Synthesis, biological evaluation and docking studies of casuarine analogues: effects of structural modifications at ring B on inhibitory activity towards glucoamylase

Year: 2010

Authors: Bonaccini C., Chioccioli M., Parmeggiani C., Cardona F., Lo Re D., Soldaini G., Vogel P., Bello C., Goti A., Gratteri P.

Autors Affiliation: 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 Ugo Schiff 6, 50019 Sesto Fiorentino, Firenze, Italy; Department of Chemistry “Ugo Schiff ”, Laboratory of Design, Synthesis and Study of Biologically Active Heterocycles (HeteroBioLab), University of Florence, Via della Lastruccia 3-13, 50019 Sesto Fiorentino, Firenze, Italy; Laboratory of Glycochemistry and Asymmetric Synthesis(LGSA), Swiss Institute of Technology (EPFL), Batochime, 1015 Lausanne, Switzerland

Abstract: We report the total synthesis of a series of pyrrolizidine analogues of casuarine (1) and their 6-O-alpha-glucoside derivatives. The synthetic strategy is based on a totally regio- and stereoselective 1,3-dipolar cycloaddition of suitably substituted alkenes and a carbohydrate-based nitrone. We also report the evaluation of the biological activity of casuarine and its derivatives towards a wide range of glycosidases and a molecular modeling study focused on glucoamylase (GA) in which the binding modes of the newly synthesized compounds within the enzyme cavity are investigated. The results highlight the prominent structural features of casuarine and its derivatives that make them selective glucoamylase inhibitors.

Journal/Review: EUROPEAN JOURNAL OF ORGANIC CHEMISTRY

Volume: 29      Pages from: 5574  to: 5585

More Information: We thank the Minister dell\’Istruzione , dell\’Universita e della Ricerca (PRIN 2007 and 2008) and the Ente Cassa di Risparmio di Firenze, Italy, for financial support. Ente Cassa di Risparmio di Firenze. Italy, is also gratefully acknowledged for a et-ant to C. B. and for granting a 400 MHz NMR spectrometer. B. Innocenti and M. Passaponti (Dipartimento di Chimica \”Ugo Schiff\”) arc acknowledged for technical assistance. Consorzio Interuniversitario Nazionale \”Metodologie e Processi Innovativi di Sintesi\” is gratefully acknowledged for a grant to C. P. We also thank the Swiss National Science Foundation for financial support and Dr. L. Menin and Dr. A. Razaname for the HRMS measurements.
KeyWords: azasugars; enzymes; inhibitors; molecular modeling; biological activity
DOI: 10.1002/ejoc.201000632

Citations: 50
data from “WEB OF SCIENCE” (of Thomson Reuters) are update at: 2024-11-17
References taken from IsiWeb of Knowledge: (subscribers only)
Connecting to view paper tab on IsiWeb: Click here
Connecting to view citations from IsiWeb: Click here