Synthesis and Glycosidase Inhibition Properties of Calix[8]arene-Based Iminosugar Click Clusters

Abstract

A set of 6- to 24-valent clusters was constructed with terminal deoxynojirimycin (DNJ) inhibitory heads through C6 or C9 linkers by way of Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) reactions between mono- or trivalent azido-armed iminosugars and calix[8]arene scaffolds differing in their valency and their rigidity but not in their size. The power of multivalency to upgrade the inhibition potency of the weak DNJ inhibitor (monovalent DNJ Ki being at 322 and 188 µM for C6 or C9 linkers, respectively) was evaluated on the model glycosidase Jack Bean α-mannosidase (JBα-man). Although for the clusters with the shorter C6 linker the rigidity of the scaffold was essential, these parameters had no influence for clusters with C9 chains: all of them showed rather good relative affinity enhancements per inhibitory epitopes between 70 and 160 highlighting the sound combination of the calix[8]arene core and the long alkyl arms. Preliminary docking studies were performed to get insights into the preferred binding modes.

Bambus[4,6]urils as Dual Scaffolds for Multivalent Iminosugar Presentation and Ion Transport: Access to Unprecedented Glycosidase-Directed Anion Caging Agents

“…With the longer C9 linker, the impact of the central scaffold, whatever its size, is abolished, giving similar affinity enhancement per DNJ (entries 4, 9 and 10) with C9 enhancement being at least one order of magnitude higher than for the C6 series. This result is in line with previous findings using other scaffolds [ 15 , 16 , 17 , 18 , 19 , 20 , 43 ]. The best results were obtained with clusters 5 and 11 grafted with the trivalent dendron with affinity enhancements one order of magnitude higher than those of compounds 4 , 7 and 10 .…”

“…As in a previous study with calix[ 8 ]arene-based clusters [ 43 ], the scaffold has a strong impact on inhibition with the C6 shorter linker. Whereas the inhibitory heads of cluster 3 based on the smaller BU[4] scaffold are individually four times more potent than the reference ( rp/n = 4), the ones of clusters 6 , 8 and 9 based on BU[6] are less active than the monovalent reference ( rp/n < 1) and show a different inhibition mode ( Table 1 entries 6-8).…”

Hybrid Multivalent Jack Bean α-Mannosidase Inhibitors: The First Example of Gold Nanoparticles Decorated with Deoxynojirimycin Inhitopes

“…For AuGNPs 1 – 5 , the carbohydrate moieties guarantee their water dispersibility, while the water soluble and flexible amphiphilic linker was designed to protrude the DNJ heads from the glyco-coated nanoparticle core. In addition, the N -C 6 aliphatic linker of the active component DNJ is taking part in the interaction with the catalytic site entry [ 11 , 24 ]. This strategy of ligand presentation was based on our previous experience with similar constructs [ 21 , 22 , 25 ].…”

Phosphorus Dendrimers for Metal‐Free Ligation: Design of Multivalent Pharmacological Chaperones against Gaucher Disease

“…Two N ‐alkylated derivatives thereof, Zavesca® and Miglitol®, are approved drugs respectively against Gaucher disease [15] (GD), the most common lysosomal storage disease [16,17] (LSD), and against type II diabetes mellitus [18] . Since 2009, the DNJ inhitope has been grafted onto a large variety of multivalent scaffolds such as fullerenes, dendrimers, calixarenes, cyclodextrins, cyclopeptides inter alia to generate multivalent glycosidases inhibitors [7,19–26] . These studies have highlighted the importance of both platform topology and valency on the resulting biological activity.…”

“…Génisson dendrimers, calixarenes, cyclodextrins, cyclopeptides inter alia to generate multivalent glycosidases inhibitors. [7,[19][20][21][22][23][24][25][26] These studies have highlighted the importance of both platform topology and valency on the resulting biological activity. To graft the inhitope onto the surface of the multivalent scaffold, the Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) remains the preferred reaction.…”