A series of iminoxylitol derivatives carrying a C-linked di-O-acyl or di-O-alkyl glyceryl substituent were prepared and characterized. All of these compounds, which were designed as
glucosylceramide (GlcCer) mimics, were nanomolar inhibitors of lysosomal β-
glucosidase (
glucocerebrosidase, GCase). Two of these pseudoglycolipids were further evaluated for their ability to enhance the activity of mutant GCase in human Gaucher cells. Although the di-O-hexyl
ether was surprisingly devoid of chaperoning activity on both N370S and L444P GCases, the di-O-decanoyl
ester was a potent chaperone of the L444P
hydrolase, capable of increasing the residual activity of the
enzyme by
a factor of two at a very low concentration (50 nM); such a significant effect on the L444P mutation in human fibroblasts has not yet been observed. In heat-stress studies, the diether was found to be much more effective in stabilizing the wild-type
enzyme than the diester. Four representative pseudoglycolipids were also assayed as inhibitors of
GlcCer synthase, because such compounds could find use in the substrate reduction
therapy approach to treat
lysosomal storage diseases, but these compounds revealed only moderate activity. As efficient pharmacological chaperones, new structures such as the di-C10 -
ester constitute leads for the development of therapeutic agents for types 2 and 3
Gaucher disease, the most severe neuronopathic forms of this lysosomal disease.