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Stereoselective synthesis of 2-acetamido-1,2-dideoxynojirimycin (DNJNAc) and ureido-DNJNAc derivatives as new hexosaminidase inhibitors

 

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Opened Access Stereoselective synthesis of 2-acetamido-1,2-dideoxynojirimycin (DNJNAc) and ureido-DNJNAc derivatives as new hexosaminidase inhibitors
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Author: Fuente, Alex de la
Mena Barragán, Teresa
Farrar-Tobar, Ronald A.
Verdaguer, Xavier
García Fernández, José Manuel
Ortiz Mellet, Carmen
Riera, Antoni
Department: Universidad de Sevilla. Departamento de Química orgánica
Date: 2015
Published in: Organic and Biomolecular Chemistry, 13, 6500-6510.
Document type: Article
Abstract: 2-Acetamido-1,2-dideoxyiminosugars are selective and potent inhibitors of hexosaminidases and therefore show high therapeutic potential for the treatment of various diseases, including several lysosomal storage disorders. A stereoselective synthesis of 2-acetamido-1,2-dideoxynojirimycin (DNJNAc), the iminosugar analog of N-acetylglucosamine, with a high overall yield is here described. This novel procedure further allowed accessing ureido-DNJNAc conjugates through derivatization of the endocyclic amine on a key pivotal intermediate. Remarkably, some of the ureido-DNJNAc representatives behaved as potent and selective inhibitors of β-hexosaminidases, including the human enzyme, being the first examples of neutral sp2-iminosugar-type inhibitors reported for these enzymes. Moreover, the amphiphilic character of the new ureido-DNJNAc is expected to confer better drug-like properties.
Cite: Fuente, A.d.l., Mena Barragán, T., Farrar-Tobar, R.A., Verdaguer, X., García Fernández, J.M., Ortiz Mellet, C. y Riera, A. (2015). Stereoselective synthesis of 2-acetamido-1,2-dideoxynojirimycin (DNJNAc) and ureido-DNJNAc derivatives as new hexosaminidase inhibitors. Organic and Biomolecular Chemistry, 13, 6500-6510.
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URI: http://hdl.handle.net/11441/64349

DOI: 10.1039/C5OB00507H

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