Stereodivergent synthesis of right- and left-handed iminoxylitol heterodimers and monomers. Study of their impact on ß-glucocerebrosidase activity.
Org Biomol Chem
; 15(17): 3681-3705, 2017 May 03.
Article
in En
| MEDLINE
| ID: mdl-28401966
ABSTRACT
A library of dimers and heterodimers of both enantiomers of 2-O-alkylated iminoxylitol derivatives has been synthesised and evaluated on ß-glucocerebrosidase (GCase), the enzyme responsible for Gaucher disease (GD). Although the objective was to target simultaneously the active site and a secondary binding site of the glucosidase, the (-)-2-iminoxylitol moiety seemed detrimental for imiglucerase inhibition and no significant enhancement was obtained in G202R, N370S and L444P fibroblasts. However, all compounds having at least one (+)-2-O-alkyl iminoxylitol are GCase inhibitors in the nano molar range and are significant GCase activity enhancers in G202R fibroblats, as confirmed by a decrease of glucosylceramide levels and by co-localization studies.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Xylitol
/
Dimerization
/
Enzyme Inhibitors
/
Glucosylceramidase
Limits:
Humans
Language:
En
Journal:
Org Biomol Chem
Journal subject:
BIOQUIMICA
/
QUIMICA
Year:
2017
Type:
Article