Hydrothermal preparation of highly photoactive TiO2 nanoparticles

TiO2 nanoparticles have been prepared by amine assisted sol–gel precipitation of Ti4+ aqueous solutions and further hydrothermal treatment. The effect of different starting acidic solution (nitric, chlorhydric and acetic acids) as well as the addition of triethylamine (TEA) at different pH has been widely investigated. It has been stated that different amounts of TEA could have interesting effects upon hydrothermal treatment. Surface and morphological features significantly differ from TiO2 prepared using different synthetic route. In all cases, amine precipitated TiO2 obtained exhibit high conversion values for phenol photo-oxidation reaction, being in certain conditions higher than that exhibited by TiO2 Degussa P25. The precipitation of the acetic acidified solution leads to high surface area values and well crystallized anatase with small crystallite size. In addition, this set of catalysts show the cleanest surface after the hydrothermal treatment. The conjunction of these features would be the characteristic features responsible of the best photocatalytic activity observed

Compuestos potenciadores de la actividad de glicosidasas mutantes

[EN] Compounds promoting the activity of mutant glycosidases having inhibitory activity for glycosidase enzymes, furthermore relating to a procedure for activation of mutant β-glycosidase (β-glucocerebrosidase) and mutant β-galactosidase in patients suffering lysosomal storage disorders through administration of said enzyme competitor inhibitor compounds, characterised by very high bonding specificity and a favourable ratio between the concentration thereof for pharmacological chaperone activity and the concentration thereof for inhibitor activity.[ES] Compuestos potenciadores de la actividad de glicosidasas mutantes, con actividad inhibidoras de enzimas glicosidasas y también se refiere a un procedimiento para la activación de ss-glucosidasa mutante (ss- glucocerebrosidasa) y ss-galactosidasa mutante en pacientes que padecen trastornos de almacenamiento lisosómico mediante la administración de dichos compuestos inhibidores competitivos de las enzimas, caracterizados por una especificidad de unión muy alta y una relación favorable entre su concentración para actividad de chaperona farmacológica y su concentración para actividad inhibidora.Peer reviewedConsejo Superior de Investigaciones Científicas (España), Universidad Complutense de Sevilla, International University of Health and Welfare, Tottori UniversityA1 Solicitud de patentes con informe sobre el estado de la técnic

Cyclodextrin-mediated Crystallization of Acid β-glucosidase in Complex with Amphiphilic Bicyclic Nojirimycin Analogues

Cyclodextrin-based host-guest chemistry has been exploited to facilitate co-crystallization of recombinant human acid β-glucosidase (β-glucocerebrosidase, GlcCerase) with amphiphilic bicyclic nojirimycin analogues of the sp2-iminosugar type. Attempts to co-crystallize GlcCerase with 5-N,6-O-[N′-(n-octyl)iminomethylidene]nojirimycin (NOI-NJ) or with 5-N,6-S-[N′-(n-octyl)iminomethylidene]-6-thionojirimycin (6S-NOI-NJ), two potent inhibitors of the enzyme with promising pharmacological chaperone activity for several Gaucher disease-associated mutations, were unsuccessful probably due to the formation of aggregates that increase the heterogeneity of the sample and affect nucleation and growth of crystals. Cyclomaltoheptaose (β-cyclodextrin, βCD) efficiently captures NOI-NJ and 6S-NOI-NJ in aqueous media to form inclusion complexes in which the lipophilic tail is accommodated in the hydrophobic cavity of the cyclooligosaccharide. The dissociation constant of the complex of the amphiphilic sp2-iminosugars with βCD is two orders of magnitude higher than that of the corresponding complex with GlcCerase, allowing the efficient transfer of the inhibitor from the βCD cavity to the GlcCerase active site. Enzyme-inhibitor complexes suitable for X-ray analysis were thus grown in the presence of βCD. In contrast to what was previously observed for the complex of GlcCerase with the more basic derivative, 6-amino-6-deoxy-5-N,6-N-[N′-(n-octyl)iminomethylidene]nojirimycin (6N-NOI-NJ), the β-anomers of both NOI-NJ and 6S-NOI-NJ were seen in the active site, even though the α-anomer was exclusively detected both in aqueous solution and in the corresponding βCD:sp2-iminosugar complexes. Our results further suggest that cyclodextrin derivatives might serve as suitable delivery systems of amphiphilic glycosidase inhibitors in a biomedical context.Ministerio de Ciencia e Innovación CTQ2007-61180/PPQ, SAF2010-15670, CTQ2010-15848Junta de Andalucía P08-FQM-03711Fondo Europeo de Desarrollo Regional 03122, ISSG-CT-2007-03719

A Bicyclic 1-Deoxygalactonojirimycin Derivative as a Novel Pharmacological Chaperone for GM1 Gangliosidosis

Lysosomal β-galactosidase (β-Gal) deficiency causes a group of disorders that include neuronopathic GM1 gangliosidosis and non-neuronopathic Morquio B disease. We have previously proposed the use of small molecule ligands of β-Gal as pharmacological chaperones (PCs) for the treatment of GM1 gangliosidosis brain pathology. Although it is still under development, PC therapy has yielded promising preclinical results in several lysosomal diseases. In this study, we evaluated the effect of bicyclic 1-deoxygalactonojirimycin (DGJ) derivative of the sp2-iminosugar type, namely 5N,6S-(N′-butyliminomethylidene)-6-thio-1- deoxygalactonojirimycin (6S-NBI-DGJ), as a novel PC for human mutant β-Gal. In vitro, 6S-NBI-DGJ had the ability to inhibit the activity of human β-Gal in a competitive manner and was able to protect this enzyme from heat-induced degradation. Computational analysis supported that the rigid glycone bicyclic core of 6S-NBI-DGJ binds to the active site of the enzyme, with the aglycone N′-butyl substituent, in a precise E-orientation, located at a hydrophobic region nearby. Chaperone potential profiling indicated significant increases of enzyme activity in 24 of 88 β-Gal mutants, including four common mutations. Finally, oral administration of 6S-NBI-DGJ ameliorated the brain pathology of GM1 gangliosidosis model mice. These results suggest that 6S-NBI-DGJ is a novel PC that may be effective on a broad range of β-Gal mutants.Ministerio de Ciencia e Innovación de España. SAF2010-15670 y CTQ2010-15848Junta de Andalucía. P08-FQM-0371

Compuestos potenciadores de la actividad de glicosidasas mutantes

Compuestos potenciadores de la actividad de glicosidasas mutantes, con actividad inhibidoras de enzimas glicosidasas y también se refiere a un procedimiento para la activación de -glucosidasa mutante ( -glucocerebrosidasa) y -galactosidasa mutante en pacientes que padecen trastornos de almacenamiento lisosómico mediante la administración de dichos compuestos inhibidores competitivos de las enzimas, caracterizados por una especificidad de unión muy alta y una relación favorable entre su concentración para actividad de chaperona farmacológica y su concentración para actividad inhibidora.Peer reviewedPeer reviewedConsejo Superior de Investigaciones Científicas (España), Universidad de Sevilla, International University of Health and Welfare, Tottori UniversityA1 Solicitud de patentes con informe sobre el estado de la técnic

Synthesis of Thiohydantoin-Castanospermine Glycomimetics as Glycosidase Inhibitors

4 páginas, 2 figuras, 1 tabla, 2 esquemas.The preparation of bicyclic carbohydrate mimics related to (+)-castanospermine incorporating a thiohydantoin moiety is reported. The synthetic approach is compatible with molecular diversity-oriented strategies and involves alpha-azidoesters, built at the C-5/C-6 segment in gluco- or galactofuranose scaffolds, as the key precursors. Reduction to the corresponding alpha-amino ester and in situ coupling with isothiocyanates afford thioureidoester intermediates that undergo spontaneous cyclization to the corresponding hydantoins, beta-elimination, and furanose --> indolizidine rearrangement in a tandem manner. Biological evaluation of the new sp(2)-iminosugar-type glycomimetics evidenced a strong influence of the nature of the substituents at the nitrogen or oxygen atoms on the glycosidase inhibitory properties.We thank the Spanish Ministerio de Educación y Ciencia (contract numbers CTQ2007-61180/PPQ and CTQ2006-15515-C02-01/BQU) and the Junta de Andalucía for financial support.Peer reviewe

Intramolecular Benzyl Protection Delivery: A Practical Synthesis of DMDP and DGDP from d-Fructose

3 páginas, 4 esquemas.A two-step protection of 1,2-diols as the corresponding o-xylylene cyclic ethers, involving an intramolecular ring-closing O-benzylation reaction, has been developed to overcome the problems associated to regioselective benzylation reactions. The strategy has been applied to the high-yielding synthesis of the pyrrolidine glycosidase inhibitors DMDP and DGDP.We thank the Spanish Ministerio de Educación y Ciencia for financial support (contracts number BQU2003-00937 and CTQ2004-05854/BQU).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

Synthesis and Biological Evaluation of Guanidine-Type Iminosugars

4 páginas, 1 tabla, 5 esquemas.The preparation of carbohydrate mimics in which the endocyclic oxygen has been replaced by a guanidine-type nitrogen atom is reported. The synthetic strategy involves the furanose --> piperidine rearrangement of 5-deoxy-5-guanidino-L-idose precursors. The reaction proceeds through elimination of water to give 3-oxopiperidines, which were isolated as the corresponding hydrates. Biological evaluation of the new glycomimetics evidenced a strong influence of the nature of the substituents at the nitrogen atoms on the glycosidase inhibitory properties.We thank the Spanish Ministerio de Educación y Ciencia (contract nos. CTQ2007-61180/PPQ and CTQ2006-15515-C02-01/BQU) and the Junta de Andalucía for financial support.Peer reviewe