title: Synthesis and analysis of potential α1,3-fucosyltransferase inhibitors.
abstract: Fucosyltransferases catalyze the transfer of l-fucose from an activated GDP-β-l-fucose to various acceptor molecules such as N-acetyllactosamine. Frequently fucosylation is the final step within the glycosylation machinery, and the resulting glycans are involved in various cellular processes such as cell-cell recognition, adhesion and inflammation or tumor metastasis. The selective blocking of these interactions would thus be a potential promising therapeutic strategy. The syntheses and analyses of various potential α1,3-fucosyltransferase inhibitors derived from GDP-β-l-fucose containing a triazole linker unit is summarized and the observed inhibitory effect was compared with that of small molecules such as GDP or fucose. To examine their specificity and selectivity, all inhibitors were tested with human α1,3-fucosyltransferase IX and Helicobacter pylori α1,3-fucosyltransferase, which is to date the only α1,3-fucosyltransferase with a known high resolution structure. Specific inhibitors which inhibit either H. pylori α1,3-fucosyltransferase or human fucosyltransferase IX with Ki values in the micromolar range were identified. In that regard, acetylated GDP-galactose derivative Ac-3 turned out to inhibit H. pylori α1,3-fucosyltransferase but not human fucosyltransferase IX, whereas GDP-6-amino-β-l-fucose 17 showed an appreciably better inhibitory effect on fucosyltransferase IX activity than on that of H. pylori fucosyltransferase.
authors.affiliation: Biochemistry, Department of Chemistry, Faculty of Sciences, Hamburg University, Martin-Luther-King-Platz 6, 20146 Hamburg, Germany.
authors.forename: Katrin
authors.initials: K
authors.lastname: Seelhorst
authors.affiliation: Organic Chemistry, Department of Chemistry, Faculty of Sciences, Hamburg University, Martin-Luther-King-Platz 6, 20146 Hamburg, Germany.
authors.forename: Tomas
authors.initials: T
authors.lastname: Piernitzki
authors.affiliation: Organic Chemistry, Department of Chemistry, Faculty of Sciences, Hamburg University, Martin-Luther-King-Platz 6, 20146 Hamburg, Germany.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Lunau
authors.affiliation: Organic Chemistry, Department of Chemistry, Faculty of Sciences, Hamburg University, Martin-Luther-King-Platz 6, 20146 Hamburg, Germany. Electronic address: chris.meier@chemie.uni-hamburg.de.
authors.forename: Chris
authors.initials: C
authors.lastname: Meier
authors.affiliation: Biochemistry, Department of Chemistry, Faculty of Sciences, Hamburg University, Martin-Luther-King-Platz 6, 20146 Hamburg, Germany. Electronic address: uli.hahn@uni-hamburg.de.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Hahn
mesh_terms: D001426:Bacterial Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D005647:Fucosyltransferases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006154:Guanosine Diphosphate Fucose / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D016480:Helicobacter pylori / Q000201:enzymology; D006801:Humans; D007700:Kinetics; D011485:Protein Binding; D014230:Triazoles / Q000737:chemistry
chemical_list: D001426:Bacterial Proteins; D004791:Enzyme Inhibitors; D014230:Triazoles; D006154:Guanosine Diphosphate Fucose; C519500:FUT9 protein, human; D005647:Fucosyltransferases
keywords: Carbohydrates; Fucose; Fucosyltransferases; Glycosylation; Inhibition