Bioisosteres of Carbohydrate Functional Groups in Glycomimetic Design

Abstract

The aberrant presentation of carbohydrates has been linked to a number of diseases, such as cancer metastasis and immune dysregulation. These altered glycan structures represent a target for novel therapies by modulating their associated interactions with neighboring cells and molecules. Although these interactions are highly specific, native carbohydrates are characterized by very low affinities and inherently poor pharmacokinetic properties. Glycomimetic compounds, which mimic the structure and function of native glycans, have been successful in producing molecules with improved pharmacokinetic (PK) and pharmacodynamic (PD) features. Several strategies have been developed for glycomimetic design such as ligand pre-organization or reducing polar surface area. A related approach to developing glycomimetics relies on the bioisosteric replacement of carbohydrate functional groups. These changes can offer improvements to both binding affinity (e.g., reduced desolvation costs, enhanced metal chelation) and pharmacokinetic parameters (e.g., improved oral bioavailability). Several examples of bioisosteric modifications to carbohydrates have been reported; this review aims to consolidate them and presents different possibilities for enhancing core interactions in glycomimetics.

The Role of Fluorine in Glycomimetic Drug Design

“…The introduction of a CF 3 group to either C‐6 of Fuc or a NHAc affords a significant enhancement in lipophilicity, which similarly improves uptake into cells and can strengthen hydrophobic contacts with the protein surface [12b, 59] . As the CF 3 group is larger in size than CH 3 (see section 5.1), this approach is only suitable for ligand interactions that are not sterically restricted.…”

“…As O‐glycosides can be prone to hydrolytic degradation, non‐hydrolyzable mimetics have been explored to improve bioavailability. One widely utilized approach has been to substitute the exocyclic O atom with atoms such as N, C, S, and Se, which form less labile glycosidic bonds, [12b] but this can alter the physical and chemical properties of the glycan such as charge, polarity, hydrogen‐bonding, conformation, flexibility, and stability.…”

Sweet turning bitter: Carbohydrate sensing of complement in host defence and disease

“…Another option to turn carbohydrate ligands into viable drug candidates is the development of glycomimetics, in which individual moieties of a saccharide lead are replaced by non‐carbohydrate entities and/or the structure is extended by aglycons (Hevey, 2019a; Hevey, 2019b). By increasing hydrophobicity and designing new, target‐specific contacts, the pharmacodynamic and pharmacokinetic properties can thereby be improved.…”

On-water synthesis of glycosyl selenocyanate derivatives and their application in the metal free organocatalytic preparation of nonglycosidic selenium linked pseudodisaccharide derivatives

“…pseudodisaccharides) have been considered as useful glycomimetics for their use as stable enzyme inhibitors. 7 One of the important techniques for the preparation of glycomimetics is to exchange the interglycosidic oxygen atom with other heteroatoms such as nitrogen, sulphur, selenium, etc. [8][9][10] Due to their increased stability towards hydrolysis, a variety of thiosugars and thioglycosides have been prepared for their use in the biochemical investigations of the carbohydrate processing enzymes.…”