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

Authors

  • Audrey Hottin,

    1. 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), Fax: (+33) 326913166
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  • Daniel W. Wright,

    1. Structural Biology Laboratory, Department of Chemistry, University of York, York YO10 5DD (UK)
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  • Agata Steenackers,

    1. Université Lille Nord de France, Université Lille 1, Unité de Glycobiologie Structurale et Fonctionnelle, CNRS UMR 8576, IFR 147, 59650 Villeneuve d'Ascq Cedex (France)
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  • Prof. Philippe Delannoy,

    1. Université Lille Nord de France, Université Lille 1, Unité de Glycobiologie Structurale et Fonctionnelle, CNRS UMR 8576, IFR 147, 59650 Villeneuve d'Ascq Cedex (France)
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  • Dr. Faustine Dubar,

    1. Université Lille Nord de France, Université Lille 1, Unité de Catalyse et Chimie du Solide, CNRS UMR 8181, 59652 Villeneuve d'Ascq Cedex (France)
    2. Present address: School of Chemistry, University of Glasgow, Glasgow, G12 8QQ (UK)
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  • Prof. Christophe Biot,

    1. Université Lille Nord de France, Université Lille 1, Unité de Glycobiologie Structurale et Fonctionnelle, CNRS UMR 8576, IFR 147, 59650 Villeneuve d'Ascq Cedex (France)
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  • Prof. Gideon J. Davies,

    1. Structural Biology Laboratory, Department of Chemistry, University of York, York YO10 5DD (UK)
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  • Dr. Jean-Bernard Behr

    Corresponding author
    1. 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), Fax: (+33) 326913166
    • 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), Fax: (+33) 326913166

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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.

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