Glucocerebrosidase enhancers for selected Gaucher disease genotypes by modification of α-1-C-substituted imino-D-xylitols (DIXs) by click chemistry

ChemMedChem. 2014 Aug;9(8):1744-54. doi: 10.1002/cmdc.201402023. Epub 2014 Jun 27.


A series of hybrid analogues was designed by combination of the iminoxylitol scaffold of parent 1C9-DIX with triazolylalkyl side chains. The resulting compounds were considered potential pharmacological chaperones in Gaucher disease. The DIX analogues reported here were synthesized by CuAAC click chemistry from scaffold 1 (α-1-C-propargyl-1,5-dideoxy-1,5-imino-D-xylitol) and screened as imiglucerase inhibitors. A set of selected compounds were tested as β-glucocerebrosidase (GBA1) enhancers in fibroblasts from Gaucher patients bearing different genotypes. A number of these DIX compounds were revealed as potent GBA1 enhancers in genotypes containing the G202R mutation, particularly compound DIX-28 (α-1-C-[(1-(3-trimethylsilyl)propyl)-1H-1,2,3-triazol-4-yl)methyl]-1,5-dideoxy-1,5-imino-D-xylitol), bearing the 3-trimethylsilylpropyl group as a new surrogate of a long alkyl chain, with approximately threefold activity enhancement at 10 nM. Despite their structural similarities with isofagomine and with our previously reported aminocyclitols, the present DIX compounds behaved as non-competitive inhibitors, with the exception of the mixed-type inhibitor DIX-28.

Keywords: Gaucher disease; activity enhancement; chaperones; click chemistry; glucosyl ceramide; iminoxylitol.

MeSH terms

  • Cells, Cultured
  • Click Chemistry
  • Enzyme Inhibitors / chemistry*
  • Fibroblasts / cytology
  • Gaucher Disease / metabolism
  • Gaucher Disease / pathology
  • Genotype
  • Glucosylceramidase / antagonists & inhibitors*
  • Glucosylceramidase / genetics
  • Glucosylceramidase / metabolism
  • Humans
  • Imino Pyranoses / chemical synthesis
  • Imino Pyranoses / chemistry
  • Imino Pyranoses / metabolism
  • Mutation
  • Protein Binding
  • Xylitol / chemical synthesis
  • Xylitol / chemistry*
  • Xylitol / metabolism


  • Enzyme Inhibitors
  • Imino Pyranoses
  • isofagomine
  • Glucosylceramidase
  • Xylitol