Second‐Generation Iminoxylitol‐Based Pharmacological Chaperones for the Treatment of Gaucher Disease

Abstract

A series of O-alkyl iminoxylitol derivatives was synthesized and evaluated as β-glucocerebrosidase (GCase) inhibitors. This structure-activity study shows a dramatic influence of the position of the alkyl chain (α-C1, O2, O3, or O4) on human GCase inhibition. Remarkably, 1,2-shift of the alkyl chain from C1 to O2 was found to maintain high inhibitory potency toward GCase as well as chaperone activity at sub-inhibitory concentration (10 nM). Removal of the stereogenic center at the pseudo-anomeric position led to shorter and more practical synthetic sequences. 2-O-Alkyl iminoxylitol derivatives constitute a new promising class of leads for the treatment of Gaucher disease by means of pharmacological chaperone therapy.

Glucocerebrosidase Enhancers for Selected Gaucher Disease Genotypes by Modification of α‐1‐C‐Substituted Imino‐D‐xylitols (DIXs) by Click Chemistry

“…In particular, six different genotypes, together with WT fibroblasts, were used in this study (see Experimental Section). 1C9-DIX, [17] with a reported enhancement of N370S enzyme activity (1.6-fold at 10 nm), was used as a reference. In order to determine whether this compound was active against other mutant GBAs, we tested it on the fibroblasts used in this study.…”

“…[23,24] As with the aminocyclitol analogues, [23,24] compounds with an aliphatic chain (DIX-17, DIX-18, and DIX-26) were among the most potent members of the series with IC 50 values in the low nanomolar range, similar to that of 1C9-DIX. In general, the affinity of alkylated iminosugar [15][16][17] or aminocyclitol [24] derivatives toward GBA1 increases with the length of the alkyl chain. However, long alkyl chain derivatives may also be cytotoxic, mainly due to membrane insertion and pore formation.…”

“…Thus, a series of potent iminocyclitol derivatives [15,16] culminated in the second generation iminoxylitol derivative 1C9-DIX (Figure 1), whose efficiency as pharmacological chaperone at low nanomolar concentration in N370S fibroblasts from GD patients was reported. [17] Interestingly, this compound was used by Overkleeft as a chemical tool to understand GC metabolism and the basis of GD. [18,19] Similarly, with a series of aliphatic N-alkyl aminocyclitols, [20,21] interesting GBA1 enhancement in patient fibroblasts with different enzyme mutations were obtained.…”

Phosphatidyl myo‐Inositol Mannosides Mimics Built on an Acyclic or Heterocyclic Core: Synthesis and Anti‐inflammatory Properties

“…Synthesis of PIM2 analogues incorporating an aza-inositol: The synthesis of PIM2 analogues built on a 3,4,5-trihydroxy-piperidine scaffold was achieved by way of the symmetrical 3-Obenzyl-iminoxylitol derivative 21, which is readily available from diacetone-d-glucose in five simple steps and in very high yield. [36,37] This approach leads to a core structure that has the non-natural xylo configuration. Thus compound, 21, was N-debenzylated with Pearlman's catalyst and then N-trifluoroacetylated with trifluoroacetic anhydride (TFAA) to give piperidine diol 23 (Scheme 4).…”

Alkylation studies of a polyhydroxylated-cyano-piperidine scaffold

“…[1][2][3][4] These compounds have been designed as therapeutic solutions in several diseases [5][6][7][8][9][10] (type II diabetes, viral and bacterial infections, lysosomal storage disorders, tumor metastasis). They have also been found in a number of natural [11][12][13][14][15][16] or synthetic [17][18][19][20][21][22][23][24] heterocyclic compounds, such as castanospermine and…”