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α-L-Fucosidase Inhibition by Pyrrolidine–Ferrocene Hybrids: Rationalization of Ligand-Binding Properties by Structural Studies

DOI: 10.1002/chem.201301001 DOI Help
PMID: 23740878 PMID Help

Authors: Audrey Hottin (Université de Reims Champagne-Ardenne, Institut de Chimie Moléculaire de Reims, CNRS) , Daniel W. Wright (University of York) , Agata Steenackers (Université Lille Nord de France) , Philippe Delannoy (Université Lille Nord de France) , Faustine Dubar (Université Lille Nord de France) , Christophe Biot (Université Lille Nord de France) , Gideon J. Davies (University of York) , Jean-bernard Behr (Université de Reims Champagne-Ardenne)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Chemistry - A European Journal , VOL 19 (29) , PAGES 9526 - 9533

State: Published (Approved)
Published: July 2013

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 3E 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.

Journal Keywords: Antineoplastic; Cattle; Cell; Drug; Enzyme; Ferrous; Glycoside; Humans; Hydrolases; Molecular; Pyrrolidines; alpha-L-Fucosidase

Subject Areas: Chemistry, Biology and Bio-materials, Medicine

Instruments: I03-Macromolecular Crystallography , I04-1-Macromolecular Crystallography (fixed wavelength)

Other Facilities: ESRF

Added On: 30/09/2013 15:29

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