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.

Synthesis of modified 1,5-imino-d-xylitols as ligands for lysosomal β-glucocerebrosidase

“…8 ). This might be an explanation for the exceptional ligand properties as well as the selectivity of C-1-substituted DIX derivatives, which has been observed previously by others and us for similar alkyl-iminoxylitols [ 30 , 34 , 36 – 40 ].

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“…We decided to introduce either an ester group or an imidazole residue. Both functional groups have been found to be suitable for ligand properties of GCase [ 34 , 36 ].…”

“…Compain and co-workers synthesized a library of 1- C -triazolylalkyl side chain-modified DIX analogues (Fig. 4 ), including compounds 12 , by a click chemistry approach, and found that some of these are GCase enhancers for selected Gaucher disease genotype mutants [ 35 , 36 ].

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N-Alkylated Iminosugar Based Ligands: Synthesis and Inhibition of Human Lysosomal β-Glucocerebrosidase

“…Paradigmatic examples are shown in Figure 2 . Compounds 7 [ 38 ] have been introduced by Mellet and coworkers, d - xylo configured 1- C -alkyl iminosugars 8 [ 39 ] represent another important family which is also true for compounds 9 [ 40 ], all showing significant properties as pharmacological chaperones for mutant GCases.…”

Triazole‐Linked Iminosugars and Aromatic Systems as Simplified UDP‐Galf Mimics: Synthesis and Preliminary Evaluation as Galf‐Transferase Inhibitors

“…However, while several examples of N ‐ and O ‐armed alkynyl iminosugars have been published, only one example of a 1‐ C ‐propargyl compound has been reported to date in the piperidine series (i.e., 1‐ C ‐propargyl‐1‐deoxyimino‐ d ‐xylitol) . A few examples based on a pyrrolidine core have been obtained by organocatalysis or through addition to cyclic N,O‐acetals or to cyclic nitrones …”