Exploiting the Hydrophobic Terrain in Fucosidases with Aryl‐Substituted Pyrrolidine Iminosugars. Issue 2 (26th November 2014)

• Record Type: Journal Article
• Authors: Hottin, Audrey; Wright, Daniel W.; Davies, Gideon J.; Behr, Jean‐Bernard
• Is Part Of: Chembiochem. Volume 16:Issue 2(2015)
• Page Start: 277
• Page End: 283
• Publication Date: 2014-11-26
• Subjects: Biochemistry -- Periodicals; Molecular biology -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1002/cbic.201402509
• Languages: English
• ISSNs: 1439-4227

Abstract

<abstract abstract-type="main" xml:lang="en"> <title>Abstract</title> <p>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 (<italic>K</italic>_i=4.8 n<sc>M</sc>), thus giving rise to one of the most potent pyrrolidine‐type inhibitors of this enzyme known to date.</p> </abstract>