Scientific Results

Synthesis and glycosidase inhibition studies of 5-methyl-substituted tetrahydroxyindolizidines and -pyrrolizidines related to natural hyacinthacines B

Year: 2013

Authors: Martella D., Cardona F., Parmeggiani C., Franco F., Tamayo J.A., Robina I., Moreno-Clavijo E., Moreno-Vargas A.J., Goti A.

Autors Affiliation: Dipartimento di Chimica Ugo Schiff, Università di Firenze, Polo Scientifico e Tecnologico, Via della Lastruccia 3-13, 50019 Sesto Fiorentino (FI), Italy;
Departamento de Química Farmacéutica y Orgánica, Facultad de Farmacia, Campus de la Cartuja S/n., 18071 Granada, Spain;
CNR-INO and European Laboratory for Non-Linear Spectroscopy (LENS), University of Florence, Via N. Carrara 1, Sesto Fiorentino (FI), Italy;
Departamento de Química Orgánica, Facultad de Química, Universidad de Sevilla, c/ Prof. García González 1, 41012, Sevilla, Spain

Abstract: The synthesis of three tetrahydroxyindolizidines and one tetrahydroxypyrrolizidine related to natural hyacinthacines B and their biological evaluation as glycosidase inhibitors is reported. The target molecules were obtained through highly stereoselective cycloadditions between sugriched allylic and homoallylic alcohols. This allowed the installation of a methyl group at C5 – a common feature of many natural hyacinthacines – with high control over the stereoselectivity. The new compounds inhibit amyloglucosidase from Aspergillus niger and β-glucosidase from almonds. Compound 1 is a competitive inhibitor of amyloglucosidase and shows a fair selectivity towards this enzyme. The presence of C5-Me substitution in indolizidines 2 and 3 slightly diminishes the inhibitory activity towards amyloglucosidase whereas it improves the inhibitory properties towards β-glucosidase. Cycloaddition between a carbohydrate-derived nitrone and suitable chemoenzymatically prepared enantioenriched allylic and homoallylic alcohols allowed the straightforward synthesis of three tetrahydroxyindolizidines and one tetrahydroxypyrrolizidine related to natural hyacinthacines B. They inhibit amyloglucosidase from Aspergillus niger and β-glucosidase from almonds.

Journal/Review: EUROPEAN JOURNAL OF ORGANIC CHEMISTRY

Volume: (19)      Pages from: 4047  to: 4056

KeyWords: Alkaloids; Azasugars; Cycloaddition; Enzyme catalysis; Inhibitors
DOI: 10.1002/ejoc.201300103

Citations: 23
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English