C₂‐Symmetrical Thiodigalactoside Bis‐Benzamido Derivatives as High‐Affinity Inhibitors of Galectin‐3: Efficient Lectin Inhibition through Double Arginine–Arene Interactions

Abstract

Inhibitors of galectin‐3, which has been implicated in cancer‐ and immunity‐related processes, can be synthesized from thiodigalactoside derivatives with aromatic amide substituents at both C3 positions (see structure). Dissociation constant (Kd) values as low as 33 nM have been obtained. Computer modeling suggests that such high affinity stems from double arginine–arene stacking interactions.

A Galectin-3 Ligand Corrects the Impaired Function of Human CD4 and CD8 Tumor-Infiltrating Lymphocytes and Favors Tumor Rejection in Mice

“…EC 50 s were estimated for LacNAc at 9 and 18 μmol/L, respectively. Different modified citrus pectins and synthetic ligands were previously shown to detach galectin-3 in a solid-phase assay with EC 50 as low as 1 mmol/L (22,(39)(40)(41)(42). The most effective synthetic galectin-3 ligand seems to be a thiodigalactoside derivative that has a K d of 33 nmol/L (39).…”

The Inhibitory Effects of a Rhamnogalacturonan Ι (RG-I) Domain from Ginseng Pectin on Galectin-3 and Its Structure-Activity Relationship

“…Because galectin-3 contributes to tumor progression, numerous studies have focused on the development of specific galectin-3 inhibitors including peptide antagonists (14), lactu-* This work was supported by National Natural Science Foundation of lose amines (15), and galactose-based inhibitors (16,17). In addition to these synthetic molecules, a natural product, pectin, has emerged as a good source for generating high affinity galectin-3 inhibitors with low toxicity.…”

Structure-Based Optimization of Angiostatic Agent 6DBF7, an Allosteric Antagonist of Galectin-1

“…Most other known galectin antagonists are b-galactoside analogs and glycomimetics that target the canonical carbohydrate binding site, primarily to antagonize galectins 1, 3, 7, 8, and 9. These include aryl O-and S-galactosides and lactosides (Giguere et al, 2006;Sirois et al, 2006), carbohydrate-based triazoles and isoxazoles (Salameh et al, 2005;Giguere et al, 2006), O-galactosyl aldoximes (Tejler et al, 2005), phenyl thio-b-Dgalactopyranoside analogs (Cumpstey et al, 2005a), thioureido N-acetyllactosamine derivatives (Salameh et al, 2006), talosides (Collins et al, 2012), and various multivalent sugarbased compounds (Cumpstey et al, 2005b;Ingrassia et al, 2006;Rabinovich et al, 2006;Tejler et al, 2006). Most of these compounds, unlike 6DBF7 and its analogs, bind galectins rather weakly (K d values .100 mM).…”