Multivalent glycocalixarenes for recognition of biological macromolecules: glycocalyx mimics capable of multitasking

Abstract

The glycoside cluster effect, a special case of multivalency involving carbohydrates, is a powerful tool exploited by Nature to make relatively weak interactions stronger and more specific. Organic and supramolecular chemists have been applying this concept and are devising a plethora of neo-glycoconjugates which can interfere with a series of pathological events such as infections due to viruses and bacteria, tumour progression and migration, and inflammation processes. In the present Tutorial Review, we will illustrate the factors that make calixarenes, the cyclic oligomers obtained by the condensation of phenols/resorcinols and aldehydes, unique scaffolds for the construction of multivalent glycosylated ligands, individually analysing how structural parameters such as the size, valency, conformation, self-assembling behaviour of the macrocycle and especially the topology of the saccharide presentation in space influence the biological properties. We will not only survey the most significant results obtained to date in the inhibition of carbohydrate binding proteins (lectins), but we will also try to paint a picture of the potential that multivalent glycocalixarenes might have in bionanotechnology and nanomedicine, that are especially related to their combined ability to load cargo and to specifically deliver that cargo to target cells.

Synthesis and Antiviral Evaluation of Some <i>C</i>₃-Symmetrical Trialkoxy-Substituted 1,3,5-Triazines and Their Molecular Geometry

“…Specific interactions of these carbohydrates with lectins (protein receptors) are important biological processes, including the processes of bacterial or viral infection and tumor metastasis. [1][2][3] From the viewpoint of molecular symmetry, many host receptors that consist of homo-oligometric units (homomultiligands) often construct symmetric macromolecule architectures such as C 2 -or C 3 -symmetrical geometry receptor systems. These phenomena of macromolecules connected with many biological stages have encouraged scientists to develop new multivalent symmetrical synthetic molecules to find new bioactive compounds or leads.…”

Carbohydrate Multivalent Systems: Synthesis and Therapeutic Opportunities

“…Glycocalixarenes can form complexes with small hydrophobic molecules in water due to hydrophobic effects inside its lipophilic cavity. Moreover, the functionalization of the upper or lower rims with adequate polar groups also allows for the binding of polar guests, cations or anions [72]. It was demonstrated that glucosylthioureido calixarenes present high binding affinities towards a series of monoamine neurotransmitters (serotonin, norepinephrine, epinephrine, and dopamine) of relevant interest for neurodegenerative pathologies, such as schizophrenia and Parkinson's or Alzheimer's diseases.…”

“…Calixarenes, the cyclic oligomers obtained by the condensation of phenols and formaldehyde, are ideal scaffolds for the construction of multivalent glycosylated compounds with unique properties [72]. These carbohydrate multivalent systems have demonstrated an ability to interact with biological macromolecules and, consequently, to be potentially useful in interfering in many pathological phenomena.…”

“…that are frequently used for the conjugation of different ligands. Glycocalixarenes can also carry out other tasks potentially useful in nanomedicine [72]. Glycocalixarenes can form complexes with small hydrophobic molecules in water due to hydrophobic effects inside its lipophilic cavity.…”

Guiding Principles in The Design of Ligand-Targeted Nanomedicines

“…Not surprisingly, such formulations can reduce NP uptake by the MPS [85] without promoting nonspecific adsorption to proteins and cell surfaces. However, because cell surface lectins and receptors exist for many saccharides [86], care must be taken to avoid the use of those sugars that exhibit a tropism for a specific protein or cell type. Examples of such unwanted saccharide affinities include galactose for the asialoglycoprotein receptor in the liver [87], mannose for the mannose receptor on M2 macrophages [88] and sialyl Lewis X for selectins on endothelial and immune cell surfaces [89,90].…”