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Mucopolysaccharidosis type IIIB is a devastating neurological disease caused by a lack of the lysosomal enzyme, α‐N‐acetylglucosaminidase (NAGLU), leading to a toxic accumulation of heparan sulfate. Herein we explored a pharmacological chaperone approach to enhance the residual activity of NAGLU in patient fibroblasts. Capitalizing on the three‐dimensional structures of two modest homoiminosugar‐based NAGLU inhibitors in complex with bacterial homolog of NAGLU, CpGH89, we have synthesized a library of 17 iminosugar C‐glycosides mimicking N‐acetyl‐D‐glucosamine and bearing various pseudo‐anomeric substituents of both α‐ and β‐configuration. Elaboration of the aglycon moiety results in low micromolar selective inhibitors of human recombinant NAGLU, but surprisingly it is the non‐functionalized and wrongly configured β‐homoiminosugar that was proved to act as the most promising pharmacological chaperone, promoting a 2.4 fold activity enhancement of mutant NAGLU at its optimal concentration. [ABSTRACT FROM AUTHOR]

This account describes our efforts dedicated to: 1) the design of glycomimetics aimed at targeting therapeutically relevant carbohydrate processing enzymes, and 2) the observation, characterization, and exploitation of glycosyl cations as a tool for studying the glycosylation reaction. These findings have brought important data regarding this key ionic species as well as innovative strategies to access iminosugars of interest. 1 Introduction 2 The Glycosyl Cation, A Central Species in Glycosciences 2.1 A Selection of the Strategies Developed so far to Gain Insights into Glycosyl Cations Structure 2.2 When Superacids Meet Carbohydrates 3 Chemical Probes to Gain Insights into the Pseudorotational Itinerary of Glycosides During Glycosidic Bond Hydrolysis 3.1 Conformationally Locked Glycosides 3.1.1 The Xylopyranose Case 3.1.2 The Mannopyranose Case 3.2 Conformationally Flexible Iminosugars 3.2.1 Nojirimycin Ring Homologues 3.2.2 Noeuromycin Ring Homologues 3.2.3 Seven-Membered Iminosugar C -Glycosides 4 N-Acetyl- d -glucosamine Mimics 5 Ring Contraction: A Useful Tool to Increase Iminosugar's Structural Diversity 6 Regioselective Deprotection of Iminosugar C -Glycosides to Introduce Diversity at C2 Position 7 Conclusion [ABSTRACT FROM AUTHOR]

The synthesis of a series of six‐membered 2‐acetamido l‐iminosugar C‐alkyl and C‐aryl glycosides is reported. A diastereoselective sugar‐ring enlargement/C‐alkylation (or arylation) /ring‐contraction sequence applied to d‐gluco‐ and d‐manno‐configured 2‐acetamido azidolactols provides new l‐iminosugar C‐glycosides. The 1,2‐trans stereocontrolled introduction of the pseudoanomeric substituent in these heterocycles strongly suggests a NHAc neighbouring‐group participation. In their deprotected form, the nine iminosugars exhibit moderate hexosaminidases and β‐glucuronidase inhibition. A Staudinger/azawittig/Grignard/ring‐contraction sequence applied to two d‐glycopyranose derivatives bearing an acetamido group at the C‐2 position and an azido group at the C‐6 position allows access to unprecedented six‐membered l‐iminosugars C‐glycosides as GlcNAc and ManNAc mimics. The high 1,2‐trans diastereoselectivity observed for the Grignard addition strongly suggests an anchimeric assistance by the NHAc group. [ABSTRACT FROM AUTHOR]

A set of multivalent polyhydroxylated acetamidoazepanes based on ethylene glycol, glucoside, or cyclodextrin scaffolds was prepared. The compounds were assessed against plant, mammalian, and therapeutically relevant hexosaminidases. Multimerization was shown to improve the inhibitory potency with synergy, and to fine tune the selectivity profile between related hexosaminidases. [ABSTRACT FROM AUTHOR]

The synthesis of 1,2-cis-homoiminosugars bearingan NHAc group at the C-2 position is described. The key step to preparethese α-d-GlcNAc and α-d-GalNAc mimicsutilizes a β-amino alcohol skeletal rearrangement applied toan azepane precursor. This strategy also allows access to naturallyoccurring α-HGJ and α-HNJ. The α-d-GlcNAc-configurediminosugar was coupled to a glucoside acceptor to yield a novel pseudodisaccharide.Preliminary glycosidase inhibition evaluation indicates that the α-d-GalNAc-configured homoiminosugar is a potent and selectiveα-N-acetylgalactosaminidase inhibitor. [ABSTRACT FROM AUTHOR]

The first synthesis of 1,2-trans-homoiminosugarsdevised as mimics of β-d-GlcNAc and α-d-ManNAc is described. Key steps include a regioselective azidolysisof a cyclic sulfite and a β-amino alcohol skeletal rearrangementapplied to a polyhydroxylated azepane. The β-d-GlcNAcderivative has been coupled to serine to deliver an iminosugar C-amino acid. The two homoiminosugars demonstrate moderateglycosidase inhibition. [ABSTRACT FROM AUTHOR]

The conformational analysis of a series of tri- and tetrahydroxyazepanes 1–6 designed as noeuromycin mimics has been carried out using 1H NMR spectroscopy assisted by molecular mechanics, molecular dynamics and Monte Carlo calculations. A marked flexibility for these compounds has been found. Superimposition of the branched azepanes with known glycosidase inhibitors (DMJ, DNJ, IFG and noeuromycin) was in accordance with the glycosidase inhibition profile of the polyhydroxylated azepanes. Additional STD experiments confirmed the potency and competitive character of azepane 3 towards almond β-glucosidase. [ABSTRACT FROM AUTHOR]

Two bicyclic iminosugars have been synthesized from polyhydroxylated azepanes by ring isomerization followed by debenzylative cyclization. Their conformations have been studied by NMR and molecular modeling and their glycosidase inhibition profiles were determined. They both adopt a chair conformation for the piperidine ring and display weak inhibition on α-glucosidases. [ABSTRACT FROM PUBLISHER]

Capitalizing on a previously developed Staudinger/azaWittig/Grignard (SAWG)-ring contraction sequence that furnished protected six-membered L-iminosugar C,C -glycosides bearing an allyl group and various substituents at the pseudoanomeric position, the synthesis and glycosidase inhibition of a small library of six- and seven-membered L-iminosugar C,C -glycosides is reported. Their hydrogenolysis or cyclization by RCM followed by deprotection afforded eleven L-iminosugars including spirocyclic derivatives. All compounds adopt a 1C 4 conformation in solution according to NMR data. Compared to previously reported branched L-iminosugars, the L-iminosugar C,C -glycosides reported herein were less potent glycosidase inhibitors. However, some of these compounds showed micromolar inhibition of human lysosome β-glucocerebrosidase suggesting that such iminosugars could be useful to access potent CGase inhibitors by adjusting the structure/length of the pseudoanomeric substituents. [Display omitted] • First biological evaluation of L-iminosugar C,C -glycosideson glycosidases including lysosomal enzymes. • First synthesis of a seven-membered L-iminosugar C,C -glycoside bearing a spirocycle at the pseudoanomeric position. • The six-membered L-iminosugar C,C -glycosides adopt a 1 C 4 conformation according to NMR data. [ABSTRACT FROM AUTHOR]

A ring-contraction strategy applied to β-azido,γ-hydroxyazepanes yielded after functional group manipulation new tetrahydroxylated pyrrolidines displaying an acetamido moiety, one of these iminosugars demonstrating low micromolar inhibition on N-acetylglucosaminidases. [ABSTRACT FROM AUTHOR]

The Ho crossed aldol condensation provides access to a series of carbon branched iminosugars as exemplified by the synthesis of enantiomeric pairs of isoDMDP, isoDGDP, and isoDAB, allowing comparison of their biological activities with three linear isomeric natural products DMDP, DGDP, and DAB and their enantiomers. L-IsoDMDP [(2S,3S,4R)-2,4-bis(hydroxymethyl)pyrrolidine-3,4-diol], prepared in 11 steps in an overall yield of 45% from D-lyxonolactone, is a potent specific competitive inhibitor of gut disaccharidases [Ki 0.081 μM for rat intestinal maltase] and is more effective in the suppression of hyperglycaemia in a maltose loading test than miglitol, a drug presently used in the treatment of late onset diabetes. The partial rescue of the defective F508del-CFTR function in CF-KM4 cells by L-isoDMDP is compared with miglustat and isoLAB in an approach to the treatment of cystic fibrosis. [ABSTRACT FROM AUTHOR]

Abstract: Four branched tetra- and pentahydroxylated azepanes have been synthesized from a common azepane precursor through dihydroxylation followed by deoxygenation. They have been assayed as glycosidase inhibitors on a panel of 22 glycosidases and one methylated azepane displayed selective, competitive, and moderate inhibition toward bovine kidney α-l-fucosidase. [Copyright &y& Elsevier]

A flexible synthetic access to six-membered l- and d-iminosugar C-glycosides is reported starting from the easily available 6-azido-6-deoxy-2,3,4-tri-O-benzyl-d-glucopyranose precursor. This methodology involves a highly diastereoselective tandem ring enlargement/alkylation and a stereocontrolled ring contraction. It allows an efficient synthesis of iminosugar C-glycosides displaying structural diversity at both C-1 and C-6. [ABSTRACT FROM AUTHOR]

Abstract: Noeuromycin is a highly potent albeit unstable glycosidase inhibitor due to its hemiaminal function. While stable d-gluco-like analogs have been reported, no data are available for d-manno-like structures. A series of tri- and tetrahydroxylated seven-membered iminosugars displaying either a d-manno-or a l-gulo-like configuration, were synthesized from methyl α-d-mannopyranoside using a reductive amination-mediated ring expansion as the key step. Screening towards a range of commercial glycosidases demonstrated their potency as competitive glycosidase inhibitors while cellular assay showed selective albeit weak glycoprotein processing mannosidase inactivation. [Copyright &y& Elsevier]

Abstract: Acetonides are the only protecting groups used in the syntheses of isoDAB from d-ribose and of isoLAB from d-tagatose. isoDAB is a potent and highly specific competitive α-glucosidase inhibitor (for rice α-glucosidase, K i =4μM for isoDAB compared to K i 14μM for DAB). isoDAB is not an—whereas DAB is a potent—inhibitor of glycogen phosphorylase. This is the first example of any potent inhibition of glycosidases by a carbon-branched iminosugar pyrrolidine. Although isoLAB shows no inhibition of any glycosidase, preliminary experiments suggest that isoLAB partially rescues the defective F508del-CFTR function and so may have a role in the study of cystic fibrosis. [Copyright &y& Elsevier]

Abstract: A series of seven-membered iminosugars bearing an acetamido group β- or γ- to the endocyclic nitrogen have been synthesized via simple transformations of previously described polysubstituted azepanes. These tetra- and trihydroxylated acetamido azepanes are ring homologues of 2-acetamido-1,2-dideoxy-glyconojirimycins and 2-acetamido-1-N-iminosugars respectively. Screening of these azepanes towards a range of commercially available glycosidases demonstrated their potential as selective and potent hexosaminidase inhibitors with K i’s in the submicromolar range. A correlation between the relative configuration of the azepanes and their ability to inactivate hexosaminidases was also observed for the first time for this class of compounds with one notable exception for the most potent compound. [Copyright &y& Elsevier]

A set of bicyclic iminosugar C-glycosides, based on an octahydrofuro[3,2-b]pyridine motif, has been synthesized from a C -allyl iminosugar exploiting a debenzylative iodocycloetherification and an iodine nucleophilic displacement as the key steps. The halogen allowed the introduction of a range of aglycon moieties of different sizes bearing several functionalities such as alcohol, amine, amide and triazole. In these carbohydrate mimics the fused THF ring forces the piperidine to adopt a flattened 4 C 1 conformation according to NMR and DFT calculations studies. In their deprotected form, these bicycles were assayed on a panel of 23 glycosidases. The iminosugars displaying hydrophobic aglycon moieties proved to be superior glycosidase inhibitors, leading to a low micromolar inhibition of human lysosome β-glucosidase (compound 11 ; IC 50 = 2.7 μM) and rice α-glucosidase (compound 10 ; IC 50 = 7.7 μM). Finally, the loose structural analogy of these derivatives with Thiamet G, a potent OGA bicyclic inhibitor, was illustrated by the weak OGA inhibitory activity (Ki = 140 μM) of iminosugar 5. [Display omitted] • Bicyclic iminosugars disclosed to mimic the oxocarbenium character of hexosaminidases TS and the substrate assisted catalysis. • synthetic methodology allows introduction of structural diversity at the aglycon moiety. • Conformational analysis demonstrates a conformation close to the one observed for NAG thiazoline. • Evaluation as glycosidase inhibitors leads to weak hexosaminidase but potent α-glucosidase inhibitors. [ABSTRACT FROM AUTHOR]