Design and synthesis of iminosugar-based inhibitors of glucosylceramide synthase

The search for new therapeutic agents against Gaucher disease

Charlotte Boucheron, Valérie Desvergnes, Philippe Compain, Olivier R. Martin, Alan Lavi, Muhammad Mukram Mohamed Mackeen, Mark Wormald, Raymond Dwek, Terry D. Butters

Research output: Contribution to journalArticle

44 Citations (Scopus)

Abstract

A series of iminosugars bearing two or three alkyl chains ('iminoglycolipids') were designed as ceramide mimics and analogues of N-butyl 1-deoxynojirimycin (N-Bu DNJ, Zavesca®). This orally active iminosugar inhibits the biosynthesis of glucosylceramides, which accumulate pathologically in macrophages of patients with Gaucher disease (substrate reduction therapy, SRT). Molecular modeling and kinetic experiments have suggested that N-Bu DNJ is a competitive inhibitor that mimics the ceramide acceptor but not the donor substrate (UDP-glucose) in the glucosylceramide synthase-catalyzed process. Kinetic measurements were made with the glucosyltransferase to assess the selectivity of the new iminoglycolipids with respect to the length (C4 or C8) and the position of the second alkyl chain (C-1, O-2 and/or O-4). This structure-activity relationship study showed that the addition of a second alkyl chain, to obtain better ceramide mimics, led to less potent inhibitors. Moreover, the synthase active site did not discriminate inhibitors differing by the position of the second alkyl chain (C-1, O-2 or O-4). Best inhibition was found for 1,5-dideoxy-1,5-imino-N-octyl-4-O-octyl-d-glucitol (IC50 134 μM).

Original languageEnglish
Pages (from-to)1747-1756
Number of pages10
JournalTetrahedron Asymmetry
Volume16
Issue number10
DOIs
Publication statusPublished - 23 May 2005
Externally publishedYes

Fingerprint

ceramide glucosyltransferase
Ceramides
Gaucher Disease
inhibitors
Bearings (structural)
synthesis
1-Deoxynojirimycin
Glucosylceramides
Glucosyltransferases
Uridine Diphosphate Glucose
Kinetics
biosynthesis
macrophages
Molecular modeling
Sorbitol
Macrophages
Biosynthesis
kinetics
Substrates
Structure-Activity Relationship

ASJC Scopus subject areas

  • Inorganic Chemistry
  • Organic Chemistry
  • Materials Chemistry
  • Drug Discovery

Cite this

Design and synthesis of iminosugar-based inhibitors of glucosylceramide synthase : The search for new therapeutic agents against Gaucher disease. / Boucheron, Charlotte; Desvergnes, Valérie; Compain, Philippe; Martin, Olivier R.; Lavi, Alan; Mohamed Mackeen, Muhammad Mukram; Wormald, Mark; Dwek, Raymond; Butters, Terry D.

In: Tetrahedron Asymmetry, Vol. 16, No. 10, 23.05.2005, p. 1747-1756.

Research output: Contribution to journalArticle

Boucheron, Charlotte ; Desvergnes, Valérie ; Compain, Philippe ; Martin, Olivier R. ; Lavi, Alan ; Mohamed Mackeen, Muhammad Mukram ; Wormald, Mark ; Dwek, Raymond ; Butters, Terry D. / Design and synthesis of iminosugar-based inhibitors of glucosylceramide synthase : The search for new therapeutic agents against Gaucher disease. In: Tetrahedron Asymmetry. 2005 ; Vol. 16, No. 10. pp. 1747-1756.
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