5-Thio-D-glycopyranosylamines and their amidinium salts as potential transition-state mimics of glycosyl hydrolases: synthesis, enzyme inhibitory activities, X-ray crystallography, and molecular modeling

Lizie M. Kavlekar, Douglas A. Kuntz, Xin Wen, Blair D. Johnston, Birte Svensson, David R. Rose, B. Mario Pinto

    Research output: Contribution to journalJournal articleResearchpeer-review

    Abstract

    The synthesis of new glycosidase inhibitors, namely, the glycosylamines of 5-thioglucose and 5-thiomannose and their corresponding amidinium salts are described. We report also the crystal structures of 5-thio-D-mannopyranosyl amine 1 and 5-thio-D-mannopyranosylamidinium bromide 2 bound in the enzyme active site of Golgi alpha-mannosidase II (GM II). Compounds 1 and 2 have been found to be inhibitors with IC50 values of 0.07 and 0.9 mM, respectively. We also report the docked structures of 5-thin-D-glucopyranosylamine 3 and 5-thio-D-glucopyranosylamidinium bromide 4 in the active site of glucoamylase G2, derived by molecular modeling. Compounds 3 and 4 were found to be inhibitors with K-i values of 0.015 and 0.098 mM, respectively. The results led to conclusions about the nature of the transition state and strategy for the inhibition of glycosyl hydrolases in general. (C) 2005 Elsevier Ltd. All rights reserved.
    Original languageEnglish
    JournalTetrahedron: Asymmetry
    Volume16
    Issue number5
    Pages (from-to)1035-1046
    ISSN0957-4166
    DOIs
    Publication statusPublished - 2005

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