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Carmen Ortiz Mellet - One of the best experts on this subject based on the ideXlab platform.
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construction of giant glycosidase inhibitors from Iminosugar substituted fullerene macromonomers
Journal of Materials Chemistry B, 2017Co-Authors: Thi Minh Nguyet Trinh, Carmen Ortiz Mellet, Philippe Compain, Jose Garcia M Fernandez, Isabel M Garciamoreno, Anne Bodlenner, Michel Holler, Jeremy P Schneider, Jean-françois NierengartenAbstract:An ultra-fast synthetic procedure based on grafting of twelve fullerene macromonomers onto a fullerene hexa-adduct core was used for the preparation of a giant molecule with 120 peripheral Iminosugar residues. The inhibition profile of this giant Iminosugar ball was evaluated against various glycosidases. In the particular case of the Jack bean α-mannosidase, a dramatic enhancement of the glycosidase inhibitory effect was observed for the giant molecule with 120 peripheral subunits as compared to that of the corresponding mono- and dodecavalent model compounds.
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inhibitor versus chaperone behaviour of d fagomine dab and lab sp 2 Iminosugar conjugates against glycosidases a structure activity relationship study in gaucher fibroblasts
European Journal of Medicinal Chemistry, 2016Co-Authors: Teresa Menabarragan, Jose Garcia M Fernandez, Isabel M Garciamoreno, Eiji Nanba, Katsumi Higaki, Alda Lisa Concia, Pere Clapes, Carmen Ortiz MelletAbstract: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.
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efficient stereoselective synthesis of 2 acetamido 1 2 dideoxyallonojirimycin dajnac and sp2 Iminosugar conjugates novel hexosaminidase inhibitors with discrimination capabilities between the mature and precursor forms of the enzyme
European Journal of Medicinal Chemistry, 2016Co-Authors: Alex De La Fuente, Carmen Ortiz Mellet, Jose Garcia M Fernandez, Rocio Risquezcuadro, Xavier Verdaguer, Eiji Nanba, Katsumi Higaki, Antoni RieraAbstract:Due to their capacity to inhibit hexosaminidases, 2-acetamido-1,2-dideoxy-Iminosugars have been widely studied as potential therapeutic agents for various diseases. An efficient stereoselective synthesis of 2-acetamido-1,2-dideoxyallonojirimycin (DAJNAc), the most potent inhibitor of human placenta β-N-acetylglucosaminidase (β-hexosaminidase) among the epimeric series, is here described. This novel procedure can be easily scaled up, providing enough material for structural modifications and further biological tests. Thus, two series of sp(2)-Iminosugar conjugates derived from DAJNAc have been prepared, namely monocyclic DAJNAc-thioureas and bicyclic 2-iminothiazolidines, and their glycosidase inhibitory activity evaluated. The data evidence the utmost importance of developing diversity-oriented synthetic strategies allowing optimization of electrostatic and hydrophobic interactions to achieve high inhibitory potencies and selectivities among isoenzymes. Notably, strong differences in the inhibition potency of the compounds towards β-hexosaminidase from human placenta (mature) or cultured fibroblasts (precursor form) were encountered. The ensemble of data suggests that the ratio between them, and not the inhibition potency towards the placenta enzyme, is a good indication of the chaperoning potential of TaySachs disease-associated mutant hexosaminidase.
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influence of the configurational pattern of sp2 Iminosugar pseudo n s o and c glycosides on their glycoside inhibitory and antitumor properties
Carbohydrate Research, 2016Co-Authors: Elena M Sanchezfernandez, Jose Garcia M Fernandez, Rocio Risquezcuadro, Rita Goncalvespereira, Gabriela B Plata, Jose M Padron, Carmen Ortiz MelletAbstract:The synthesis of a complete series of cyclic carbamate-type sp(2)-Iminosugar N-, S-, O- and C-octyl pseudoglycosides related to nojirimycin, mannojirimycin and galactonojirimycin, all having the α-pseudoanomeric configuration, is reported. The gem-diamine-type N-pseudoglycosides can be accessed directly from the corresponding reducing sp(2)-imisosugar precursors by reaction with octylamine in methanol, whereas per-O-acetyl or 1-fluoro derivatives were used as pseudoglycosyl donors for the preparation of S-pseudoglycosides or O- and C-pseudoglycosides, respectively. Evaluation of their inhibitory properties against a panel of glycosidases evidenced selectivity profiles that strongly depend on the configurational pattern and the nature of the glycosidic linkage. On the contrary, the antiproliferative activity determined against a panel of tumor cell lines was largely independent of the relative orientation of the hydroxyl groups in the sp(2)-Iminosugar moiety. Indeed, sp(2)-Iminosugar representatives exhibiting significant growth inhibition potencies were identified in all three configurationally different types of compounds studied, namely α-d-gluco, α-d-manno and α-d-galacto glycoside analogs. Interestingly, none of the compounds affected viability and mortality of normal cells at the used concentrations. Altogether, the results strongly suggest that the anticancer activity of amphiphilic sp(2)-Iminosugar glycosides might be unrelated, or not solely related, to their glycosidase inhibitory activity.
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topological effects and binding modes operating with multivalent Iminosugar based glycoclusters and mannosidases
Journal of the American Chemical Society, 2013Co-Authors: Yoan Brissonnet, Sandrine Morandat, Isabel Garcia M Moreno, David Deniaud, Susan E Matthews, Karim El Kirat, Sébastien Vidal, Carmen Ortiz Mellet, Sergej Šesták, Sebastien G GouinAbstract:Multivalent Iminosugars have been recently explored for glycosidase inhibition. Affinity enhancements due to multivalency have been reported for specific targets, which are particularly appealing when a gain in enzyme selectivity is achieved but raise the question of the binding mode operating with this new class of inhibitors. Here we describe the development of a set of tetra- and octavalent Iminosugar probes with specific topologies and an assessment of their binding affinities toward a panel of glycosidases including the Jack Bean α-mannosidase (JBαMan) and the biologically relevant class II α-mannosidases from Drosophila melanogaster belonging to glycohydrolase family 38, namely Golgi α-mannosidase ManIIb (GM) and lysosomal α-mannosidase LManII (LM). Very different inhibitory profiles were observed for compounds with identical valencies, indicating that the spatial distribution of the Iminosugars is critical to fine-tune the enzymatic inhibitory activity. Compared to the monovalent reference, the bes...
Sebastien G Gouin - One of the best experts on this subject based on the ideXlab platform.
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evaluation of monovalent and multivalent Iminosugars to modulate candida albicans β 1 2 mannosyltransferase activities
Carbohydrate Research, 2016Co-Authors: Emeline Fabre, Ghenima Sfihiloualia, Thomas Hurtaux, Boualem Sendid, Florence Delplace, Yoan Brissonnet, Julie Bouckaert, Jean-maurice Mallet, Sebastien G GouinAbstract:β-1,2-Linked oligomannosides substitute the cell wall of numerous yeast species. Several of those including Candida albicans may cause severe infections associated with high rates of morbidity and mortality, especially in immunocompromised patients. β-1,2-Mannosides are known to be involved in the pathogenic process and to elicit an immune response from the host. In C. albicans, the synthesis of β-mannosides is under the control of a family of nine genes coding for putative β-mannosyltransferases. Two of them, CaBmt1 and CaBmt3, have been shown to initiate and prime the elongation of the β-mannosides on the cell-wall mannan core. In the present study, we have assessed the modulating activities of monovalent and multivalent Iminosugar analogs on these enzymes in order to control the enzymatic bio-synthesis of β-mannosides. We have identified a monovalent deoxynojirimycin (DNJ) derivative that inhibits the CaBmt1-catalyzed initiating activity, and mono-, tetra- and polyvalent deoxymannojirimycin (DMJ) that modulate the CaBmt1 activity toward the formation of a single major product. Analysis of the aggregating properties of the multivalent Iminosugars showed their ability to elicit clusterization of both CaBmt1 and CaBmt3, without affecting their activity. These results suggest promising roles for multivalent Iminosugars as controlling agents for the biosynthesis of β-1,2 mannosides and for monovalent DNJ derivative as a first target for the design of future β-mannosyltransferase inhibitors.
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Topological effects and binding modes operating with multivalent Iminosugar-based glycoclusters and mannosidases.
Journal of the American Chemical Society, 2013Co-Authors: Yoan Brissonnet, Sandrine Morandat, David Deniaud, Susan E Matthews, Karim El Kirat, Sébastien Vidal, Sergej Šesták, M. Isabel García-moreno, Carmen Ortiz Mellet, Sebastien G GouinAbstract:Multivalent Iminosugars have been recently explored for glycosidase inhibition. Affinity enhancements due to multivalency have been reported for specific targets, which are particularly appealing when a gain in enzyme selectivity is achieved but raise the question of the binding mode operating with this new class of inhibitors. Here we describe the development of a set of tetra- and octavalent Iminosugar probes with specific topologies and an assessment of their binding affinities toward a panel of glycosidases including the Jack Bean α-mannosidase (JBαMan) and the biologically relevant class II α-mannosidases from Drosophila melanogaster belonging to glycohydrolase family 38, namely Golgi α-mannosidase ManIIb (GM) and lysosomal α-mannosidase LManII (LM). Very different inhibitory profiles were observed for compounds with identical valencies, indicating that the spatial distribution of the Iminosugars is critical to fine-tune the enzymatic inhibitory activity. Compared to the monovalent reference, the best multivalent compound showed a dramatic 800-fold improvement in the inhibitory potency for JBαMan, which is outstanding for just a tetravalent ligand. The compound was also shown to increase both the inhibitory activity and the selectivity for GM over LM. This suggests that multivalency could be an alternative strategy in developing therapeutic GM inhibitors not affecting the lysosomal mannosidases. Dynamic light scattering experiments and atomic force microscopy performed with coincubated solutions of the compounds with JBαMan shed light on the multivalent binding mode. The multivalent compounds were shown to promote the formation of JBαMan aggregates with different sizes and shapes. The dimeric nature of the JBαMan allows such intermolecular cross-linking mechanisms to occur.
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topological effects and binding modes operating with multivalent Iminosugar based glycoclusters and mannosidases
Journal of the American Chemical Society, 2013Co-Authors: Yoan Brissonnet, Sandrine Morandat, Isabel Garcia M Moreno, David Deniaud, Susan E Matthews, Karim El Kirat, Sébastien Vidal, Carmen Ortiz Mellet, Sergej Šesták, Sebastien G GouinAbstract:Multivalent Iminosugars have been recently explored for glycosidase inhibition. Affinity enhancements due to multivalency have been reported for specific targets, which are particularly appealing when a gain in enzyme selectivity is achieved but raise the question of the binding mode operating with this new class of inhibitors. Here we describe the development of a set of tetra- and octavalent Iminosugar probes with specific topologies and an assessment of their binding affinities toward a panel of glycosidases including the Jack Bean α-mannosidase (JBαMan) and the biologically relevant class II α-mannosidases from Drosophila melanogaster belonging to glycohydrolase family 38, namely Golgi α-mannosidase ManIIb (GM) and lysosomal α-mannosidase LManII (LM). Very different inhibitory profiles were observed for compounds with identical valencies, indicating that the spatial distribution of the Iminosugars is critical to fine-tune the enzymatic inhibitory activity. Compared to the monovalent reference, the bes...
Sundarababu Baskaran - One of the best experts on this subject based on the ideXlab platform.
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one pot synthesis of structurally diverse Iminosugar based hybrid molecules
Journal of Organic Chemistry, 2018Co-Authors: Sure Siva Prasad, Narra Rajashekar Reddy, Sundarababu BaskaranAbstract:A one-pot iminium-ion-based strategy has been developed for the synthesis of structurally novel Iminosugar-based hybrid molecules. Iminium ion derived from l-rhamnose lactol-mesylate reacted with electron-rich aromatic systems in an inter/intra molecular fashion to furnish pyrrolidine-based Iminosugar C-aryl glycosides with a high degree of stereoselectivity. Iminium ion also reacted readily with active methylene compounds such as 4-hydroxycoumarin, 4-hydroxyquinolinone, and lawsone to provide Iminosugar C-coumarin/quinolinone/naphthoquinonyl glycosides in very good yields. Azomethine ylide generated from an iminium ion derivative underwent dipolar cycloaddition reaction with 1,4-quinones to furnish novel isopyrrolonaphtho/anthroquinon-based Iminosugar-hybrids. The preliminary cytotoxic activities of some of the synthesized Iminosugar-hybrids have been assayed against various human cancer cell lines and some of the hybrid molecules exhibited promising anticancer activities.
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Iminosugar c nitromethyl glycoside stereoselective synthesis of isoxazoline and isoxazole fused bicyclic Iminosugars
Journal of Organic Chemistry, 2018Co-Authors: Sure Siva Prasad, Sundarababu BaskaranAbstract:A simple and efficient method for the stereoselective synthesis of isoxazoline/isoxazole-fused Iminosugar derivatives has been developed using intramolecular nitrile oxide cycloaddition (INOC) as a key step. Iminosugar C-nitromethyl glycosides, derived from simple carbohydrates, served as excellent nitrile oxide precursors in 1,3-dipolar cycloaddition reactions. N-Alkenyl Iminosugar C-nitromethyl glycosides afforded novel isoxazoline-fused indolizidine-, pyrrolizidine-, and quinolizidine-based Iminosugars in excellent yields with a high degree of stereoselectivity, whereas N-alkynyl Iminosugar C-nitromethyl glycosides furnished the corresponding isoxazole containing tricyclic Iminosugars in very good yields.
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One-Pot Synthesis of Structurally Diverse Iminosugar-Based Hybrid Molecules
2018Co-Authors: Sure Siva Prasad, Narra Rajashekar Reddy, Sundarababu BaskaranAbstract:A one-pot iminium-ion-based strategy has been developed for the synthesis of structurally novel Iminosugar-based hybrid molecules. Iminium ion derived from l-rhamnose lactol-mesylate reacted with electron-rich aromatic systems in an inter/intra molecular fashion to furnish pyrrolidine-based Iminosugar C-aryl glycosides with a high degree of stereoselectivity. Iminium ion also reacted readily with active methylene compounds such as 4-hydroxycoumarin, 4-hydroxyquinolinone, and lawsone to provide Iminosugar C-coumarin/quinolinone/naphthoquinonyl glycosides in very good yields. Azomethine ylide generated from an iminium ion derivative underwent dipolar cycloaddition reaction with 1,4-quinones to furnish novel isopyrrolonaphtho/anthroquinon-based Iminosugar-hybrids. The preliminary cytotoxic activities of some of the synthesized Iminosugar-hybrids have been assayed against various human cancer cell lines and some of the hybrid molecules exhibited promising anticancer activities
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Iminosugar C‑Nitromethyl Glycoside: Stereoselective Synthesis of Isoxazoline and Isoxazole-Fused Bicyclic Iminosugars
2018Co-Authors: Sure Siva Prasad, Sundarababu BaskaranAbstract:A simple and efficient method for the stereoselective synthesis of isoxazoline/isoxazole-fused Iminosugar derivatives has been developed using intramolecular nitrile oxide cycloaddition (INOC) as a key step. Iminosugar C-nitromethyl glycosides, derived from simple carbohydrates, served as excellent nitrile oxide precursors in 1,3-dipolar cycloaddition reactions. N-Alkenyl Iminosugar C-nitromethyl glycosides afforded novel isoxazoline-fused indolizidine-, pyrrolizidine-, and quinolizidine-based Iminosugars in excellent yields with a high degree of stereoselectivity, whereas N-alkynyl Iminosugar C-nitromethyl glycosides furnished the corresponding isoxazole containing tricyclic Iminosugars in very good yields
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Iminosugar c nitromethyl glycosides and divergent synthesis of bicyclic Iminosugars
Organic Letters, 2017Co-Authors: Sure Siva Prasad, Soundararasu Senthilkumar, Akriti Srivastava, Sundarababu BaskaranAbstract:An efficient one-pot method for the stereoselective synthesis of novel Iminosugar C-nitromethyl glycosides is described. This new class of Iminosugar glycosides has versatile nitromethyl functionality whose utility was further demonstrated in the single-step synthesis of bicyclic Iminosugars. Under reagent-free conditions, the N-allyl-C-nitromethyl glycosides resulted in intramolecular cyclization to Iminosugar-oximes, whereas under SET oxidation, they furnished cyclopropane-fused Iminosugars. The N-propargyl-C-nitromethyl glycosides underwent an unprecedented ketenimine–acrylamidine–Michael addition cascade reaction to give bicyclic amidines.
Philippe Compain - One of the best experts on this subject based on the ideXlab platform.
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Giant Glycosidase Inhibitors: First- and Second-Generation Fullerodendrimers with a Dense Iminosugar Shell
Chemistry - A European Journal, 2018Co-Authors: Jean-françois Nierengarten, Antoine Joosten, Anne Bodlenner, Jérémy Schneider, Mathieu Lepage, Thi Minh Nguyet Trinh, Michel Holler, M. Isabel García-moreno, Carmen Ortiz mellet, Philippe CompainAbstract:The multivalent effect in glycosidase inhibition is a new topic in glycoscience that has emerged a few years ago, with the discovery of neoglycoclusters displaying strong binding enhancements over the corresponding monovalent inhibitor. Iminosugar–fullerene conjugates with high valencies have been prepared from Iminosugar‐terminated dendrons and a clickable fullerene hexa‐adduct scaffold. The simultaneous grafting of twelve dendrons allows for a very fast dendritic growth thus limiting the number of synthetic steps required to prepare compounds with a high number of peripheral units. The grafting of first‐ and second‐generation dendrons provided fullerodendrimers surrounded by 36 and 108 peripheral Iminosugars, respectively. Inhibition studies have been carried out with a panel of glycosidases. In the particular case of Jack bean α‐mannosidase, the 108‐valent nanoconstruct displays inhibition in the nanomolar range and an additional binding enhancement of one order of magnitude when compared to the 36‐valent analogues.
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construction of giant glycosidase inhibitors from Iminosugar substituted fullerene macromonomers
Journal of Materials Chemistry B, 2017Co-Authors: Thi Minh Nguyet Trinh, Carmen Ortiz Mellet, Philippe Compain, Jose Garcia M Fernandez, Isabel M Garciamoreno, Anne Bodlenner, Michel Holler, Jeremy P Schneider, Jean-françois NierengartenAbstract:An ultra-fast synthetic procedure based on grafting of twelve fullerene macromonomers onto a fullerene hexa-adduct core was used for the preparation of a giant molecule with 120 peripheral Iminosugar residues. The inhibition profile of this giant Iminosugar ball was evaluated against various glycosidases. In the particular case of the Jack bean α-mannosidase, a dramatic enhancement of the glycosidase inhibitory effect was observed for the giant molecule with 120 peripheral subunits as compared to that of the corresponding mono- and dodecavalent model compounds.
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Toward a Molecular Lego Approach for the Diversity-Oriented Synthesis of Cyclodextrin Analogues Designed as Scaffolds for Multivalent Systems
2015Co-Authors: Mathieu L. Lepage, Jérémy P. Schneider, Anne Bodlenner, Philippe CompainAbstract:A modular strategy has been developed to access a diversity of cyclic and acyclic oligosaccharide analogues designed as prefunctionalized scaffolds for the synthesis of multivalent ligands. This convergent approach is based on bifunctional sugar building blocks with two temporarily masked functionalities that can be orthogonally activated to perform Cu(I)-catalyzed azide–alkyne cycloaddition reactions (CuAAC). The reducing end is activated as a glycosyl azide and masked as a 1,6-anhydro sugar, while the nonreducing end is activated as a free alkyne and masked as a triethylsilyl-alkyne. Following a cyclooligomerization approach, the first examples of close analogues of cyclodextrins composed of d-glucose residues and triazole units bound together through α-(1,4) linkages were obtained. The cycloglucopyranoside analogue containing four sugar units was used as a template to prepare multivalent systems displaying a protected d-mannose derivative or an Iminosugar by way of CuAAC. On the other hand, the modular approach led to acyclic alkyne-functionalized scaffolds of a controlled size that were used to synthesize multivalent Iminosugars
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A Convergent Strategy for the Synthesis of Second-Generation Iminosugar Clusters Using “Clickable” Trivalent Dendrons
European Journal of Organic Chemistry, 2014Co-Authors: Antoine Joosten, Anne Bodlenner, Jérémy Schneider, Mathieu Lepage, Celine Tarnus, Philippe CompainAbstract:A convergent strategy to access high‐valency Iminosugar clusters based on two successive CuI‐catalysed azide–alkyne cycloadditions is reported. The key step of this approach relies on the grafting of azide‐armed trivalent Iminosugar dendrons onto polyalkyne “clickable” scaffolds, thus tripling their initial valency. As a proof of concept, the synthesis of cyclodextrin‐based clusters containing the highest number of peripheral Iminosugar ligands reported to date has been achieved. Evaluation of these compounds as mannosidase inhibitors revealed one of the strongest multivalent effects observed so far in glycosidase inhibition.
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A Systematic Investigation of Iminosugar Click Clusters as Pharmacological Chaperones for the Treatment of Gaucher Disease
ChemBioChem, 2014Co-Authors: Antoine Joosten, Camille Decroocq, Anne Bodlenner, Jérémy Schneider, Julien De Sousa, Emile Etame, Terry Butters, Philippe CompainAbstract:A series of 18 mono‐ to 14‐valent Iminosugars with different ligands, scaffolds, and alkyl spacer lengths have been synthesized and evaluated as inhibitors and pharmacological chaperones of β‐glucocerebrosidase (GCase). Small but significant multivalent effects in GCase inhibition have been observed for two Iminosugar clusters. Our study provides strong confirmation that compounds that display the best affinity for GCase are not necessarily the best chaperones. The best chaperoning effect observed for a deprotected Iminosugar cluster has been obtained with a tetravalent 1‐deoxynojirimycin (DNJ) analogue (3.3‐fold increase at 10 μM). In addition, our study provides the first evidence of the high potential of prodrugs for the development of potent pharmacological chaperones. Acetylation of a trivalent DNJ derivative, to give the corresponding acetate prodrug, leads to a pharmacological chaperone that produces higher enzyme activity increases (3.0‐fold instead of 2.4‐fold) at a cellular concentration (1 μM) reduced by one order of magnitude.
Hang Song - One of the best experts on this subject based on the ideXlab platform.
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dual action lipophilic Iminosugar improves glycemic control in obese rodents by reduction of visceral glycosphingolipids and buffering of carbohydrate assimilation
Journal of Medicinal Chemistry, 2010Co-Authors: Tom Wennekes, Marco Van Eijk, Rolf G. Boot, Johanna E. M. Groener, Nora Bijl, Albert K. Groen, Roelof Ottenhoff, Alfred J Meijer, Karen Ghauharali, Hang SongAbstract:The lipophilic Iminosugar N-[5-(adamantan-1-ylmethoxy)pentyl]-1-deoxynojirimycin (2, AMP-DNM) potently controls hyperglycemia in obese rodent models of insulin resistance. The reduction of visceral glycosphingolipids by 2 is thought to underlie its beneficial action. It cannot, however, be excluded that concomitant inhibition of intestinal glycosidases and associated buffering of carbohydrate assimilation add to this. To firmly establish the mode of action of 2, we developed a panel of lipophilic Iminosugars varying in configuration at C-4/C-5 and N-substitution of the Iminosugar. From these we identified the l-ido derivative of 2, l-ido-AMP-DNM (4), as a selective inhibitor of glycosphingolipid synthesis. Compound 4 lowered visceral glycosphingolipids in ob/ob mice and ZDF rats on a par with 2. In contrast to 2, 4 did not inhibit sucrase activity or sucrose assimilation. Treatment with 4 was significantly less effective in reducing blood glucose and HbA1c. We conclude that the combination of reduction of...
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dual action lipophilic Iminosugar improves glycemic control in obese rodents by reduction of visceral glycosphingolipids and buffering of carbohydrate assimilation
Journal of Medicinal Chemistry, 2010Co-Authors: Tom Wennekes, Marco Van Eijk, Rolf G. Boot, Johanna E. M. Groener, Nora Bijl, Albert K. Groen, Roelof Ottenhoff, Alfred J Meijer, Karen Ghauharali, Hang SongAbstract:The lipophilic Iminosugar N-[5-(adamantan-1-ylmethoxy)pentyl]-1-deoxynojirimycin (2, AMP-DNM) potently controls hyperglycemia in obese rodent models of insulin resistance. The reduction of visceral glycosphingolipids by 2 is thought to underlie its beneficial action. It cannot, however, be excluded that concomitant inhibition of intestinal glycosidases and associated buffering of carbohydrate assimilation add to this. To firmly establish the mode of action of 2, we developed a panel of lipophilic Iminosugars varying in configuration at C-4/C-5 and N-substitution of the Iminosugar. From these we identified the l-ido derivative of 2, l-ido-AMP-DNM (4), as a selective inhibitor of glycosphingolipid synthesis. Compound 4 lowered visceral glycosphingolipids in ob/ob mice and ZDF rats on a par with 2. In contrast to 2, 4 did not inhibit sucrase activity or sucrose assimilation. Treatment with 4 was significantly less effective in reducing blood glucose and HbA1c. We conclude that the combination of reduction of glycosphingolipids in tissue and buffering of carbohydrate assimilation by 2 produces a superior glucose homeostasis.
