The Multivalent Effect in Glycosidase Inhibition: Probing the Influence of Architectural Parameters with Cyclodextrin‐based Iminosugar Click Clusters

Abstract

In contrast to most lectins, glycosidases may appear to 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 of Cu(I) -catalyzed azide-alkyne cycloaddition reaction under microwave activation between propargylated multivalent β-cyclodextrins and an azide-armed N-alkyl 1-deoxynojirimycin derivative. Evaluation with a panel of glycosidases of this new class of glycomimetic clusters revealed the strongest affinity enhancement observed to date for a multivalent glycosidase inhibitor, with binding enhancement up to four orders of magnitude over the corresponding monovalent ligand for α-mannosidase. These results demonstrate that the multivalency concept extends beyond carbohydrate-lectin recognition processes to glycomimetic-enzyme inhibition.

Cyclodextrin-based multivalent glycodisplays: covalent and supramolecular conjugates to assess carbohydrate–protein interactions

“…The iminosugar clicked-cluster with the C 9 spacer (56, n = 8) exhibited the highest multivalent effect reported up to date against a glycosyl hydrolase: an inhibition constant (K i ) against Jack bean a-mannosidase of 0.022 mM was determined, as compared with 188-204 mM for monovalent DNJ controls, meaning a four orders of magnitude affinity enhancement. 108 The efficiency of the Sonogashira cross-coupling reaction in multiconjugation schemes was further illustrated by the synthesis of the 21-valent aMan conjugate 58 from heptakis(2,3,6-tri-O-propargyl)bCD 57 (Scheme 26). 112 Unfortunately, no systematic evaluation of lectin binding properties has been reported up to date for glycoclusters obtained using this strategy.…”

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

“…Another interest of the pyrene scaffold lies in its rigidity, a property that may favourably impact inhibitory multivalent effects [9,11,16,19]. A convergent approach comprising the attachment of azide-armed iminosugars 4 [11–12] on polyalkyne “clickable” scaffolds 5 and 6 via Cu(I)-catalyzed azide–alkyne cycloaddition (CuAAC) was performed for achieving our synthetic goals (Fig. 2) [56–57].…”

“…Following a robust strategy developed in our group [11–12], the last stages of the multivalent probe synthesis involved the attachment of peracetylated azido iminosugars 4 on the scaffolds via CuAAC reaction and afterwards O -deacetylation using an anion exchange resin. First attempts to perform CuAAC reactions with triyne substrate 6b bearing a tetraethylene glycol chain tethered to the boron center via an ethynyl bond proved difficult.…”

“…Despite their high therapeutic potential, the extensive studies in the field and the myriad of compounds synthesized, very few examples of multivalent iminosugars were reported in the literature until recently [9–10]. From 2010, the field has however experienced a major take-off with the discovery of the first strong multivalent effects in glycosidase inhibition observed with DNJ clusters based on β-cyclodextrin or C 60 cores showing strong affinity enhancements over the corresponding monomers (up to 610-fold per DNJ unit) [11–12]. In the following years, an impressive ever-growing number of multivalent iminosugars based on various scaffolds, ligands and linkers have been synthesized to further investigate the impact of multivalency on glycosidase inhibition [9–26].…”

Searching for Glycomimetics That Target Protein Misfolding in Rare Diseases: Successes, Failures, and Unexpected Progress Made in Organic Synthesis

“…104 To improve the multivalent effect further and to probe the influence of architectural parameters, we synthesized seven-to fourteen-valent iminosugar derivatives based on a cyclodextrin (β-CD) core. 105 The best compound of the series, the 14-valent DNJ-cyclodextrin conjugate 79 with a C 9 linker, was found to be a nanomolar inhibitor of JBα-Man ( Figure 12). Interestingly, it has been reported very recently that tetravalent DNJ clusters based on a rigid porphyrin scaffold also show a strong multivalent effect (over 200 on a molar basis).…”