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From the same journal

α-L-fucosidase inhibition by pyrrolidine-ferrocene hybrids: Rationalization of ligand-binding properties by structural studies

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Published copy (DOI)

Author(s)

  • A. Hottin
  • D.W. Wright
  • A. Steenackers
  • P. Delannoy
  • F. Dubar
  • C. Biot
  • G.J. Davies
  • J.-B. Behr

Department/unit(s)

Publication details

JournalChemistry - A European Journal
DatePublished - 15 Jul 2013
Issue number29
Volume19
Pages (from-to)9526-9533
Original languageEnglish

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 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. Transition-state-mimicking E conformations (see picture) are evident from the three-dimensional structures of ferrocenyl iminosugar/ fucosidase complexes. Novel pyrrolidine-ferrocene conjugates show strong anti-fucosidase and antiproliferative action, with up to 100 % inhibition of proliferation of an MDA-MB-231 cancer-cell line at 50 μM.

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