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N ‐Guanidino Derivatives of 1,5‐Dideoxy‐1,5‐imino‐ d ‐xylitol are Potent, Selective, and Stable Inhibitors of β‐Glucocerebrosidase
Author(s) -
Sevšek Alen,
Šrot Luka,
Rihter Jakob,
Čelan Maša,
van Ufford Linda Quarles,
Moret Ed E.,
Martin Nathaniel I.,
Pieters Roland J.
Publication year - 2017
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201700050
Subject(s) - glucocerebrosidase , xylitol , chemistry , moiety , guanidine , urea , enzyme , recombinant dna , biochemistry , stereochemistry , xylose , molecular model , fermentation , gene
A series of lipidated guanidino and urea derivatives of 1,5‐dideoxy‐1,5‐imino‐ d ‐xylitol were prepared from d ‐xylose using a concise synthetic protocol. Inhibition assays with a panel of glycosidases revealed that the guanidino analogues display potent inhibition against human recombinant β‐glucocerebrosidase with IC 50 values in the low nanomolar range. Related urea analogues of 1,5‐dideoxy‐1,5‐imino‐ d ‐xylitol were also synthesized and evaluated in the same fashion and found to be selective for β‐galactosidase from bovine liver. No inhibition of human recombinant β‐glucocerebrosidase was observed for the urea analogues. Computational studies provided insight into the potent activity of analogues bearing the substituted guanidine moiety in the inhibition of lysosomal glucocerebrosidase (GBA).