Design and synthesis of novel 3-triazolyl-1-thiogalactosides as galectin-1, -3 and -8 inhibitors

Abstract

A new series of potent galectin ligands based on the galactose and triazole moieties was designed and synthesised.

Glycocalix[4]arenes and their affinity to a library of galectins: the linker matters

“…7 Novel carbohydrate inhibitors can be designed by constructing oligosaccharides (especially of blood-group-antigen 8 or poly-LacNAc-type) 9 or by chemical derivatization of the galactopyranose ring. [10][11][12] Another possible way of increasing the relatively low affinity of natural β-galactoside ligands to galectins is their multivalent presentation. In the past, multivalent systems such as glycodendrimers, 13,14 various types of synthetic polymers, 7,15 or peptide nanofibers 16 have been presented.…”

Lactose-Functionalized Carbosilane Glycodendrimers Are Highly Potent Multivalent Ligands for Galectin-9 Binding: Increased Glycan Affinity to Galectins Correlates with Aggregation Behavior

“…In our present study, the positive impact of the N -triazole linker adjacent to the carbohydrate moiety is evident for all galectin types, including tandem-repeat galectins. The N -triazole part interacts with the less conserved subsite E in the binding grove, which has so far been only marginally studied, especially in connection with glycomimetic thiodigalactoside inhibitors. , There, arginine-π interactions have been deemed responsible for the affinity increase, particularly with Gal-3 (Arg186). Since conserved arginine residues are found in the subsite E of galectins (i.e., Arg74 for Gal-1, Arg254 for Gal-8C, Arg87 for Gal-9N, and Arg260 for Gal-9C), we hypothesize that this might be a particular conserved feature of the galectin CRD domain influencing linker binding to subsite E; however, this can only be reliably confirmed by a crystallography study.…”

“…22−24 Substantial differences in the binding modes are also found in the interactions with the less defined subsite E, localized at the reducing end of carbohydrate ligands. 25,26 The multivalent presentation of glycan ligands in macromolecules represents another natural strategy to ensure effective ligand−protein interaction. In multivalent ligand molecules, the overall binding potency can exceed the sole sum of monovalent ligand affinities by orders of magnitude.…”

“…Gal-1 compared to Gal-3 also contains a specific residue, His52, interacting with ligands in subsites C and D; in contrast to Gal-3, Gal-1 is well known to be acting as an exo-type lectin for longer oligosaccharide ligands, recognizing only the terminal disaccharide. The systematic development of small-molecule glycomimetic ligands revealed the influence of configuration and substitution at individual positions of the carbohydrate, e.g., an aromatic substitution at the C-3 position, on the potency and selectivity of the ligand. − Substantial differences in the binding modes are also found in the interactions with the less defined subsite E, localized at the reducing end of carbohydrate ligands. , The multivalent presentation of glycan ligands in macromolecules represents another natural strategy to ensure effective ligand–protein interaction. In multivalent ligand molecules, the overall binding potency can exceed the sole sum of monovalent ligand affinities by orders of magnitude. , Moreover, unlike monovalent systems, the multivalent glycoconjugates can form unique two- and three-dimensional lattices with galectin receptors.…”

Inhibition of galectins in cancer: Biological challenges for their clinical application

“…The first described galectin inhibitors are molecules capable of binding to the CRD and preventing further ligand binding. Galectin inhibitors based on these competitive interactions consist of chemically modified mono or disaccharides structured around galactose ( 58 , 122 – 125 ), lactose ( 58 , 125 – 127 ), thiodigalactose (TDG) ( 34 , 128 – 132 ), talose ( 133 , 134 ) and lactulose ( 135 ). One of the first tempts to use this type of inhibitor in cancer consisted of administering a β-D-lactosyl-steroid.…”