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Antonio Delgado - One of the best experts on this subject based on the ideXlab platform.
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new glucocerebrosidase inhibitors by exploration of chemical diversity of n substituted Aminocyclitols using click chemistry and in situ screening
Journal of Medicinal Chemistry, 2011Co-Authors: Lucía Díaz, Jordi Bujons, Amadeu Llebaria, Josefina Casas, Antonio DelgadoAbstract:A library of Aminocyclitols derived from CuAAC reaction between N-propargylaminocyclitol 4 and a series of azides [1−25] is described and tested against GCase. Azides have been chosen from a large collection of potential candidates that has been filtered according to physical and reactivity constraints. A synthetic methodology has been optimized in order to avoid the use of protecting groups on the aminocyclitol scaffold. Because the reaction can be carried out in an aqueous system, the resulting library members can be screened in situ with minimal manipulation. From the preliminary GCase inhibition data, the most potent library members have been individually resynthesized for further biological screening and complete characterization. Some of the library members have shown biochemical data (IC50, Ki, and stabilization ratio) similar or superior to those reported for NNDNJ. Docking studies have been used to postulate ligand−enzyme interactions to account for the experimental results.
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Medicinal chemistry of Aminocyclitols.
Current medicinal chemistry, 2010Co-Authors: Lucía Díaz, Antonio DelgadoAbstract:Aminocyclitols comprise an important group of compounds with remarkable biological activities. From a structural standpoint, Aminocyclitols are amino polyhydroxy cycloalkanes that can be found in nature in several families of natural products. Among them, the aminoglycoside antibiotics, since the discovery of streptomycin, have become particularly relevant at the forefront of the antibacterial treatment. Another group of Aminocyclitols, generally referred to as aminocarbasugars, have been found as key structural components of some families of alkaloids that have evolved as suitable leads for the development of potent glycosidase inhibitors with a vast array of applications in medicinal chemistry, both as therapeutically useful agents as well as valuable pharmacological tools. On the other hand, the aminocyclitol moiety has been used by medicinal chemists as a versatile scaffold in drug design. Thus, in the antiviral arena, it is found as the key component of several families of carbocyclic nucleoside analogues, designed as metabolically stable surrogates of the natural nucleosides. Finally, in a still relatively unexplored area, some aminocyclitol derivatives are being used as key components of artificial receptors for which promising applications in drug research can be envisaged. In all cases, the development of the modern regio- and stereoselective synthetic methodologies enables a large variety of stereochemically defined aminocyclitol analogues in order to study in depth the influence of this moiety on the structure-activity relationships from a given lead.
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Small-Scale One-Pot ReductiveAlkylation of Unprotected Aminocyclitols with Supported Reagents
Synthesis, 2008Co-Authors: Miroslav Sisa, Amadeu Llebaria, Ana Trapero, Antonio DelgadoAbstract:Α protocol for the reductive alkylation of unprotected Aminocyclitols with supported reagents and scavengers is described. The method is operatively simple and provides the corresponding secondary amines in high yields and purities.
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recent advances in the chemistry of Aminocyclitols eur j org chem 23 2008
European Journal of Organic Chemistry, 2008Co-Authors: Antonio DelgadoAbstract:The cover picture shows three different approaches to the synthesis of Aminocyclitols. Aminocyclitols are found as structural components of several families of natural products with different biological properties. Several synthetic strategies for this kind of compounds have been devised over the last years. Interestingly, some synthetic Aminocyclitols show interesting properties as glucosidase inhibitors. This is the case for voglibose, a drug marketed as an oral antidiabetic drug and whose three-dimensional structure is shown in the background. Details are presented in the Microreview by A. Delgado on p. 3893 ff.
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Recent Advances in the Chemistry of Aminocyclitols
European Journal of Organic Chemistry, 2008Co-Authors: Antonio DelgadoAbstract:Aminocyclitols are a group of natural products with remarkable biological activities. Over the last years, significant efforts have been made to develop synthetic methodologies directed not only towards their total synthesis but also towards the design of structural analogues with improved or novel biological properties. The aim of this review is to provide the reader with a concise update of the most relevant methods for the synthesis of Aminocyclitols described in the literature. The review is organized according to the methodologies used for the construction of the aminocyclitol framework. These methodologies include chemoenzymatic approaches, intramolecular cyclizations, reactions of cyclitol derivatives with nitrogen nucleophiles, and rearrangement reactions.(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008)
Amadeu Llebaria - One of the best experts on this subject based on the ideXlab platform.
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Potent Aminocyclitol Glucocerebrosidase Inhibitors are Subnanomolar Pharmacological Chaperones for Treating Gaucher Disease
2016Co-Authors: Ana Trapero, Terry D. Butters, Amadeu LlebariaAbstract:ABSTRACT: Amino-myo-inositol derivatives have been found to be potent inhibitors of glucocerebrosidase (GCase), the β-glucosidase enzyme deficient in Gaucher disease (GD). When tested using lymphoblasts derived from patients with GD homozygous for N370S or L444P mutations, the compounds enhanced GCase activity at very low concen-trations. The most potent inhibitor, (1R,2S,3R,4S,5S,6R)-5-(nonylamino)-6-(nonyloxy)cyclohexane-1,2,3,4-tetraol had a Ki of 1 nM using isolated enzyme and an IC50 of 4.3 nM when assayed in human fibroblast cell culture. This aminocyclitol produced maximum increases of GCase activities of 90 % in N370S lymphoblasts at 1 nM and 40 % in L444P at 0.01 nM following a three-day incubation. In addition to inhibitory potency, this compound has the permeability, subcellular distribution, and cell metabolism characteristics that are important for use as a pharmacological chaperone. It is a remarkable finding that picomolar concentrations of Aminocyclitols are sufficient t
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Synthesis and Evaluation of HydroxymethylAminocyclitols as Glycosidase Inhibitors
2015Co-Authors: Ana Trapero, Meritxell Egido-gabás, Jordi Bujons, Amadeu LlebariaAbstract:Four series of C7N aminocyclitol analogues of glucose were synthesized by stereocontrolled epoxide opening of hydroxyl protected forms of the cyclohexane epoxides cyclophellitol and 1,6-epi-cyclophellitol. The resulting hydroxymethyl substituted Aminocyclitols were tested as glycosidase inhibitors. Cyclitols having an amino group in an α configuration at a position equivalent to the anomeric in the sugar were found to be low micromolar inhibitors of the α-glucosidase from baker’s yeast with Ki’s near to 2 μM. On the other hand, N-octyl Aminocyclitols having the nitrogen substituents in an α or β configuration were found to be good inhibitors of recombinant β-glucocerebrosidase with Ki values between 8.3 and 17 μM, and also inhibited lysosomal β-glucosidase activity in live cells at low-micromolar concentrations. A computational docking study suggests a differential binding among the different series of β-glucocerebrosidase inhibitors. In agreement with the experimental results, the binding poses obtained indicate that the presence of an alkyl lipid substituent in the inhibitor mimicking one of the lipid chains in the substrate is critical for potency. In contrast, the matching of hydroxymethyl substituents in the Aminocyclitols and the parent glucosylceramide does not seem to be strictly necessary for potent inhibition, indicating the risk of simplifying structural analogies in sugar mimetic design
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Potent aminocyclitol glucocerebrosidase inhibitors are subnanomolar pharmacological chaperones for treating gaucher disease.
Journal of medicinal chemistry, 2012Co-Authors: Ana Trapero, Terry D. Butters, Patricia González-bulnes, Amadeu LlebariaAbstract:Amino-myo-inositol derivatives have been found to be potent inhibitors of glucocerebrosidase (GCase), the β-glucosidase enzyme deficient in Gaucher disease (GD). When tested using lymphoblasts derived from patients with GD homozygous for N370S or L444P mutations, the compounds enhanced GCase activity at very low concentrations. The most potent inhibitor, (1R,2S,3R,4S,5S,6R)-5-(nonylamino)-6-(nonyloxy)cyclohexane-1,2,3,4-tetraol had a K(i) of 1 nM using isolated enzyme and an IC(50) of 4.3 nM when assayed in human fibroblast cell culture. This aminocyclitol produced maximum increases of GCase activities of 90% in N370S lymphoblasts at 1 nM and 40% in L444P at 0.01 nM following a three-day incubation. In addition to inhibitory potency, this compound has the permeability, subcellular distribution, and cell metabolism characteristics that are important for use as a pharmacological chaperone. It is a remarkable finding that picomolar concentrations of Aminocyclitols are sufficient to enhance activity in the L444P variant, which produces a severe neuronopathic form of GD without clinical treatment.
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Potent Aminocyclitol Glucocerebrosidase Inhibitors are Subnanomolar Pharmacological Chaperones for Treating Gaucher Disease
2012Co-Authors: Ana Trapero, Terry D. Butters, Patricia González-bulnes, Amadeu LlebariaAbstract:Amino-myo-inositol derivatives have been found to be potent inhibitors of glucocerebrosidase (GCase), the β-glucosidase enzyme deficient in Gaucher disease (GD). When tested using lymphoblasts derived from patients with GD homozygous for N370S or L444P mutations, the compounds enhanced GCase activity at very low concentrations. The most potent inhibitor, (1R,2S,3R,4S,5S,6R)-5-(nonylamino)-6-(nonyloxy)cyclohexane-1,2,3,4-tetraol had a Ki of 1 nM using isolated enzyme and an IC50 of 4.3 nM when assayed in human fibroblast cell culture. This aminocyclitol produced maximum increases of GCase activities of 90% in N370S lymphoblasts at 1 nM and 40% in L444P at 0.01 nM following a three-day incubation. In addition to inhibitory potency, this compound has the permeability, subcellular distribution, and cell metabolism characteristics that are important for use as a pharmacological chaperone. It is a remarkable finding that picomolar concentrations of Aminocyclitols are sufficient to enhance activity in the L444P variant, which produces a severe neuronopathic form of GD without clinical treatment
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new glucocerebrosidase inhibitors by exploration of chemical diversity of n substituted Aminocyclitols using click chemistry and in situ screening
Journal of Medicinal Chemistry, 2011Co-Authors: Lucía Díaz, Jordi Bujons, Amadeu Llebaria, Josefina Casas, Antonio DelgadoAbstract:A library of Aminocyclitols derived from CuAAC reaction between N-propargylaminocyclitol 4 and a series of azides [1−25] is described and tested against GCase. Azides have been chosen from a large collection of potential candidates that has been filtered according to physical and reactivity constraints. A synthetic methodology has been optimized in order to avoid the use of protecting groups on the aminocyclitol scaffold. Because the reaction can be carried out in an aqueous system, the resulting library members can be screened in situ with minimal manipulation. From the preliminary GCase inhibition data, the most potent library members have been individually resynthesized for further biological screening and complete characterization. Some of the library members have shown biochemical data (IC50, Ki, and stabilization ratio) similar or superior to those reported for NNDNJ. Docking studies have been used to postulate ligand−enzyme interactions to account for the experimental results.
Xinzhi Chen - One of the best experts on this subject based on the ideXlab platform.
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synthesis of 1 2 3 triazoles from azide derivatised Aminocyclitols by catalytic diazo transfer and cuaac click chemistry
European Journal of Organic Chemistry, 2014Co-Authors: Guoquan Zhou, Chao Qian, Xinzhi ChenAbstract:CuII-catalysed diazo transfer and CuI-catalysed azide–alkyne 1,3-dipolar cycloaddition (CuAAC) “click chemistry” were used to synthesis C7N aminocyclitol-derivatised 1,2,3-triazoles. In the course of this work, the -N=N- moiety was transferred onto C7N Aminocyclitols such as validamine, valienamine and valiolamine by employing imidazole-1-sulfonyl azide as the diazo transfer reagent with catalysis by CuII, ZnII and NiII, in moderate to good yields. The obtained azidocyclitols were coupled with various terminal alkynes under modified Meldal's conditions with good to excellent yields. The stereo- and regiochemistry of the products were confirmed by 2D-NMR (NOESY and HMBC). One-pot syntheses of the corresponding 1,2,3-triazoles, as safer and more efficient procedures, were also investigated and gave moderate to good yields.
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Synthesis of 1,2,3‐Triazoles from Azide‐Derivatised Aminocyclitols by Catalytic Diazo Transfer and CuAAC Click Chemistry
European Journal of Organic Chemistry, 2014Co-Authors: Guo‐quan Zhou, Chao Qian, Xinzhi ChenAbstract:CuII-catalysed diazo transfer and CuI-catalysed azide–alkyne 1,3-dipolar cycloaddition (CuAAC) “click chemistry” were used to synthesis C7N aminocyclitol-derivatised 1,2,3-triazoles. In the course of this work, the -N=N- moiety was transferred onto C7N Aminocyclitols such as validamine, valienamine and valiolamine by employing imidazole-1-sulfonyl azide as the diazo transfer reagent with catalysis by CuII, ZnII and NiII, in moderate to good yields. The obtained azidocyclitols were coupled with various terminal alkynes under modified Meldal's conditions with good to excellent yields. The stereo- and regiochemistry of the products were confirmed by 2D-NMR (NOESY and HMBC). One-pot syntheses of the corresponding 1,2,3-triazoles, as safer and more efficient procedures, were also investigated and gave moderate to good yields.
Jose Luis Chiara - One of the best experts on this subject based on the ideXlab platform.
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Synthesis of Aminocyclitols by Intramolecular Reductive Coupling of Carbohydrate Derived δ- and ε-Functionalized Oxime Ethers Promoted by Tributyltin Hydride or Samarium Diiodide†
The Journal of organic chemistry, 1997Co-Authors: José Marco-contelles, Pilar Gallego, M. Mercedes Rodriguez‐fernandez, Noureddine Khiar, Christine Destabel, Manuel Bernabé, § And Angeles Martínez-grau, Jose Luis ChiaraAbstract:The intramolecular reductive coupling of a series of simple or polyoxygenated oxime ethers δ- or e-functionalized with bromide, α,β-unsaturated ester, aldehyde, or ketone groups is reported. The cyclization of a nitrile-tethered aldehyde is also studied. These reductive couplings are promoted by tributyltin hydride or samarium diiodide. The reactions proceed under mild conditions, in good chemical yield, and with high stereoselectivity. When applied to highly functionalized substrates derived from carbohydrates, this approach provides a selective entry to enantiomerically pure Aminocyclitols of varying regio- and stereochemistry. In particular, the reductive coupling reaction of carbonyl-tethered oxime ethers promoted by samarium diiodide can be performed in a one-pot sequence, following a Swern oxidation step, allowing the direct transformation of hydroxyl-tethered oxime ethers into the corresponding Aminocyclitols. Moreover, the resultant O-benzylhydroxylamine products of these cyclizations can be furth...
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synthesis of Aminocyclitols by intramolecular reductive coupling of carbohydrate derived δ and e functionalized oxime ethers promoted by tributyltin hydride or samarium diiodide
Journal of Organic Chemistry, 1997Co-Authors: Jose Marcocontelles, Pilar Gallego, Noureddine Khiar, Christine Destabel, Manuel Bernabé, Mercedes M Rodriguezfernandez, And Angeles Martinezgrau, Jose Luis ChiaraAbstract:The intramolecular reductive coupling of a series of simple or polyoxygenated oxime ethers δ- or e-functionalized with bromide, α,β-unsaturated ester, aldehyde, or ketone groups is reported. The cyclization of a nitrile-tethered aldehyde is also studied. These reductive couplings are promoted by tributyltin hydride or samarium diiodide. The reactions proceed under mild conditions, in good chemical yield, and with high stereoselectivity. When applied to highly functionalized substrates derived from carbohydrates, this approach provides a selective entry to enantiomerically pure Aminocyclitols of varying regio- and stereochemistry. In particular, the reductive coupling reaction of carbonyl-tethered oxime ethers promoted by samarium diiodide can be performed in a one-pot sequence, following a Swern oxidation step, allowing the direct transformation of hydroxyl-tethered oxime ethers into the corresponding Aminocyclitols. Moreover, the resultant O-benzylhydroxylamine products of these cyclizations can be furth...
Lahssen El Blidi - One of the best experts on this subject based on the ideXlab platform.
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fructose 1 6 bisphosphate aldolase mediated synthesis of Aminocyclitols analogues of valiolamine and their evaluation as glycosidase inhibitors
Chemcatchem, 2009Co-Authors: Lahssen El Blidi, Zeinab Assaf, Flora Camps Bres, H Veschambre, Vincent TheryAbstract:A highly stereoselective method for the preparation of nitro- and Aminocyclitols, using fructose-1,6-bisphosphate aldolase, which catalyzes the aldol reaction of dihydroxyacetone phosphate (DHAP) on hydroxynitrobutanals, is reported. The key part of the synthesis is based on a one-pot /two-enzyme process whereby three reactions take place; rabbit muscle aldolase (RAMA) catalyzed aldolization, phytase-catalyzed phosphate hydrolysis, and intramolecular spontaneous nitroaldolization. Two families of nitrocyclitols were obtained depending on the carbon configuration in the β position to the nitro group. Reduction of the latter afforded the Aminocyclitols. Evaluation of the inhibition properties of the amines towards five commercially available glycosidases has shown selectivity for β-glucosidase and β-galactosidase.
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Fructose‐1,6‐Bisphosphate Aldolase‐Mediated Synthesis of Aminocyclitols (Analogues of Valiolamine) and their Evaluation as Glycosidase Inhibitors
ChemCatChem, 2009Co-Authors: Lahssen El Blidi, Jean Bolte, Zeinab Assaf, Flora Camps Bres, H Veschambre, Vincent Thery, Marielle LemaireAbstract:A highly stereoselective method for the preparation of nitro- and Aminocyclitols, using fructose-1,6-bisphosphate aldolase, which catalyzes the aldol reaction of dihydroxyacetone phosphate (DHAP) on hydroxynitrobutanals, is reported. The key part of the synthesis is based on a one-pot /two-enzyme process whereby three reactions take place; rabbit muscle aldolase (RAMA) catalyzed aldolization, phytase-catalyzed phosphate hydrolysis, and intramolecular spontaneous nitroaldolization. Two families of nitrocyclitols were obtained depending on the carbon configuration in the β position to the nitro group. Reduction of the latter afforded the Aminocyclitols. Evaluation of the inhibition properties of the amines towards five commercially available glycosidases has shown selectivity for β-glucosidase and β-galactosidase.
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Synthèse chimioenzymatique et évaluation d'inhibiteurs potentiels de glycosidases, analogues de la valiolamine
2006Co-Authors: Lahssen El BlidiAbstract:Les glycosidases sont des enzymes impliquées dans un grand nombre de processus biologiques. Leurs inhibiteurs présentent un potentiel thérapeutique en tant qu'agents antidiabétiques, agents antiviraux ou agents pour traiter des maladies génétiques. Au cours de ce travail, nous nous sommes attachés à développer une voie de synthèse chimioenzymatique permettant d'accéder à des analogues de la valiolamine, puissant inhibiteurs d'alpha-glucosidases. Les Aminocyclitols que nous avions pour objectif de préparer diffèrent de la valiolamine par la position du groupement amino et des stéréochimies des hydroxyles. Nous avons synthétisé ces Aminocyclitols selon une méthode originale, basée sur un procédé en un seul pot mettant en jeu deux enzymes et trois réactions : une aldolisation catalysée par la fructose-1,6- biphosphate aldolase, une déphosphorylation catalysée par une phytase et une nitroaldolisation intramoléculaire. Ainsi deux liaisons C-C sont formées de façon hautement stéréosélective en une seule étape. Nous avons synthétisé neuf nouveaux Aminocyclitols et deux nouveaux zwitterions et dérivé N-alkylé. Quelque Aminocyclitols se sont révélés des inhibiteurs sélectifs de la béta-glucosidase d'amandes douces et de la béta-galactosidase d'Aspergillus oryzae.
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Straightforward chemo-enzymatic synthesis of new Aminocyclitols, analogues of valiolamine and their evaluation as glycosidase inhibitors.
Tetrahedron: Asymmetry, 2006Co-Authors: Lahssen El Blidi, Mustapha Ahbala, Jean Bolte, Marielle LemaireAbstract:An efficient fructose-1,6-bisphosphate aldolase mediated synthesis of new aminocyclitol analogues of valiolamine is described. The one-pot process where four stereocentres are created involves the formation of two carbon–carbon bonds. One is catalysed by the aldolase, coupling dihydroxyacetone phosphate to nitrobutyraldehydes. The other is the result of a highly stereoselective intramolecular Henry reaction occurring on the intermediate nitroketones. Depending on the configuration of the hydroxyl which is α to the nitro group, two series of configuration are accessible. The lipase resolution of the nitroalcohol ketal, precursor of the nitroaldehyde, is presented. The inhibition properties of the Aminocyclitols obtained after the reduction of the nitro group are evaluated towards five commercial glycosidases