Adamantane substituted aminocyclitols as pharmacological chaperones for Gaucher disease

Gaucher disease (GD), resulting from deficient lysosomal enzyme β-glucosidase (GCase) activity, is the most common lysosomal storage disorder. We have previously shown that aminocyclitol derivatives displayed selective inhibition of GCase and enhanced GCase activity in N370S and L444P at very low concentrations. In the present study, we combined amino-myo-inositol and amino-scyllo-inositol cores with a hydrophobic alkyl adamantyl amide to afford novel small molecules with enhanced ability to increase GCase activity in GD lymphoblasts. The most potent inhibitor, amino-myo-inositol 2, displayed a Ki value of 250 nM in isolated enzyme. This compound produced a maximum increase of GCase activity of 64% in N370S lymphoblasts at 1 μM and 150% in L444P at 100 μM following a 3 day incubation. © 2013 The Royal Society of Chemistry.Peer Reviewe

Ciclohexano hexasubstituido activador de la enzima beta-glucosidasa, procedimiento de síntesis, composición farmacéutica que lo contiene y sus aplicaciones

Fecha de presentación nacional 18.02.2005.-- Tirulares. Consejo Superior de Investigaciones Científicas (CSIC), Universitat de Barcelona.Un objeto de la invención lo constituye un compuesto modulador de la enzima beta-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

An unexpected access to 5-epi-cyclophellitol: a new cyclitol member

4 pages, 2 schemes.A thorough reinvestigation of the hydroboration–oxidation of methylene epoxycyclohexane 3 has revealed the formation of a direct precursor of the hitherto unreported 5-epi-cyclophellitol. Hydroboration of the starting precursor 3 takes place with total and opposite stereocontrol to that previously described in the literature. The stereochemistry of this new cyclophellitol isomer has been unambiguously confirmed by comparison with reference compounds obtained by independent methods.Financial support from the Ministerio de Ciencia y Tecnología, Spain (Project CTQ2005-00175/BQU), the Ministerio de Sanidad y Consumo (Spain) (Project PIO40767), Fondos Feder (EU), Generalitat de Catalunya (2005SGR01063), and CSIC is acknowledged. P.S. and M.E.-G. acknowledge the Ministerio de Educación y Ciencia (Spain) and CSIC, respectively, for pre-doctoral fellowships.Peer reviewe

Lipid and ganglioside alterations in tumor cells treated with antimitotic oleyl glycoside

Oleyl 2-acetamido-2-deoxy-α-D-glucopyranoside (1) was previously shown to exhibit antimitotic activity on glioma (C6) and melanoma (A375) cell lines. Preliminary studies about its mechanism of action using 1H MAS NMR suggested that 1 may be altering the metabolism of lipids. We have now studied the effect of 1 on the fatty acid, sphingolipid and ganglioside content in a line of carcinomic human alveolar epithelial cells (A549) using UPLC-MS. Oleic acid and NB-DNJ were used as positive controls for inhibition of fatty acid and ganglioside synthesis, respectively. Compound 1 (10 μM) was more efficient than oleic acid in reducing fatty acid levels of A549 cells, producing a decrease in the range of 40–15%, depending on the acyl chain length and the number of insaturations. In addition, glycoside 1 caused a reduction on ganglioside content of A549 tumor cell line and accumulation of lactosylceramide, the common metabolic precursor for ganglioside biosynthesis. Alteration of ganglioside metabolism was also observed with two galactosylated derivatives of 1, which caused a more pronounced increase in lactosylceramide levels. Compound 1 at higher concentrations (above 30 μM) produced drastic alterations in glycosphingolipid metabolism, leading to cell metabolic profiles very different from those obtained at 10 μM. These biochemical changes were ascribed to activation of endoplasmic reticulum stress pathways.The financial support provided by the Servicio de Salud de Castilla La Mancha Community (SESCAM), FISCAM (PI-2008/18 and PI-2008/19), and the Ministry of Ciencia e Innovación (CTQ2007-67403/BQU and SAF2008-00706) is greatly appreciated. We thank Dr Gemma Fabriàs for her encouragement and insightful suggestions and Mrs Eva Dalmau for excellent technical assistance.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

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

Derivados de aminociclitoles, procedimiento de obtención y usos

[ES] La presente invención se refiere a los compuestos de fórmula general (I) y a sus usos como composiciones farmacéuticas para el tratamiento de enfermedades relacionadas con la acumulación lisosomal de esfingolípidos, tales como la enfermedad de Gaucher, la enfermedad de Tay-Sachs, la enfermedad de Sandhoff, la enfermedad de Fabry, la enfermedad de Niemann- Pick, leucodistrofia metacromática y la enfermedad de Krabbe. Además, la invención se refiere al procedimiento de obtención de dichos compuestos. Por tanto, la invención se puede englobar en el campo químico y/o farmacéutico.[EN] The present invention relates to compounds of general formula (I) and to the uses thereof as pharmaceutical compositions for the treatment of diseases related with lysosomal accumulation of sphingolipids, such as Gaucher disease, TaySachs disease, Sandhoff disease, Fabry disease, Niemann-Pick disease, metachromatic leucodistrophy and Krabbe disease. Furthermore, the invention relates to the procedure for the obtainment of said compounds. Consequently, the invention may be included within the chemical and/or pharmaceutical field.Peer reviewedConsejo Superior de Investigaciónes Científicas (España), Universidad de BarcelonaA1 Solicitud de patente con informe sobre el estado de la técnic