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Fleetamine (3-O-alpha-D-glucopyranosyl-swainsonine): the synthesis of a hypothetical inhibitor of endo-alpha-mannosidase

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JournalTETRAHEDRON-ASYMMETRY
DatePublished - 15 Jul 2012
Issue number13
Volume23
Number of pages6
Pages (from-to)992-997
Original languageEnglish

Abstract

3-O-alpha-D-Glucopyranosyl-swainsonine was originally proposed(17) as a potential inhibitor of the mammalian enzyme endo-alpha-mannosidase, but its synthesis has not been reported. Herein we report the total synthesis of this enigmatic compound, utilizing a halide-ion catalysed glycosylation of a swainsonine lactam with a glucosyl iodide donor as the key step. The resulting inhibitor was evaluated as an inhibitor of human endo-alpha-mannosidase, and as a ligand for bacterial orthologs from Bacteroides thetaiotaomicron and Bacteroides xylanisolvens, including active-centre variants, although no evidence for binding or inhibition was observed. The surprising lack of binding was rationalized by using structural alignment with an endo-alpha-mannosidase inhibitor complex, which identified deleterious interactions with the swainsonine piperidine ring and an essential active site residue. (C) 2012 Elsevier Ltd. All rights reserved.

    Research areas

  • ENDOPLASMIC-RETICULUM, MOLECULAR-GRAPHICS, N-GLYCANS, GLYCOSIDASE INHIBITORS, ASPARAGINE-LINKED OLIGOSACCHARIDES, GLUCOSIDASE-II, CELLS, ENDOMANNOSIDASE, (-)-SWAINSONINE, GLYCOPROTEIN-BIOSYNTHESIS

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