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Journal of Lipid Research, Vol 36, 611-621, Copyright © 1995 by Lipid Research, Inc.
A Abe, NS Radin, JA Shayman, LL Wotring, RE Zipkin, R Sivakumar, JM Ruggieri, KG Carson and B Ganem
Analogs and homologs of PDMP were synthesized, based on its structure
(D-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol). This compound
had previously been found to block the synthesis of GlcCer
(glucosylceramide). Increasing the acyl chain length from 10 to 16 carbon
atoms greatly enhanced the efficacy of the enzyme inhibitor, as did the use
of a less polar cyclic amine, especially a pyrrolidine instead of a
morpholine ring. Replacement of the phenyl ring by a chain corresponding to
sphingosine also yielded a strongly inhibitory material. By using a chiral
synthetic route, we showed that the isomers active against GlcCer synthase
had the R,R-(D-threo)-configuration. However, strong inhibition of the
growth of human cancer cells in plastico was produced by both the threo and
erythro racemic compounds, showing involvement of an additional factor
(beyond simple depletion of cell glycosphingolipids by blockage of GlcCer
synthesis). The growth arresting effects could be correlated with increases
in cellular ceramide and diglyceride levels. The aliphatic pyrrolidino
compound was strongly inhibitory toward the glucosyltransferase and
produced almost complete depletion of glycolipids, but did not inhibit
growth or cause an accumulation of ceramide. Attempts were made to see
whether the differences in growth effects could be attributed to the
influence of the inhibitors on related enzymes (ceramide and sphingomyelin
synthase and ceramidase and sphingomyelinase). While some stimulation of
enzyme activity was noted, particularly at high inhibitor concentrations
(50 microM), these findings did not explain the differing effects of the
different inhibitors. The best inhibitors of GlcCer synthase compared
favorably in efficacy with some cancer chemotherapeutic drugs in current
use when tested with a battery of human cancer cells.
ARTICLES
Structural and stereochemical studies of potent inhibitors of glucosylceramide synthase and tumor cell growth
Department of Internal Medicine, University of Michigan, Ann Arbor 48109, USA.
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