title: Glucocerebrosidase enhancers for selected Gaucher disease genotypes by modification of α-1-C-substituted imino-D-xylitols (DIXs) by click chemistry.
abstract: 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.
authors: Departament de Genètica, Universitat de Barcelona (UB), IBUB; CIBER de Enfermedades Raras (CIBERER), Av. Diagonal 643, 08028, Barcelona (Spain).
authors: Jenny
authors: J
authors: Serra-Vinardell
authors: Lucía
authors: L
authors: Díaz
authors: Josefina
authors: J
authors: Casas
authors: Daniel
authors: D
authors: Grinberg
authors: Lluïsa
authors: L
authors: Vilageliu
authors: Helen
authors: H
authors: Michelakakis
authors: Irene
authors: I
authors: Mavridou
authors: Johannes M F G
authors: JM
authors: Aerts
authors: Camille
authors: C
authors: Decroocq
authors: Philippe
authors: P
authors: Compain
authors: Antonio
authors: A
authors: Delgado
mesh_terms: D002478:Cells, Cultured; D057930:Click Chemistry; D004791:Enzyme Inhibitors / Q000737:chemistry*; D005347:Fibroblasts / Q000166:cytology; D005776:Gaucher Disease / Q000378:metabolism / Q000473:pathology; D005838:Genotype; D005962:Glucosylceramidase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D050112:Imino Pyranoses / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D009154:Mutation; D011485:Protein Binding; D014993:Xylitol / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D050112:Imino Pyranoses; C098432:isofagomine; D005962:Glucosylceramidase; D014993:Xylitol
keywords: Gaucher disease; activity enhancement; chaperones; click chemistry; glucosyl ceramide; iminoxylitol