Glucocerebrosidase Enhancers for Selected Gaucher Disease Genotypes by Modification of α‐1‐C‐Substituted Imino‐D‐xylitols (DIXs) by Click Chemistry |
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| Authors: | Jenny Serra‐Vinardell Dr Lucía Díaz Dr Josefina Casas Prof Dr Daniel Grinberg Prof Dr Lluïsa Vilageliu Prof Dr Helen Michelakakis Dr Irene Mavridou Johannes M F G Aerts Dr Camille Decroocq Prof Dr Philippe Compain Prof Dr Antonio Delgado |
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| Affiliation: | 1. Departament de Genètica, Universitat de Barcelona (UB), IBUB;2. CIBER de Enfermedades Raras (CIBERER), Av. Diagonal 643, 08028, Barcelona (Spain);3. Research Unit on BioActive Molecules (RUBAM), Departament de Química Biomèdica, Institut de Química Avan?ada de Catalunya (IQAC‐CSIC), Jordi Girona 18, 08034 Barcelona (Spain);4. Department of Enzymology & Cellular Function, Institute of Child Health, Athens 11527 (Greece);5. Department of Medicinal Biochemistry, Academic Medical Center, Meibergdreef 15, 1105 AZ, Amsterdam (The Netherlands);6. Laboratoire de Synthèse Organique et Molécules Bioactives, Université de Strasbourg/CNRS (UMR 7509), Ecole Européenne de Chimie, Polymères et Matériaux, 25 rue Becquerel, 67087 Strasbourg (France);7. Institut Universitaire de France, 103 Bd. Saint‐Michel, 75005 Paris (France);8. Facultat de Farmàcia, Unitat de Química Farmacèutica (Unitat Associada al CSIC), Universitat de Barcelona (UB), Avda. Joan XXIII, s/n, 08028 Barcelona (Spain) |
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| 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. |
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| Keywords: | activity enhancement chaperones click chemistry Gaucher disease glucosyl ceramide iminoxylitol |
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