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

TY - JOUR

T1 - Fleetamine (3-O-alpha-D-glucopyranosyl-swainsonine)

T2 - the synthesis of a hypothetical inhibitor of endo-alpha-mannosidase

AU - Quach, Tim

AU - Tsegay, Sammi

AU - Thompson, Andrew J.

AU - Kukushkin, Nikolay V.

AU - Alonzi, Dominic S.

AU - Butters, Terry D.

AU - Davies, Gideon J.

AU - Williams, Spencer J.

PY - 2012/7/15

Y1 - 2012/7/15

N2 - 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.

AB - 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.

KW - ENDOPLASMIC-RETICULUM

KW - MOLECULAR-GRAPHICS

KW - N-GLYCANS

KW - GLYCOSIDASE INHIBITORS

KW - ASPARAGINE-LINKED OLIGOSACCHARIDES

KW - GLUCOSIDASE-II

KW - CELLS

KW - ENDOMANNOSIDASE

KW - (-)-SWAINSONINE

KW - GLYCOPROTEIN-BIOSYNTHESIS

UR - http://www.scopus.com/inward/record.url?scp=84864669538&partnerID=8YFLogxK

U2 - 10.1016/j.tetasy.2012.06.011

DO - 10.1016/j.tetasy.2012.06.011

M3 - Article

SN - 0957-4166

VL - 23

SP - 992

EP - 997

JO - TETRAHEDRON-ASYMMETRY

JF - TETRAHEDRON-ASYMMETRY

IS - 13

ER -