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Exploiting the Hydrophobic Terrain in Fucosidases with Aryl‐Substituted Pyrrolidine Iminosugars
Author(s) -
Hottin Audrey,
Wright Daniel W.,
Davies Gideon J.,
Behr JeanBernard
Publication year - 2015
Publication title -
chembiochem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.05
H-Index - 126
eISSN - 1439-7633
pISSN - 1439-4227
DOI - 10.1002/cbic.201402509
Subject(s) - chemistry , pyrrolidine , linker , aryl , stereochemistry , fucosidase , iminosugar , enzyme , potency , combinatorial chemistry , fucose , biochemistry , organic chemistry , in vitro , glycoprotein , alkyl , computer science , operating system
Fucosidase inhibition shows potential in numerous therapeutic contexts. Substitution of fucose‐like iminosugars with hydrophobic “aglycons” yields significant improvements in potency of fucosidase inhibition. Here we have prepared three new 2‐aryl‐3,4‐dihydroxy‐5‐methylpyrrolidines featuring phenyl substituents in variable orientations with respect to the iminocyclitol core and at various distances from it to explore the key binding interactions that stabilise the enzyme–inhibitor complex. The presence of a triazole linker in one structure resulted in nanomolar inhibition of the fucosidase from bovine kidney ( K i =4.8 n M ), thus giving rise to one of the most potent pyrrolidine‐type inhibitors of this enzyme known to date.