Total Syntheses of Casuarine and Its 6-O-alpha-Glucoside: Complementary Inhibition towards Glycoside Hydrolases of the GH31 and GH37 Families

Year: 2009

Authors: Cardona F., Parmeggiani C., Faggi E., Bonaccini C., Gratteri P., Sim L., Gloster T. M., Roberts S., Davies G. J., Rose D. R., Goti A.

Autors Affiliation: Department of Organic Chemistry “U. Schiff” Laboratory of Design, Synthesis and Study of Biologically Active Heterocycles (HeteroBioLab)University of Florence, Via della Lastruccia, 13 50019 Sesto Fiorentino (FI) Italy;
Laboratory of Molecular Modeling Cheminformatics & QSAR, Department of Pharmaceutical Sciences Laboratory of Design, Synthesis and Study of Biologically Active Heterocycles (HeteroBioLab) University of Florence, Via U. Schiff 6
50019 Sesto Fiorentino (FI) Italy;
Ontario Cancer Institute and Department of Medical Biophysics University of Toronto, 101 College St., Toronto M5G 1L7 Canada;
York Structural Biology Laboratory, Department of Chemistry University of York, Heslington, York, YO10 5YW (UK)

Abstract: Total synthesis of naturally occurring casuarine (1) and the first total synthesis of casuarine 6-O-alpha-glucoside (2) were achieved through complete stereoselective nitrone cycloaddition, Tamao-Fleming oxidation and selective alpha-glucosylation as key steps. Biological assays of the two compounds proved their strong and selective inhibitory properties towards glucoamylase NtMGAM and trehalase Tre37A, respectively, which place them among the most powerful inhibitors of these enzymes. The structural determination of the complexes of NtMGAM with 1 and of Tre37A with 2 revealed interesting similarities in the catalytic sites of these two enzymes which belong to different families and clans.

Journal/Review: CHEMISTRY-A EUROPEAN JOURNAL

Volume: 15 (7)      Pages from: 1627  to: 1636

More Information: We thank MiUR and Ente Cassa di Rispartruo di Firenze, Italy, for financial support. Ente CRF is also acknowledged for granting a 400 MHz NMR spectrometer. Brunella Innocenti and Maurizio Passaponti (Dipartimento di Chimica Organica \”U. Schiff\”) are acknowledged for technical assistance. CINMPIS is gratefully acknowledged for a grant to C.P. L.S. holds a scholarship from NSERC Canada and D.R.R. grants from CIHR (MOP79400) and Heart and Stroke Canada (NA-6305). The York laboratory would like to thank the BBSRC for funding. G.J.D. is a recipient of a Royal Society/Wolfson Research Merit award. T.M.G. is a Sir Henry Wellcome postdoctoral fellow. The Cornell High Energy Synchrotron Source (CHESS), is supported by the National Science Foundation under award DMR-0225180, and the Macromolecular Diffraction at CHESS (MacCHESS) facility, by award RR-01646 from the National Institutes of Health, through its National Center for Research Resources.
DOI: 10.1002/chem.200801578

Citations: 86
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