title: α-L-fucosidase inhibition by pyrrolidine-ferrocene hybrids: rationalization of ligand-binding properties by structural studies.
abstract: Enhanced metabolism of fucose through fucosidase overexpression is a signature of some cancer types, thus suggesting that fucosidase-targetted ligands could play the role of drug-delivery vectors. Herein, we describe the synthesis of a new series of pyrrolidine-ferrocene conjugates, consisting of a L-fuco-configured dihydroxypyrrolidine as the fucosidase ligand armed with a cytotoxic ferrocenylamine moeity. Three-dimensional structures of several of these fucosidase inhibitors reveal transition-state-mimicking (3)E conformations. Elaboration with the ferrocenyl moiety results in sub-micromolar inhibitors of both bovine and bacterial fucosidases, with the 3D structure of the latter revealing electron density indicative of highly mobile alkylferrocene compounds. The best compounds show a strong antiproliferative effect, with up to 100% inhibition of the proliferation of MDA-MB-231 cancer cells at 50 μM.
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: Agata
authors.initials: A
authors.lastname: Steenackers
authors.forename: Philippe
authors.initials: P
authors.lastname: Delannoy
authors.forename: Faustine
authors.initials: F
authors.lastname: Dubar
authors.forename: Christophe
authors.initials: C
authors.lastname: Biot
authors.forename: Gideon J
authors.initials: GJ
authors.lastname: Davies
authors.forename: Jean-Bernard
authors.initials: JB
authors.lastname: Behr
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry*; D002417:Cattle; D049109:Cell Proliferation; D016503:Drug Delivery Systems; D004791:Enzyme Inhibitors / Q000737:chemistry; D005296:Ferrous Compounds / Q000737:chemistry*; D006026:Glycoside Hydrolases / Q000737:chemistry*; D006801:Humans; D006867:Hydrolases / Q000737:chemistry*; D000075163:Metallocenes; D008968:Molecular Conformation; D015394:Molecular Structure; D011759:Pyrrolidines / Q000737:chemistry*; D005644:alpha-L-Fucosidase / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D005296:Ferrous Compounds; D000075163:Metallocenes; D011759:Pyrrolidines; D006867:Hydrolases; D006026:Glycoside Hydrolases; D005644:alpha-L-Fucosidase; C032519:pyrrolidine; C004998:ferrocene
keywords: antitumor agents; glycosidases; hydrolases; inhibition; protein structures