Bicyclic (galacto)nojirimycin analogues as glycosidase inhibitors: Effect of structural modifications in their pharmacological chaperone potential towards β-glucocerebrosidase

A molecular-diversity-oriented approach for the preparation of bicyclic sp2-iminosugar glycomimetics related to nojirimycin and galactonojirimycin is reported. The synthetic strategy takes advantage of the ability of endocyclic pseudoamide-type atoms in five-membered cyclic iso(thio)ureas and guanidines to undergo intramolecular nucleophilic addition to the masked carbonyl group of monosaccharides. The stereochemistry of the resulting hemiaminal stereocenter is governed by the anomeric effect, with a large preference for the axial (pseudo-α) orientation. A library of compounds differing in the stereochemistry at the position equivalent to C-4 in monosaccharides (D-gluco and D-galacto), the heterocyclic core (cyclic isourea, isothiourea or guanidine) and the nature of the exocyclic nitrogen substituent (apolar, polar, linear or branched) has been thus prepared and the glycosidase inhibitory activity evaluated against commercial glycosidases. Compounds bearing lipophilic substituents behaved as potent and very selective inhibitors of β-glucosidases. They further proved to be good competitive inhibitors of the recombinant human β-glucocerebrosidase (imiglucerase) used in enzyme replacement therapy (ERT) for Gaucher disease. The potential of these compounds as pharmacological chaperones was assessed by measuring their ability to inhibit thermal-induced denaturation of the enzyme in comparison with N-nonyl-1-deoxynojirimycin (NNDNJ). The results indicated that amphiphilic sp2-iminosugars within this series are more efficient than NNDNJ at stabilizing β-glucocerebrosidase and have a strong potential in pharmacological chaperone (PC) and ERT-PC combined therapies.The Spanish Ministerio de Ciencia e Innovaci ´on (contract numbers CTQ2006-15515-CO2-01, CTQ2009-14551-C02-01, CTQ- 2010-15848, CTQ2008-01426/BQU and SAF2010-15670;cofinanced with the Fondo Europeo de Desarrollo Regional FEDER), the Fundaci´on Ram´on Areces, and the Junta de Andaluc´ıa (P08-FQM-03711) are thanked for funding. Imiglucerase was generously supplied by Genzyme Corporation.Peer reviewe

Procedimiento para la extraccción de los lípidos internos de la lana confluidos supercríticos

Fecha de presentación nacional18.02.2005.-- Titular: Consejo Superior de Investigaciones Científicas (CSIC).Un objeto de la invención lo constituye un compuesto modulador de la enzima {be}-glucosidasa, preferentemente activador, caracterizado porque es un ciclohexano hexasubstituido de fórmula general I. Este compuesto activador puede ser utilizado para la fabricación de composiciones farmacéuticas útiles para el tratamiento de la enfermedad de Gaucher y el cáncer. La ventaja de este compuesto es su alta especificidad por la enzima responsable de la enfermedad de Gaucher, y la posibilidad de administrarlo conjuntamente con la enzima beta-glucosidasa recombinante sustitutiva con el consiguiente gran ahorro económico.Peer reviewe

Spot promoció de la Biblioteca - 2020

Spot promocional de la Biblioteca de la Universitat de Girona adreçat als estudiants que té com a objectiu difondre d'una manera amena i atractiva els serveis que la biblioteca oferei