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.