Tight-binding inhibition of jack bean α-mannosidase by glycoimidazole clusters.

The best multivalent effects observed in glycosidase inhibition have been achieved so far with jack bean α-mannosidase (JBα-man) using iminosugar clusters based on weakly binding mismatching active-site-directed inhibiting epitopes (inhitopes) in the d-gluco series. Here, we synthesize and evaluate as JBα-man inhibitors a series of mono- to 14-valent glycoimidazoles with inhitopes displaying inhibition values up to the range of hundreds of nMs to study the impact of inhitope affinity on the multivalent effect. The most potent inhibitor of the series, a 14-valent mannoimidazole derivative, inhibits JBα-man with a nanomolar Ki value (2 ± 0.5 nM) and binding enhancements observed are, at best, relatively small (up to 25-fold on a valency-corrected basis). The results of this study support the fact that JBα-man-inhitope affinity and the strength of the inhibitory multivalent effect evolve in the opposite direction. The major impact of the glycoimidazole-based inhitope is found on the binding scenario; most of the synthesized mannoimidazole clusters as well as a 14-valent glucoimidazole derivative prove to be tight binding inhibitors of JBα-man.

Selective Targeting of the Interconversion between Glucosylceramide and Ceramide by Scaffold Tailoring of Iminosugar Inhibitors.

A series of simple C-alkyl pyrrolidines already known as cytotoxic inhibitors of ceramide glucosylation in melanoma cells can be converted into their corresponding 6-membered analogues by means of a simple ring expansion. This study illustrated how an isomerisation from iminosugar pyrrolidine toward piperidine could invert their targeting from glucosylceramide (GlcCer) formation toward GlcCer hydrolysis. Thus, we found that the 5-membered ring derivatives did not inhibit the hydrolysis reaction of GlcCer catalysed by lysosomal ß-glucocerebrosidase (GBA). On the other hand, the ring-expanded C-alkyl piperidine isomers, non-cytotoxic and inactive regarding ceramide glucosylation, revealed to be potent inhibitors of GBA. A molecular docking study showed that the positions of the piperidine ring of the compound 6b and its analogous 2-O-heptyl DIX 8 were similar to that of isofagomine. Furthermore, compound 6b promoted mutant GBA enhancements over 3-fold equivalent to that of the related O-Hept DIX 8 belonging to one of the most potent iminosugar-based pharmacological chaperone series reported to date.

Stereodivergent synthesis of right- and left-handed iminoxylitol heterodimers and monomers. Study of their impact on ß-glucocerebrosidase activity.

A library of dimers and heterodimers of both enantiomers of 2-O-alkylated iminoxylitol derivatives has been synthesised and evaluated on ß-glucocerebrosidase (GCase), the enzyme responsible for Gaucher disease (GD). Although the objective was to target simultaneously the active site and a secondary binding site of the glucosidase, the (-)-2-iminoxylitol moiety seemed detrimental for imiglucerase inhibition and no significant enhancement was obtained in G202R, N370S and L444P fibroblasts. However, all compounds having at least one (+)-2-O-alkyl iminoxylitol are GCase inhibitors in the nano molar range and are significant GCase activity enhancers in G202R fibroblats, as confirmed by a decrease of glucosylceramide levels and by co-localization studies.

Correction: Stereodivergent synthesis of right- and left-handed iminoxylitol heterodimers and monomers. Study of their impact on ß-glucocerebrosidase activity.

Correction for 'Stereodivergent synthesis of right- and left-handed iminoxylitol heterodimers and monomers. Study of their impact on ß-glucocerebrosidase activity' by Fabien Stauffert et al., Org. Biomol. Chem., 2017, 15, 3681-3705.

Iminosugar-based ceramide mimicry for the design of new CERT START domain ligands.

The enigmatical dichotomy between the two CERT/GPBP protein isoforms, their vast panel of biological implications and the scarcity of known antagonist series call for new ligand chemotypes identification. We report the design of iminosugar-based ceramide mimics for the development of new START domain ligands potentially targeting either protein isoforms. Strategic choice of (i) an iminoxylitol core structure and (ii) the positioning of two dodecyl residues led to an extent of protein binding comparable to that of the natural cargo lipid ceramide or the archetypical inhibitor HPA-12. Molecular docking study evidenced a possible mode of protein binding fully coherent with the one observed in crystalline co-structures of known ligands. The present study thus paves the way for cellular CERT inhibition studies en route to the development of pharmacological tools aiming at deciphering the respective function and therapeutic potential of the two CERT/GPBP protein isoforms.

Iminosugars as a new class of cholinesterase inhibitors.

To further extend the scope of iminosugar biological activity, a systematic structure-activity relationship investigation has been performed by synthesizing and evaluating as cholinesterase inhibitors a library of twenty-three iminoalditols with different substitutions and stereochemistry patterns. These compounds have been evaluated in vitro for the inhibition of cholinesterases (different sources of acetylcholinesterase and butyrylcholinesterase). Some compounds have IC50 values in the micromolar range and display significant inhibition selectivity for butyrylcholinesterase over acetylcholinesterase. These are the first examples of iminosugar-based inhibitors of cholinesterases.

Design, synthesis and photochemical properties of the first examples of iminosugar clusters based on fluorescent cores.

The synthesis and photophysical properties of the first examples of iminosugar clusters based on a BODIPY or a pyrene core are reported. The tri- and tetravalent systems designed as molecular probes and synthesized by way of Cu(I)-catalysed azide-alkyne cycloadditions are fluorescent analogues of potent pharmacological chaperones/correctors recently reported in the field of Gaucher disease and cystic fibrosis, two rare genetic diseases caused by protein misfolding.