sp2-Iminosugar O-, S-, and N-glycosides as conformational mimics of α-linked disaccharides; implications for glycosidase inhibition

Sánchez-Fernández, Elena M, Rísquez-Cuadro, Rocío, Ortiz Mellet, Carmen, García Fernández, José M, Nieto, Pedro M and Angulo, Jesús ORCID: https://orcid.org/0000-0001-7250-5639 (2012) sp2-Iminosugar O-, S-, and N-glycosides as conformational mimics of α-linked disaccharides; implications for glycosidase inhibition. Chemistry - A European Journal, 18 (27). pp. 8527-8539. ISSN 0947-6539

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The synthesis of mimics of the a(1?6)- and a(1?4)-linked disaccharides isomaltose and maltose featuring a bicyclic sp(2)-iminosugar nonreducing moiety O-, S-, or N-linked to a glucopyranoside residue is reported. The strong generalized anomeric effect operating in sp(2)-iminosugars determines the a-stereochemical outcome of the glycosylation reactions, independent of the presence or not of participating protecting groups and of the nature of the heteroatom. It also imparts chemical stability to the resulting aminoacetal, aminothioacetal, or gem-diamine functionalities. All the three isomaltose mimics behave as potent and very selective inhibitors of isomaltase and maltase, two a-glucosidases that bind the parent disaccharides either as substrate or inhibitor. In contrast, large differences in the inhibitory properties were observed among the maltose mimics, with the O-linked derivative being a more potent inhibitor than the N-linked analogue; the S-linked pseudodisaccharide did not inhibit either of the two target enzymes. A comparative conformational analysis based on NMR and molecular modelling revealed remarkable differences in the flexibility about the glycosidic linkage as a function of the nature of the linking atom in this series. Thus, the N-pseudodisaccharide is more rigid than the O-linked derivative, which exhibits conformational properties very similar to those of the natural maltose. The analogous pseudothiomaltoside is much more flexible than the N- or O-linked derivatives, and can access a broader area of the conformational space, which probably implies a strong entropic penalty upon binding to the enzymes. Together, the present results illustrate the importance of taking conformational aspects into consideration in the design of functional oligosaccharide mimetics.

Item Type: Article
Additional Information: Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
Faculty \ School: Faculty of Science > School of Pharmacy
UEA Research Groups: Faculty of Science > Research Groups > Drug Delivery and Pharmaceutical Materials (former - to 2017)
Faculty of Science > Research Groups > Pharmaceutical Materials and Soft Matter
Depositing User: Pure Connector
Date Deposited: 21 Oct 2013 15:46
Last Modified: 24 Oct 2022 04:49
URI: https://ueaeprints.uea.ac.uk/id/eprint/43775
DOI: 10.1002/chem.201200279

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