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Journal of Lipid Research, Vol 28, 565-571, Copyright © 1987 by Lipid Research, Inc.
J Inokuchi and NS Radin
1-Phenyl-2-decanoylamino-3-morpholino-1-propanol was previously shown to be
an effective inhibitor of the glucosyltransferase in liver that forms
glucosylceramide. Since the inhibitor consists of four isomers, it was
important for further testing to determine which isomer was most effective
and to devise a method for preparation of this isomer. The mixture of
isomers was synthesized as described before and separated by
crystallization into two diastereomers, differing in migration rate with
thin-layer chromatography (TLC) and in retention time with high performance
liquid chromatography (HPLC). The slower moving diastereomer, which proved
to be the active inhibitor, was separated into its enantiomers by
crystallization with dibenzoyltartaric acid isomers. The inhibitory
activity resided in the less soluble salt formed with the D-tartaric acid
compound. The optical isomers could be characterized by TLC as their
(1R)-(-)-camphanate esters. Using a second synthetic route, starting with
L-threo- and DL-erythro-1-phenyl- 2-amino-1,3-propanediol, we tentatively
established the active form of the inhibitor to be the D-threo (1S,2R)
isomer. 13C NMR spectroscopy supported the threo and erythro assignments.
Kinetic analysis showed that it acted uncompetitively against UDP-glucose
and by mixed competition against ceramide, with Ki of 0.7 microM. The
DL-erythro and DL-threo compounds inhibited brain galactosylceramide
synthetase to a small extent. Glucosylceramide glucosidase activity of
liver was unaffected by the DL-threo mixture.
ARTICLES
Preparation of the active isomer of 1-phenyl-2-decanoylamino-3- morpholino-1-propanol, inhibitor of murine glucocerebroside synthetase
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