title: Exploiting the hydrophobic terrain in fucosidases with aryl-substituted pyrrolidine iminosugars.
abstract: 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 (Ki =4.8 nM), thus giving rise to one of the most potent pyrrolidine-type inhibitors of this enzyme known to date.
authors.affiliation: Université de Reims Champagne-Ardenne, Institut de Chimie Moléculaire de Reims, CNRS UMR 7312, UFR des Sciences Exactes et Naturelles, 51687 Reims Cedex 2 (France).
authors.forename: Audrey
authors.initials: A
authors.lastname: Hottin
authors.forename: Daniel W
authors.initials: DW
authors.lastname: Wright
authors.forename: Gideon J
authors.initials: GJ
authors.lastname: Davies
authors.forename: Jean-Bernard
authors.initials: JB
authors.lastname: Behr
mesh_terms: D000818:Animals; D002417:Cattle; D060326:Chemistry Techniques, Synthetic; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D057927:Hydrophobic and Hydrophilic Interactions; D050111:Imino Sugars / Q000737:chemistry* / Q000494:pharmacology; D007668:Kidney / Q000201:enzymology; D011487:Protein Conformation; D011759:Pyrrolidines / Q000737:chemistry; D013329:Structure-Activity Relationship; D005644:alpha-L-Fucosidase / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D050111:Imino Sugars; D011759:Pyrrolidines; D005644:alpha-L-Fucosidase; C032519:pyrrolidine
keywords: azasugars; fucosidases; hydrophobic interactions; inhibition; structure