Search

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]

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]

Enzyme inhibition through mimicry of the transition state is a major area for the design of new therapeutic agents. Emerging evidence suggests that many retaining glycosidases that are active on α- or β-mannosides harness unusual B2,5 (boat) transition states. Here we present the analysis of 25 putative β-mannosidase inhibitors, whose Ki values range from nanomolar to millimolar, on the Bacteroides thetaiotaomicron β-mannosidase BtMan2A. B2,5 or closely related conformations were observed for all tightly binding compounds. Subsequent linear free energy relationships that correlate log Ki with log Km/kcat for a series of active center variants highlight aryl-substituted mannoimidazoles as powerful transition state mimics in which the binding energy of the aryl group enhances both binding and the degree of transition state mimicry. Support for a B2,5 transition state during enzymatic β-mannosidase hydrolysis should also facilitate the design and exploitation of transition state mimics for the inhibition of retaining α-mannosidases—an area that is emerging for anticancer therapeutics. [ABSTRACT FROM AUTHOR]

Abstract: 1,6-Dideoxygalactostatin, the mirror image of 1-deoxy-l-fuconojirimycin, was efficiently prepared from 2,3-O-isopropylidene-l-lyxonolactone in four steps and evaluated as a glycosidase inhibitor. [Copyright &y& Elsevier]

Abstract: Eight new seven-membered ring iminoalditols, displaying an amino group and a hydroxymethyl group on the ring, have been synthesized from d-arabinose via epoxidation of a protected azacycloheptene and subsequent nucleophilic opening. Three of them show a potent glycosidase inhibition on amyloglucosidase and, to a lesser extend, on α-l-fucosidase. [Copyright &y& Elsevier]

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]