituents. An exponential relationship was found between the
IC50 of each inhibitor and the sum of derived hydrophobic (
) and electronic (
) parameters. This relationship demonstrated that substitutions that increased the electron-donating characteristics and decreased the lipophilic characteristics of the homologues enhanced
the potency of these compounds in blocking glucosylceramide formation.
A novel compound was subsequently designed and observed to be even more
active in blocking glucosylceramide formation. This compound,
D-threo-4'-hydroxy-P4, inhibited
glucosylceramide synthase at an IC50 of 90 nM.
In addition, a series of dioxane substitutions was designed and tested.
These included 3',4'-methylenedioxyphenyl-, 3',4'-ethylenedioxyphenyl-,
and 3'4'-trimethylenedioxyphenyl-substituted homologues.
D-threo-3',4'-Ethylenedioxy-P4-inhibited
glucosylceramide synthase was comparably active to the
p-hydroxy homologue. 4'-Hydroxy-P4 and ethylenedioxy-P4
blocked glucosylceramide synthase activity at concentrations that had
little effect on 1-O-acylceramide synthase activity. These
novel inhibitors resulted in the inhibition of glycosphingolipid
synthesis in cultured cells at concentrations that did not
significantly raise intracellular ceramide levels or inhibit cell growth.
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