1624966-50-2Relevant academic research and scientific papers
Glucocerebrosidase enhancers for selected gaucher disease genotypes by modification of α-1-C-substituted Imino- D -xylitols (DIXs) by click chemistry
Serra-Vinardell, Jenny,Díaz, Lucía,Casas, Josefina,Grinberg, Daniel,Vilageliu, Llu?sa,Michelakakis, Helen,Mavridou, Irene,Aerts, Johannes M. F. G.,Decroocq, Camille,Compain, Philippe,Delgado, Antonio
, p. 1744 - 1754 (2014)
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.
