1. α- L-Fucosidase Inhibition by Pyrrolidine-Ferrocene Hybrids: Rationalization of Ligand-Binding Properties by Structural Studies.
- Author
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Hottin, Audrey, Wright, Daniel W., Steenackers, Agata, Delannoy, Philippe, Dubar, Faustine, Biot, Christophe, Davies, Gideon J., and Behr, Jean‐Bernard
- Subjects
FUCOSIDASES ,ANTINEOPLASTIC agents ,PYRROLIDINE ,FERROCENE ,LIGAND binding (Biochemistry) ,FUCOSE ,DRUG delivery systems ,THERAPEUTICS - 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 μ M. [ABSTRACT FROM AUTHOR]- Published
- 2013
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