HOMEPRODUCTSCOMPANYCONTACTFAQResearchDictionaryPharmaSign Up FREE or Login

Structural and stereochemical studies of potent inhibitors of glucosylceramide synthase and tumor cell growth.

Abstract
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.
AuthorsA Abe, N S Radin, J A Shayman, L L Wotring, R E Zipkin, R Sivakumar, J M Ruggieri, K G Carson, B Ganem
JournalJournal of lipid research (J Lipid Res) Vol. 36 Issue 3 Pg. 611-21 (Mar 1995) ISSN: 0022-2275 [Print] United States
PMID7775872 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
Chemical References
  • Antineoplastic Agents
  • Morpholines
  • RV 538
  • Glucosyltransferases
  • ceramide glucosyltransferase
Topics
  • Animals
  • Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
  • Cell Division (drug effects)
  • Cell Line
  • Glucosyltransferases (antagonists & inhibitors)
  • Humans
  • Lipid Metabolism
  • Molecular Structure
  • Morpholines (chemical synthesis, chemistry, pharmacology)
  • Stereoisomerism
  • Structure-Activity Relationship
  • Tumor Cells, Cultured (drug effects)

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research graph!


Choose Username:
Email:
Password:
Verify Password:
Enter Code Shown: