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Fucosidase inhibitors represent captivating targets for various biological applications. Iminosugars featuring a fluoroalkyl chain in the pseudoanomeric position were synthesized by nucleophilic addition of a perfluoroalkyl Grignard reagent to a nitrone. Reduction of the N-O bond of the hydroxylamine was achieved by treatment with an aqueous solution of sulfur dioxide. The p Ka = 4.5 of the target pyrrolidine reflected a strong electronic effect of the fluoroalkyl chain. Inhibitory potencies of the fluorinated iminosugars and their corresponding hydroxylamines were evaluated against α- L-fucosidase at various pH values. [ABSTRACT FROM AUTHOR]

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]

Synthetic analogues of the naturally occurring iminosugar homoDMDP, which feature a perfluoroalkyl group at the pseudo-anomeric position, have been synthesized from the corresponding sugar-derived cyclic aldonitrone. The new fluorinated iminosugars as well as homoDMDP and its 6-deoxy counterpart were evaluated for their inhibitory activity against a panel of glycosidases. While the replacement of the (1′,2′)-dihydroxyethyl substituent of homoDMDP with –C 4 F 9 proved detrimental for enzyme binding, introduction of a –C 3 F 7 moiety tuned the inhibitory activity spectrum selectively towards α-fucosidase and α-glucosidase from yeast. [ABSTRACT FROM AUTHOR]

The synthesis and the biological evaluation of a new ferrocenyl-iminosugar conjugate designed for fucosidase inhibitory and anticancer activity is described. The compound showed strong affinity for fucosidase from bovine kidney ( K i = 23 nM) and from Bacteroides thetaiotaomicron ( K i = 150 nM), displaying a 10-fold tighter binding affinity for these enzymes than the previous analogs. The interaction pattern that improves binding has been evaluated through structural analysis of the inhibitor–enzyme complex. The ferrocenyl-iminosugar exhibits significant anticancer activity on MDA-MB-231 and SK-MEL28 cell lines at 100 μM. [ABSTRACT FROM AUTHOR]

A diagram is presented which explains the chemical process of Perfluoroalkylation of Nitrones for the Synthesis of a Series of Fucosidase Inhibitors.