19 results on '"Mena-Barragán T"'
Search Results
2. Synthesis of new fluorinated analogues from monohydroxyl-piperidines
- Author
-
Le Guen, Clothilde, Mena Barragán, T, Mellet, Carmen Ortiz, Goekjian, P.G., David, Gueyrard, Pfund, Emmanuel, Lequeux, Thierry, Laboratoire de chimie moléculaire et thioorganique (LCMT), Centre National de la Recherche Scientifique (CNRS)-Institut Normand de Chimie Moléculaire Médicinale et Macromoléculaire (INC3M), Institut de Chimie du CNRS (INC)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Normandie Université (NU)-Normandie Université (NU)-Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Université Le Havre Normandie (ULH), Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Institut de Chimie du CNRS (INC)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Normandie Université (NU), Universidad de Sevilla, Facultad de Química, Universidad de Sevilla, Chimie Organique 2-Glycochimie (CO2GLYCO), Institut de Chimie et Biochimie Moléculaires et Supramoléculaires (ICBMS), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-École Supérieure Chimie Physique Électronique de Lyon-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-École Supérieure Chimie Physique Électronique de Lyon-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), and Pfund, Emmanuel
- Subjects
[CHIM.ORGA]Chemical Sciences/Organic chemistry ,[CHIM.ORGA] Chemical Sciences/Organic chemistry ,ComputingMilieux_MISCELLANEOUS - Abstract
International audience
- Published
- 2015
3. Tuning glycosidase inhibition through aglycone interactions: pharmacological chaperones for Fabry disease and GM1 gangliosidosis
- Author
-
Aguilar-Moncayo, M., primary, Takai, T., additional, Higaki, K., additional, Mena-Barragán, T., additional, Hirano, Y., additional, Yura, K., additional, Li, L., additional, Yu, Y., additional, Ninomiya, H., additional, García-Moreno, M. I., additional, Ishii, S., additional, Sakakibara, Y., additional, Ohno, K., additional, Nanba, E., additional, Ortiz Mellet, C., additional, García Fernández, J. M., additional, and Suzuki, Y., additional
- Published
- 2012
- Full Text
- View/download PDF
4. PDA-Based Glyconanomicelles for Hepatocellular Carcinoma Cells Active Targeting Via Mannose and Asialoglycoprotein Receptors.
- Author
-
Negrete M, Romero-Ben E, Gutiérrez-Valencia A, Rosales-Barrios C, Alés E, Mena-Barragán T, Flores JA, Castillejos MC, de la Cruz-Ojeda P, Navarro-Villarán E, Cepeda-Franco C, Khiar N, and Muntané J
- Subjects
- Antineoplastic Agents chemistry, Apoptosis drug effects, Asialoglycoprotein Receptor metabolism, Carcinoma, Hepatocellular metabolism, Cell Proliferation drug effects, Endosomes metabolism, Galactose chemistry, Hep G2 Cells, Humans, Liver Neoplasms metabolism, Mannose chemistry, Mannose Receptor metabolism, Micelles, Nanoparticles chemistry, Polyacetylene Polymer chemistry, Sorafenib chemistry, Antineoplastic Agents administration & dosage, Carcinoma, Hepatocellular drug therapy, Galactose administration & dosage, Liver Neoplasms drug therapy, Mannose administration & dosage, Nanoparticles administration & dosage, Polyacetylene Polymer administration & dosage, Sorafenib administration & dosage
- Abstract
Hepatocellular carcinoma (HCC) is the sixth most common neoplasia and the fourth most common cause of cancer-related mortality worldwide. Sorafenib is the first-line molecular therapy for patients in an advanced stage of HCC. However, the recommended clinical dose of Sorafenib is associated with several complications, which derive from its lack of cell specificity and its very low water solubility. To circumvent these drawbacks, in the present study we developed two sugar-coated polydiacetylene-based nanomicelles-Sorafenib carriers targeting mannose and asialoglycoprotein receptors (MR and ASGPR, respectively). The strategies allowed the inducement of apoptosis and reduction of cell proliferation at a nanomolar, instead of micromolar, range in liver cancer cells. The study showed that, contrary to literature data, Sorafenib included into the pMicMan (Man = mannose) vector (targeting MR) is more efficient than pMicGal (Gal = galactose) (targeting ASGPR). Indeed, pMicMan increased the endosomal incorporation with an increased intracellular Sorafenib concentration that induced apoptosis and reduced cell proliferation at a low concentration range (10-20 nM).
- Published
- 2021
- Full Text
- View/download PDF
5. Unexpected loss of stereoselectivity in glycosylation reactions during the synthesis of chondroitin sulfate oligosaccharides.
- Author
-
Mena-Barragán T, de Paz JL, and Nieto PM
- Abstract
Here, we present an exploratory study on the fluorous-assisted synthesis of chondroitin sulfate (CS) oligosaccharides. Following this approach, a CS tetrasaccharide was prepared. However, in contrast to our previous results, a significant loss of β-selectivity was observed in [2 + 2] glycosylations involving N -trifluoroacetyl-protected D-galactosamine donors and D-glucuronic acid (GlcA) acceptors. These results, together with those obtained from experiments employing model monosaccharide building blocks, highlight the impact of the glycosyl acceptor structure on the stereoselectivity of glycosylation reactions. Our study provides useful data about the substitution pattern of GlcA units for the efficient synthesis of CS oligomers.
- Published
- 2019
- Full Text
- View/download PDF
6. Probing the Inhibitor versus Chaperone Properties of sp²-Iminosugars towards Human β-Glucocerebrosidase: A Picomolar Chaperone for Gaucher Disease.
- Author
-
Mena-Barragán T, García-Moreno MI, Sevšek A, Okazaki T, Nanba E, Higaki K, Martin NI, Pieters RJ, Fernández JMG, and Mellet CO
- Subjects
- 1-Deoxynojirimycin therapeutic use, Fibroblasts drug effects, Fibroblasts metabolism, Gaucher Disease genetics, Glucosamine analogs & derivatives, Glucosamine therapeutic use, Humans, Mutation, Enzyme Inhibitors therapeutic use, Gaucher Disease drug therapy, Gaucher Disease enzymology, Glucosylceramidase antagonists & inhibitors, Glucosylceramidase genetics, Imino Sugars therapeutic use, Molecular Chaperones therapeutic use
- Abstract
A series of sp²-iminosugar glycomimetics differing in the reducing or nonreducing character, the configurational pattern (d- gluco or l- ido ), the architecture of the glycone skeleton, and the nature of the nonglycone substituent has been synthesized and assayed for their inhibition properties towards commercial glycosidases. On the basis of their affinity and selectivity towards GH1 β-glucosidases, reducing and nonreducing bicyclic derivatives having a hydroxylation profile of structural complementarity with d-glucose and incorporating an N′ -octyl-isourea or -isothiourea segment were selected for further evaluation of their inhibitory/chaperoning potential against human glucocerebrosidase (GCase). The 1-deoxynojirimycin (DNJ)-related nonreducing conjugates behaved as stronger GCase inhibitors than the reducing counterparts and exhibited potent chaperoning capabilities in Gaucher fibroblasts hosting the neuronopathic G188S/G183W mutation, the isothiourea derivative being indeed one of the most efficient chaperone candidates reported up to date (70% activity enhancement at 20 pM). At their optimal concentration, the four selected compounds promoted mutant GCase activity enhancements over 3-fold; yet, the inhibitor/chaperoning balance became unfavorable at much lower concentration for nonreducing as compared to reducing derivatives.
- Published
- 2018
- Full Text
- View/download PDF
7. Inhibitor versus chaperone behaviour of d-fagomine, DAB and LAB sp(2)-iminosugar conjugates against glycosidases: A structure-activity relationship study in Gaucher fibroblasts.
- Author
-
Mena-Barragán T, García-Moreno MI, Nanba E, Higaki K, Concia AL, Clapés P, García Fernández JM, and Ortiz Mellet C
- Subjects
- Humans, Structure-Activity Relationship, Enzyme Inhibitors chemistry, Enzyme Inhibitors pharmacology, Fibroblasts drug effects, Gaucher Disease pathology, Glycoside Hydrolases antagonists & inhibitors, Imino Pyranoses chemistry, Imino Sugars chemistry
- Abstract
A library of sp(2)-iminosugar conjugates derived from the piperidine iminosugar d-fagomine and the enantiomeric pyrrolidine iminosugars DAB and LAB has been generated in only two steps involving direct coupling of the fully unprotected polyhydroxylated heterocycles with isothiocyanates, to give monocyclic thiourea adducts, and further intramolecular nucleophilic displacement of the δ-located primary hydroxyl group by the thiocarbonyl sulphur atom, affording bicyclic isothioureas. These transformations led to a dramatic shift in the inhibitory selectivity from α- to β-glucosidases, with inhibition potencies that depended strongly on the nature of the aglycone-type moiety in the conjugates. Some of the new derivatives behaved as potent inhibitors of human β-glucocerebrosidase (GCase), the lysosomal enzyme whose dysfunction is responsible for Gaucher disease. Moreover, GCase inhibition was 10-fold weaker at pH 5 as compared to pH 7, which is generally considered as a good property for pharmacological chaperones. Surprisingly, most of the compounds strongly inhibited GCase in wild type fibroblasts at rather low concentrations, showing an unfavourable chaperone/inhibitor balance on disease-associated GCase mutants in cellulo. A structure-activity relationship analysis points to the need for keeping a contiguous triol system in the glycone moiety of the conjugates to elicit a chaperone effect. In any case, the results reported here represent a proof of concept of the utmost importance of implementing diversity-oriented strategies for the identification and optimization of potent and specific glycosidase inhibitors and chaperones., (Copyright © 2015 Elsevier Masson SAS. All rights reserved.)
- Published
- 2016
- Full Text
- View/download PDF
8. pH-Responsive Pharmacological Chaperones for Rescuing Mutant Glycosidases.
- Author
-
Mena-Barragán T, Narita A, Matias D, Tiscornia G, Nanba E, Ohno K, Suzuki Y, Higaki K, Garcia Fernández JM, and Ortiz Mellet C
- Subjects
- Dose-Response Relationship, Drug, Enzyme Inhibitors chemistry, Enzyme Inhibitors pharmacology, Glycoside Hydrolases antagonists & inhibitors, Glycoside Hydrolases chemistry, Humans, Hydrogen-Ion Concentration, Ligands, Lysosomes enzymology, Lysosomes metabolism, Molecular Structure, Mutant Proteins antagonists & inhibitors, Mutant Proteins chemistry, Mutation, Protein Folding drug effects, Protein Transport drug effects, Small Molecule Libraries chemistry, Structure-Activity Relationship, Glycoside Hydrolases genetics, Glycoside Hydrolases metabolism, Mutant Proteins genetics, Mutant Proteins metabolism, Small Molecule Libraries pharmacology
- Abstract
A general approach is reported for the design of small-molecule competitive inhibitors of lysosomal glycosidases programmed to 1) promote correct folding of mutant enzymes at the endoplasmic reticulum, 2) facilitate trafficking, and 3) undergo dissociation and self-inactivation at the lysosome. The strategy is based on the incorporation of an orthoester segment into iminosugar conjugates to switch the nature of the aglycone moiety from hydrophobic to hydrophilic in the pH 7 to pH 5 window, which has a dramatic effect on the enzyme binding affinity. As a proof of concept, new highly pH-responsive glycomimetics targeting human glucocerebrosidase or α-galactosidase with strong potential as pharmacological chaperones for Gaucher or Fabry disease, respectively, were developed., (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)
- Published
- 2015
- Full Text
- View/download PDF
9. Stereoselective synthesis of 2-acetamido-1,2-dideoxynojirimycin (DNJNAc) and ureido-DNJNAc derivatives as new hexosaminidase inhibitors.
- Author
-
de la Fuente A, Mena-Barragán T, Farrar-Tobar RA, Verdaguer X, García Fernández JM, Ortiz Mellet C, and Riera A
- Subjects
- 1-Deoxynojirimycin chemical synthesis, 1-Deoxynojirimycin chemistry, 1-Deoxynojirimycin pharmacology, Acetamides chemical synthesis, Acetamides chemistry, Animals, Cattle, Chemistry Techniques, Synthetic, Drug Evaluation, Preclinical methods, Enzyme Inhibitors chemical synthesis, Humans, Molecular Structure, Stereoisomerism, Structure-Activity Relationship, beta-N-Acetylhexosaminidases isolation & purification, 1-Deoxynojirimycin analogs & derivatives, Enzyme Inhibitors chemistry, Enzyme Inhibitors pharmacology, beta-N-Acetylhexosaminidases antagonists & inhibitors
- 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 sp(2)-iminosugar-type inhibitors reported for these enzymes. Moreover, the amphiphilic character of the new ureido-DNJNAc is expected to confer better drug-like properties.
- Published
- 2015
- Full Text
- View/download PDF
10. Fluorinated hydroxypiperidines as selective β-glucosidase inhibitors.
- Author
-
Le Guen C, Mena-Barragán T, Ortiz Mellet C, Gueyrard D, Pfund E, and Lequeux T
- Subjects
- Drug Discovery, Halogenation, Humans, Structure-Activity Relationship, alpha-Glucosidases metabolism, beta-Glucosidase metabolism, Allylamine analogs & derivatives, Allylamine pharmacology, Glycoside Hydrolase Inhibitors chemistry, Glycoside Hydrolase Inhibitors pharmacology, beta-Glucosidase antagonists & inhibitors
- Abstract
A new series of fluoroallylamines derived from hydroxypiperidines was prepared and evaluated against various glycosidases. The short synthesis of target molecules involved the modified Julia reaction between aldehydes and functionalized fluoroaminosulfones. Biological studies revealed good and selective β-glucosidase inhibition in the micromolar range for two compounds, while the non-fluorinated analogue of the most active compound was selective towards α-glucosidase.
- Published
- 2015
- Full Text
- View/download PDF
11. Molecular basis of 1-deoxygalactonojirimycin arylthiourea binding to human α-galactosidase a: pharmacological chaperoning efficacy on Fabry disease mutants.
- Author
-
Yu Y, Mena-Barragán T, Higaki K, Johnson JL, Drury JE, Lieberman RL, Nakasone N, Ninomiya H, Tsukimura T, Sakuraba H, Suzuki Y, Nanba E, Mellet CO, García Fernández JM, and Ohno K
- Subjects
- 1-Deoxynojirimycin chemistry, 1-Deoxynojirimycin pharmacology, Animals, Autophagy drug effects, COS Cells, Chlorocebus aethiops, Crystallography, X-Ray, Enzyme Stability drug effects, Fabry Disease genetics, Fabry Disease pathology, Fibroblasts drug effects, Fibroblasts metabolism, Fibroblasts pathology, Humans, Molecular Docking Simulation, Mutation, Protein Transport drug effects, Trihexosylceramides metabolism, alpha-Galactosidase chemistry, alpha-Galactosidase genetics, 1-Deoxynojirimycin analogs & derivatives, Fabry Disease drug therapy, Fabry Disease enzymology, Thiourea analogs & derivatives, Thiourea pharmacology, alpha-Galactosidase metabolism
- Abstract
Fabry disease (FD) is an X-linked lysosomal storage disorder caused by mutations in the GLA gene often leading to missense α-galactosidase A (α-Gal A) variants that undergo premature endoplasmic reticulum-associated degradation due to folding defects. We have synthesized and characterized a new family of neutral amphiphilic pharmacological chaperones, namely 1-deoxygalactonojirimycin-arylthioureas (DGJ-ArTs), capable of stabilizing α-Gal A and restoring trafficking. Binding to the enzyme is reinforced by a strong hydrogen bond involving the aryl-N'H thiourea proton and the catalytic aspartic acid acid D231 of α-Gal A, as confirmed by a 2.55 Å resolution cocrystal structure. Selected candidates enhanced α-Gal A activity and ameliorate globotriaosylceramide (Gb3) accumulation and autophagy impairments in FD cell cultures. Moreover, they acted synergistically with the proteostasis regulator 4-phenylbutyric acid, appearing to be promising leads as pharmacological chaperones for FD.
- Published
- 2014
- Full Text
- View/download PDF
12. Structural basis of pharmacological chaperoning for human β-galactosidase.
- Author
-
Suzuki H, Ohto U, Higaki K, Mena-Barragán T, Aguilar-Moncayo M, Ortiz Mellet C, Nanba E, Garcia Fernandez JM, Suzuki Y, and Shimizu T
- Subjects
- 1-Deoxynojirimycin analogs & derivatives, 1-Deoxynojirimycin chemistry, 1-Deoxynojirimycin pharmacology, Catalytic Domain, Crystallography, X-Ray, Cyclohexenes chemistry, Cyclohexenes pharmacology, Enzyme Inhibitors chemistry, Enzyme Stability drug effects, Gangliosidosis, GM1 genetics, Hexosamines chemistry, Hexosamines pharmacology, Humans, Hydrogen Bonding, Hydrogen-Ion Concentration, Imino Sugars chemistry, Imino Sugars pharmacology, Inositol analogs & derivatives, Inositol chemistry, Inositol pharmacology, Kinetics, Models, Molecular, Molecular Structure, Mucopolysaccharidosis IV genetics, Mutation, Protein Structure, Tertiary, Static Electricity, Structure-Activity Relationship, beta-Galactosidase chemistry, beta-Galactosidase genetics, Enzyme Inhibitors pharmacology, Gangliosidosis, GM1 enzymology, Mucopolysaccharidosis IV enzymology, beta-Galactosidase antagonists & inhibitors
- Abstract
GM1 gangliosidosis and Morquio B disease are autosomal recessive diseases caused by the defect in the lysosomal β-galactosidase (β-Gal), frequently related to misfolding and subsequent endoplasmic reticulum-associated degradation. Pharmacological chaperone (PC) therapy is a newly developed molecular therapeutic approach by using small molecule ligands of the mutant enzyme that are able to promote the correct folding and prevent endoplasmic reticulum-associated degradation and promote trafficking to the lysosome. In this report, we describe the enzymological properties of purified recombinant human β-Gal(WT) and two representative mutations in GM1 gangliosidosis Japanese patients, β-Gal(R201C) and β-Gal(I51T). We have also evaluated the PC effect of two competitive inhibitors of β-Gal. Moreover, we provide a detailed atomic view of the recognition mechanism of these compounds in comparison with two structurally related analogues. All compounds bind to the active site of β-Gal with the sugar-mimicking moiety making hydrogen bonds to active site residues. Moreover, the binding affinity, the enzyme selectivity, and the PC potential are strongly affected by the mono- or bicyclic structure of the core as well as the orientation, nature, and length of the exocyclic substituent. These results provide understanding on the mechanism of action of β-Gal selective chaperoning by newly developed PC compounds., (© 2014 by The American Society for Biochemistry and Molecular Biology, Inc.)
- Published
- 2014
- Full Text
- View/download PDF
13. Iminosugar-based glycopolypeptides: glycosidase inhibition with bioinspired glycoprotein analogue micellar self-assemblies.
- Author
-
Bonduelle C, Huang J, Mena-Barragán T, Ortiz Mellet C, Decroocq C, Etamé E, Heise A, Compain P, and Lecommandoux S
- Subjects
- 1-Deoxynojirimycin analogs & derivatives, Drug Delivery Systems, Glycoproteins chemistry, Ligands, Micelles, 1-Deoxynojirimycin chemistry, Glycopeptides chemistry, Glycoside Hydrolases antagonists & inhibitors, Nanoparticles chemistry, Peptides chemistry
- Abstract
Biomimetic nanoparticles prepared by self-assembly of iminosugar-based glycopolypeptides evidenced remarkable multivalency properties when inhibiting α-mannosidase activity. This approach paves the way to obtain biologically active drug delivery systems having glycosidase inhibition potency.
- Published
- 2014
- Full Text
- View/download PDF
14. Synthesis of substituted exo-glucals via a modified Julia olefination and identification as selective β-glucosidase inhibitors.
- Author
-
Habib S, Larnaud F, Pfund E, Mena Barragán T, Lequeux T, Ortiz Mellet C, Goekjian PG, and Gueyrard D
- Subjects
- Dose-Response Relationship, Drug, Enzyme Inhibitors chemical synthesis, Enzyme Inhibitors chemistry, Glycosides, Molecular Structure, Monosaccharides chemical synthesis, Monosaccharides chemistry, Saccharomyces cerevisiae enzymology, Structure-Activity Relationship, beta-Glucosidase metabolism, Alkenes chemistry, Enzyme Inhibitors pharmacology, Monosaccharides pharmacology, beta-Glucosidase antagonists & inhibitors
- Abstract
A series of fluorine and non-fluorine-substituted C-glucosylidenes (exo-glucals) has been synthesized via a modified Julia olefination. The deprotected exo-glucals were prepared in five steps from commercially available d-gluconolactone. The evaluation of this original family of compounds against a panel of glycosidases showed a highly specific in vitro activity towards mammalian β-glucosidase depending on the double bond substituents.
- Published
- 2014
- Full Text
- View/download PDF
15. The multivalent effect in glycosidase inhibition: probing the influence of valency, peripheral ligand structure, and topology with cyclodextrin-based iminosugar click clusters.
- Author
-
Decroocq C, Joosten A, Sergent R, Mena Barragán T, Ortiz Mellet C, and Compain P
- Subjects
- Drug Design, Enzyme Inhibitors chemical synthesis, Enzyme Inhibitors chemistry, Enzyme Inhibitors metabolism, Enzyme Inhibitors pharmacology, Imino Sugars chemical synthesis, Imino Sugars metabolism, Ligands, Structure-Activity Relationship, Thermodynamics, Click Chemistry, Glycoside Hydrolases antagonists & inhibitors, Glycoside Hydrolases metabolism, Imino Sugars chemistry, Imino Sugars pharmacology, beta-Cyclodextrins chemistry
- Abstract
In view of recent reports of a strong multivalent effect in glycosidase inhibition, a library of β-CD-based multivalent iminosugars has been efficiently synthesized by way of Cu(I) -catalyzed azide-alkyne cycloaddition (CuAAC). In combination with the first application of isothermal titration calorimetry (ITC) experiments to the study of multivalent iminosugar-enzyme interactions, the inhibition properties of these click clusters were evaluated on a panel of glycosidases. The structural parameters that were varied include valency, peripheral ligand structure, and topology. The inhibition results obtained with the iminosugar clusters further highlight the importance of multivalency in the inhibition of α-mannosidase. Generally, the evaluated multivalent iminosugars displayed comparable thermodynamic signatures of binding towards α-mannosidase (Jack bean): that is, large negative enthalpies of complexation coupled with small entropies of either sign. In addition, the enthalpy-entropy compensation observed in all tested cases may be attributed to a common mechanism of dissociation for the enzyme-multivalent iminosugar interactions. The measured binding stoichiometries indicated that each iminosugar cluster interacts with no more than one protein molecule., (Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)
- Published
- 2013
- Full Text
- View/download PDF
16. Stereoselective synthesis of 2-acetamido-1,2-dideoxyallonojirimycin (DAJNAc), a new potent hexosaminidase inhibitor.
- Author
-
de la Fuente A, Martin R, Mena-Barragán T, Verdaguer X, García Fernández JM, Ortiz Mellet C, and Riera A
- Subjects
- 1-Deoxynojirimycin chemical synthesis, 1-Deoxynojirimycin chemistry, Female, Humans, Pregnancy, Stereoisomerism, 1-Deoxynojirimycin analogs & derivatives, Hexosaminidases analysis, Hexosaminidases chemistry, beta-N-Acetylhexosaminidases chemical synthesis, beta-N-Acetylhexosaminidases chemistry
- Abstract
A practical synthesis of the previously unreported N-acetyl-D-allosamine glycomimetic DAJNAc is described. The reaction sequence involves Pd-catalyzed allylic substitution by phthalimide in an azaheterobicyclic scaffold as the key step. The new iminosugar resulted in being a stronger β-N-acetylglucosaminidase (human placenta) competitive inhibitor than the D-gluco (DNJNAc) and D-galacto (DGJNAc) stereoisomers.
- Published
- 2013
- Full Text
- View/download PDF
17. A bicyclic 1-deoxygalactonojirimycin derivative as a novel pharmacological chaperone for GM1 gangliosidosis.
- Author
-
Takai T, Higaki K, Aguilar-Moncayo M, Mena-Barragán T, Hirano Y, Yura K, Yu L, Ninomiya H, García-Moreno MI, Sakakibara Y, Ohno K, Nanba E, Ortiz Mellet C, García Fernández JM, and Suzuki Y
- Subjects
- 1-Deoxynojirimycin pharmacology, Administration, Oral, Animals, Bridged Bicyclo Compounds, Heterocyclic pharmacology, Cells, Cultured, Computational Biology, Disease Models, Animal, Enzyme Inhibitors pharmacology, Fibroblasts drug effects, Fibroblasts metabolism, Gangliosidosis, GM1 genetics, Imino Sugars chemistry, Imino Sugars pharmacology, Lysosomes metabolism, Mice, Mice, Inbred C57BL, Mice, Knockout, Mucopolysaccharidosis IV drug therapy, Mucopolysaccharidosis IV genetics, Mutation, Recombination, Genetic, beta-Galactosidase chemistry, beta-Galactosidase genetics, 1-Deoxynojirimycin analogs & derivatives, Gangliosidosis, GM1 drug therapy, Molecular Chaperones pharmacology
- Abstract
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 sp(2)-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.
- Published
- 2013
- Full Text
- View/download PDF
18. The multivalent effect in glycosidase inhibition: probing the influence of architectural parameters with cyclodextrin-based iminosugar click clusters.
- Author
-
Decroocq C, Rodríguez-Lucena D, Russo V, Mena Barragán T, Ortiz Mellet C, and Compain P
- Subjects
- Catalysis, Click Chemistry, Copper chemistry, Models, Molecular, Glycoside Hydrolases antagonists & inhibitors, Imino Sugars chemistry, beta-Cyclodextrins chemistry
- Abstract
In contrast to most lectins, glycosidases may appear to be unpromising targets for multivalent binding because they display only a single active site. To explore the potential of multivalency on glycosidase inhibition, unprecedented cyclodextrin-based iminosugar conjugates have been designed and prepared. The synthesis was performed by way of Cu(I) -catalyzed azide-alkyne cycloaddition reaction under microwave activation between propargylated multivalent β-cyclodextrins and an azide-armed N-alkyl 1-deoxynojirimycin derivative. Evaluation with a panel of glycosidases of this new class of glycomimetic clusters revealed the strongest affinity enhancement observed to date for a multivalent glycosidase inhibitor, with binding enhancement up to four orders of magnitude over the corresponding monovalent ligand for α-mannosidase. These results demonstrate that the multivalency concept extends beyond carbohydrate-lectin recognition processes to glycomimetic-enzyme inhibition., (Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)
- Published
- 2011
- Full Text
- View/download PDF
19. Glycosidase inhibition with fullerene iminosugar balls: a dramatic multivalent effect.
- Author
-
Compain P, Decroocq C, Iehl J, Holler M, Hazelard D, Mena Barragán T, Ortiz Mellet C, and Nierengarten JF
- Subjects
- Animals, Cattle, Glycoside Hydrolases metabolism, Imino Sugars chemical synthesis, Imino Sugars pharmacology, Magnetic Resonance Spectroscopy, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization, Fullerenes chemistry, Glycoside Hydrolases antagonists & inhibitors, Imino Sugars chemistry
- Published
- 2010
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.