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

Abstract

Bambusurils, BU[4] and BU[6], were used for the first time as multivalent scaffolds to link glycosidases inhibitors derived from 1-deoxynojirimycin (DNJ). Two linear DNJ ligands having six or nine carbon alkyl azido linkers or a trivalent DNJ dendron were grafted onto octapropargylated BU[4] and dodecapropargylated BU[6] using copper-catalyzed cycloaddition (CuAAC) to yield corresponding neoglycobambus[4] and neoglycobambus[6]urils bearing 8 to 24 iminosugars. The inhibition potencies of neoglycoBU[4], neoglycoBU[6] and neoglycoBU[6] caging anions were evaluated against Jack Bean α-mannosidase and compared to monovalent DNJ derivatives. Strong affinity enhancements per inhibitory head were obtained for the clusters holding trivalent dendrons with inhibitory constants in the nanomolar range (Ki = 24 nM for BU[4] with 24 DNJ units). Interestingly, the anion (bromide or iodide) encapsulated inside the cavity of BU[6] does not modify the inhibition potency of neoglycoBU[6], opening the way to water-soluble glycosidase-directed anion caging agents that may find applications in important fields such as bio(in)organic chemistry or oncology.

From Sweet Molecular Giants to Square Sugars and Vice Versa

“…This strategy was first successfully applied to pentaerythritol and cyclodextrin as model scaffolds. 43 Neoglycodendrimers based on cyclopeptoid, 44 45 C 60 , 46 bambusuril 47 or calixarene 48 cores were then synthesized using first- and second-generation pentaerythritol-based dendrons with a valency of three and nine, respectively. The potential of [60]fullerene hexakis-adducts as building blocks to construct large molecules was further harnessed to develop an ultrafast synthetic strategy.…”

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.…”

Synthesis of Novel Phosphorus-Containing Derivatives of 1,3,4-Trimethylglycoluril via the Birum–Oleksyszyn Reaction

“…Glycoluril derivatives have attracted the attention of researchers due to their wide range of applications and, above all, due to their biological activities, particularly their nootropic, neurotropic, anxiolytic [1,2], and antibacterial properties [3,4]. Additionally, glycoluril derivatives are widely used as "building blocks" to synthesize supramolecular compounds such as bambus[n]urils [5,6], cucurbit[n]urils [7,8], and molecular clips [9,10]. Special attention has been paid to studying methods for synthesizing new glycoluril derivatives and their structural analogs and precursors as well as to the characterization of their properties [11][12][13][14][15].…”

“…H NMR (400 MHz, DMSO-d 6 ): δ 7.75-7.70 (m, 2H), 7.54-7.45 (m, 4H), 7.42-7.33 (m, 4H), 7.28-7.19 (m, 2H), 7.12-7.05 (m, 2H),6.97 (dt, J = 8.5, 1.2 Hz, 2H), 5.77 (d, J = 27.4 Hz, 1H), 5.28 (dd, J = 8.5, 1.3 Hz, 1H), 5.24 (d, J = 8.5 Hz, 1H), 2.94 (s, 3H), 2.88 (s, 3H), 2.57 (s, 3H) 13. C NMR (101 MHz, DMSO): 159.06, 158.37 (d, J = 3.7 Hz), 150.59 (d, J = 9.9 Hz), 134.76, 130.17(d, J = 18.7 Hz), 129.45 (d, J = 6.6 Hz), 129.12, 125.55 (d, J = 15.0 Hz), 120.90 (dd, J = 9.1, 4.1 Hz), 72.40, 72.14 (d, J = 5.0 Hz), 57.37 (d, J = 155.9 Hz), 30.70, 30.27, 30.13; 31 P NMR (162 MHz, DMSO-d6): δ 14.06 (d, J = 27.1 Hz).…”