Calix[n]arene‐Based Glycoclusters: Bioactivity of Thiourea‐Linked Galactose/Lactose Moieties as Inhibitors of Binding of Medically Relevant Lectins to a Glycoprotein and Cell‐Surface Glycoconjugates and Selectivity among Human Adhesion/Growth‐Regulatory Galectins

Abstract

Growing insights into the functionality of lectin-carbohydrate interactions are identifying attractive new targets for drug design. As glycan recognition is regulated by the structure of the sugar epitope and also by topological aspects of its presentation, a suitable arrangement of ligands in synthetic glycoclusters has the potential to enhance their avidity and selectivity. If adequately realized, such compounds might find medical applications. This is why we focused on lectins of clinical interest, acting either as a potent biohazard (a toxin from Viscum album L. akin to ricin) or as a factor in tumor progression (human galectins-1, -3, and -4). Using a set of 14 calix[n]arenes (n=4, 6, and 8) with thiourea-linked galactose or lactose moieties, we first ascertained the lectin-binding properties of the derivatized sugar head groups conjugated to the synthetic macrocycles. Despite their high degree of flexibility, the calix[6,8]arenes proved especially effective for the plant AB-toxin, in the solid-phase model system with a single glycoprotein (asialofetuin) and with human tumor cells in vitro. The bioactivity of the calix[n]arenes was also proven for human galectins. Notably, selectivity for the tested tandem-repeat-type galectin-4 among the three subgroups was determined at the level of solid-phase and cell assays, the large flexible macrocycles again figuring prominently as inhibitors. Alternate and cone versions of calix[4]arene with lactose units distinguished between galectins-1 and -4 versus galectin-3 in cell assays. The results thus revealed bioactivity of galactose-/lactose-presenting calix[n]arenes for medically relevant lectins and selectivity within the family of adhesion/growth-regulatory human galectins.

From structural to functional glycomics: core substitutions as molecular switches for shape and lectin affinity of N-glycans

“…determinants, this factor is supposed to be relevant for modulating avidity of interaction of glycan determinants in natural glycoproteins with lectins. Respective data on importance of branching and local density have already been presented, e.g., in the case of adhesion/growthregulatory mammalian galectins, and are being exploited in glycocluster design (André et al, 1999(André et al, , 2008Wu et al, 2004Wu et al, , 2006Dam et al, 2005;Chabre and Roy, 2009). Having herewith identified shape and local density of branch-end epitopes as salient features in glycan functionality, it is tempting to view core substitutions as molecular switches in this context, and for good reason.…”

Glycosylation pattern of brush border-associated glycoproteins in enterocyte-like cells: involvement of complex-type N-glycans in apical trafficking

“…This galectin is composed of a tandem repeat-type display of two carbohydrate recognition domains suited for potent cross-linking as probed by glycocluster reactivity (André et al, 2008). Silencing of galectin-4 expression using RNAi inhibited apical transport in the same way as previously shown to occur by GalNAc-O-bn treatment in HT-29 cells (Delacour et al, 2005).…”

Synthetic Inhibitors of Galectins: Structures and Syntheses

“…The group of Gabius and Ungaro synthesized calix[n] arene-based glycoclusters for their potential selectivity and avidity against galectins and the synthetic route is described in Scheme 35a (90).…”