Exploiting the hydrophobic terrain in fucosidases with aryl-substituted pyrrolidine iminosugars

Audrey Hottin; Daniel W. Wright; Gideon J. Davies; Jean-Bernard Behr

doi:10.1002/cbic.201402509

Exploiting the hydrophobic terrain in fucosidases with aryl-substituted pyrrolidine iminosugars

Audrey Hottin, Daniel W. Wright, Gideon J. Davies, Jean-Bernard Behr

Chemistry

Research output: Contribution to journal › Article › peer-review

Abstract

Fucosidase inhibition shows potential in numerous therapeutic contexts. Substitution of fucose-like iminosugars with hydrophobic "aglycons" yields significant improvements in potency of fucosidase inhibition. Here we have prepared three new 2-aryl-3,4-dihydroxy-5-methylpyrrolidines featuring phenyl substituents in variable orientations with respect to the iminocyclitol core and at various distances from it to explore the key binding interactions that stabilise the enzyme-inhibitor complex. The presence of a triazole linker in one structure resulted in nanomolar inhibition of the fucosidase from bovine kidney (Ki =4.8 nM), thus giving rise to one of the most potent pyrrolidine-type inhibitors of this enzyme known to date.

Original language	English
Pages (from-to)	277-283
Number of pages	7
Journal	Chembiochem
Volume	16
Issue number	2
Early online date	26 Nov 2014
DOIs	https://doi.org/10.1002/cbic.201402509
Publication status	Published - 19 Jan 2015

Bibliographical note

Keywords

Azasugars
Flucosidases
Hydrophobic interactions
Inhibition
Structure

Access to Document

10.1002/cbic.201402509

Cite this

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abstract = "Fucosidase inhibition shows potential in numerous therapeutic contexts. Substitution of fucose-like iminosugars with hydrophobic {"}aglycons{"} yields significant improvements in potency of fucosidase inhibition. Here we have prepared three new 2-aryl-3,4-dihydroxy-5-methylpyrrolidines featuring phenyl substituents in variable orientations with respect to the iminocyclitol core and at various distances from it to explore the key binding interactions that stabilise the enzyme-inhibitor complex. The presence of a triazole linker in one structure resulted in nanomolar inhibition of the fucosidase from bovine kidney (Ki =4.8 nM), thus giving rise to one of the most potent pyrrolidine-type inhibitors of this enzyme known to date.",

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