Fleetamine (3-O-α-d-glucopyranosyl-swainsonine): The synthesis of a hypothetical inhibitor of endo-α-mannosidase

Tim Quach, Sammi Tsegay, Andrew J. Thompson, Nikolay V. Kukushkin, Dominic S. Alonzi, Terry D Butters, Gideon J. Davies, Spencer John Williams

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3-O-α-d-Glucopyranosyl-swainsonine was originally proposed 17 as a potential inhibitor of the mammalian enzyme endo-α-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-α-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-α-mannosidase inhibitor complex, which identified deleterious interactions with the swainsonine piperidine ring and an essential active site residue.

Original languageEnglish
Pages (from-to)992-997
Number of pages6
JournalTetrahedron Asymmetry
Issue number13
Publication statusPublished - 15 Jul 2012
Externally publishedYes

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