Journal
CHEMISTRY-A EUROPEAN JOURNAL
Volume 23, Issue 58, Pages 14585-14596Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/chem.201703011
Keywords
enzymes; iminosugars; inhibitors; multivalency; pyrrolidine
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Funding
- Italian Ministry of Health/Regione Toscana [RF-2011-02347694]
- MIUR-Italy (PRIN) [2010L9SH3K 006]
- Ente Cassa di Risparmio di Firenze [2014/0303]
- Accademia dei Lincei/Fondazione Donegani
- MINECO (Spain) [CTQ2015-64597-C2-1-P, CTQ2012-31247, CTQ2016-77270-R]
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Novel pyrrolidine-based multivalent iminosugars, synthesized by a CuAAC approach, have shown remarkable multivalent effects towards jack bean alpha-mannosidase and a Golgi alpha-mannosidase from Drosophila melanogaster, as well as a good selectivity with respect to a lysosomal alpha-mannosidase, which is important for anticancer applications. STD NMR and molecular modeling studies supported a multivalent mechanism with specific interactions of the bioactive iminosugars with Jack bean alpha-mannosidase. TEM studies suggested a binding mode that involves the formation of aggregates, which result from the intermolecular cross-linked network of interactions between the multivalent inhibitors and two or more dimers of JBMan heterodimeric subunits.
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