A5041553746- Carbohydrate Chemistry and Synthesis
- Glycosylation and Glycoproteins Research
- Chemical Synthesis and Analysis
- Synthesis and Catalytic Reactions
- Synthetic Organic Chemistry Methods
- Lysosomal Storage Disorders Research
- Enzyme Production and Characterization
- Catalytic C–H Functionalization Methods
- Asymmetric Synthesis and Catalysis
- Click Chemistry and Applications
- Cyclopropane Reaction Mechanisms
- Chemical Synthesis and Reactions
- Sulfur-Based Synthesis Techniques
- Synthesis and Biological Evaluation
- Enzyme Catalysis and Immobilization
- Advanced Synthetic Organic Chemistry
- Biochemical and Molecular Research
- Catalytic Alkyne Reactions
- Asymmetric Hydrogenation and Catalysis
- Multicomponent Synthesis of Heterocycles
- Synthesis of Organic Compounds
- Trypanosoma species research and implications
- Oxidative Organic Chemistry Reactions
- Microbial Natural Products and Biosynthesis
- Sphingolipid Metabolism and Signaling
Université de Strasbourg
2015-2024
Centre National de la Recherche Scientifique
2015-2024
Université de Haute-Alsace
2018-2024
Laboratoire d'innovation moléculaire et applications
2018-2023
Laboratoire de Chémo-biologie synthétique et thérapeutique
2009-2019
Laboratoire de Synthèse Organique
2009-2017
Institut Européen de Chimie et Biologie
2014-2017
Institut de Chimie Organique et Analytique
2001-2017
Laboratoire National Henri Becquerel
2017
Ingenierie des Materiaux polymeres
2016
Superball! A dodecavalent iminosugar derivative with a fullerene core (see picture) shows binding enhancement of up to three orders magnitude over the corresponding monovalent ligand in glycosidase inhibition assays. This is first evidence significant multivalent effect inhibition.
Abstract Olefin metathesis is one of the most powerful synthetic tool to access amine‐containing heterocycles and alkaloids. A major drawback associated with use amines concerns their ability coordinate metal‐alkylidene complexes interfere unproductively catalytic activity. Based on literature precedents, it has been established as a “dogma” that efficient reactions are suppressed in presence basic such substrates must invariably be deactivated by conversion corresponding carbamates or...
Pushing C–H amination to its limits fosters innovative synthetic solutions and offers a deeper understanding of the reaction mechanism scope.
Remove to improve. Removal of the hydroxymethyl groups in 1 give 2 significantly enhances inhibitory potency towards glucosylceramide β-glucosidase (GCase) and abolishes inhibition α-glucosidases. Xylitol doubles residual activity GCase fibroblasts from Gaucher patients at subinhibitory concentration (10 nM). This compound is therefore a promising candidate for development small-molecule drugs treatment Gaucher's disease without side effects associated with α-glucosidase inhibition.
Abstract In contrast to most lectins, glycosidases may appear 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 Cu I ‐catalyzed azide–alkyne cycloaddition reaction under microwave activation between propargylated β‐cyclodextrins an azide‐armed N ‐alkyl...
Glycosidase inhibition with bioinspired glycoprotein analogue micellar self-assemblies.
Seven-arm chaperone: A modest μM inhibitor of glucosylceramide β-glucosidase (GCase) has been transformed into a potent low-nM by multivalency. This iminosugar acts as pharmacological chaperone and increases residual GCase activity in fibroblasts from Gaucher patients. These results open the way to new class chaperones for treatment lysosomal diseases. Detailed facts importance specialist readers are published "Supporting Information". Such documents peer-reviewed, but not copy-edited or...
A series of 18 mono- to 14-valent iminosugars with different ligands, scaffolds, and alkyl spacer lengths have been synthesized evaluated as inhibitors pharmacological chaperones β-glucocerebrosidase (GCase). Small but significant multivalent effects in GCase inhibition observed for two iminosugar clusters. Our study provides strong confirmation that compounds display the best affinity are not necessarily chaperones. The chaperoning effect a deprotected cluster has obtained tetravalent...
Abstract A series of O ‐alkyl iminoxylitol derivatives was synthesized and evaluated as β‐glucocerebrosidase (GCase) inhibitors. This structure–activity study shows a dramatic influence the position alkyl chain (α‐C1, O2, O3, or O4) on human GCase inhibition. Remarkably, 1,2‐shift from C1 to O2 found maintain high inhibitory potency toward well chaperone activity at sub‐inhibitory concentration (10 n M ). Removal stereogenic center pseudo‐anomeric led shorter more practical synthetic...
Abstract In view of recent reports a strong multivalent effect in glycosidase inhibition, library β‐CD‐based iminosugars has been efficiently synthesized by way Cu I ‐catalyzed azide–alkyne cycloaddition (CuAAC). combination with the first application isothermal titration calorimetry (ITC) experiments to study iminosugar–enzyme interactions, inhibition properties these click clusters were evaluated on panel glycosidases. The structural parameters that varied include valency, peripheral...
Abstract A series of cyclopeptoid‐based iminosugar clusters has been evaluated to finely probe the ligand content‐dependent increase in α‐mannosidase inhibition. This study led largest binding enhancement ever reported for an enzyme inhibitor (up 4700‐fold on a valency‐corrected basis), which represents substantial advance over multivalent glycosidase inhibitors previously reported. Electron microscopy imaging and analytical data support, best effects, formation strong chelate complex two...
Abstract Multivalent design of glycosidase inhibitors is a promising strategy for the treatment diseases involving enzymatic hydrolysis glycosidic bonds in carbohydrates. An essential prerequisite successful applications atomic‐level understanding how outstanding binding enhancement occurs with multivalent inhibitors. Herein we report first high‐resolution crystal structures Jack bean α‐mannosidase (JBα‐man) apo and inhibited states. The three‐dimensional structure JBα‐man complex multimeric...
Abstract A convergent strategy to access high‐valency iminosugar clusters based on two successive Cu I ‐catalysed azide–alkyne cycloadditions is reported. The key step of this approach relies the grafting azide‐armed trivalent dendrons onto polyalkyne “clickable” scaffolds, thus tripling their initial valency. As a proof concept, synthesis cyclodextrin‐based containing highest number peripheral ligands reported date has been achieved. Evaluation these compounds as mannosidase inhibitors...
We describe herein a convenient strategy for the construction of C,C-glycoside building blocks via intermediacy tertiary pseudoanomeric radicals. Application an iron-mediated hydrogen atom transfer/Michael–Giese coupling enables anomeric quaternization readily available exo-glycals with good to complete stereocontrol in pyranose and furanose series. Carefully optimized conditions allow use challenging trisubstituted derivatives prone undergo further elaboration stable neoglycoconjugates....
The first example of the formation a seven-membered ring by way intramolecular-catalyzed amination saturated C−H bonds is reported (Du Bois reaction). influence various structural parameters was studied, and it shown that unexpected regioselectivity observed in nitrogen-containing systems could be rationalized conformational factors. These results open to innovative strategies for general synthesis polyfunctionalized piperidines.
Abstract Cystic fibrosis is caused by a mutation in the gene for cystic transmembrane conductance regulator (CFTR) protein. N ‐butyl 1‐deoxynojirimycin ( ‐Bu DNJ), clinical candidate treatment of fibrosis, able to act as CFTR corrector overcoming processing defect mutant To explore potential multivalency on correction activity, library twelve DNJ click clusters with valencies ranging from 3 14 were synthesized. Significantly, trivalent analogues found be up 225‐fold more potent than and...
Cyclic N-propargyl α-peptoids of various sizes were prepared by way macrocyclizations linear N-substituted oligoglycines. These compounds used as molecular platforms to synthesize a series iminosugar clusters with different valency and alkyl spacer lengths means Cu(I)-catalysed azide-alkyne cycloadditions. Evaluation these α-mannosidase inhibitors led significant multivalent effects further demonstrated the decisive influence scaffold rigidity on binding affinity enhancements.