Glycodendrimers: novel glycotope isosteres unmasking sugar coding. Case study with T-antigen markers from breast cancer MUC1 glycoprotein

Abstract

Glycodendrimers are relatively novel synthetic biomacromolecules that are made of biologically relevant carbohydrate ligands constructed at the periphery of a wide range of highly functionalized and repetitive scaffolds having varied molecular weights and structures. They were aimed to fill the gap between glycopolymers, having generally dispersed higher molecular weight, and small glycoclusters, in the study of multivalent carbohydrate protein interactions. In a way, glycodendrimers, with their spheroidal or dendritic (wedge) type structures, were initially designed as bioisosteres of cell surface multiantennary glycans. Taken as a curiosity and elegant molecules at their beginning, they are now considered as potent inhibitors of microbial adhesins. They have also been shown to play some roles in signal transduction and in receptor cross-linking. This brief report will describe advances that have been made toward the syntheses of a range of glycodendrimers bearing the immunodominant T-antigen disaccharide [β-d-Gal-(1-3)-α-d-GalNAc] found on malignant cells of carcinomas, particularly related to breast cancer. This antigen, usually cryptic on healthy tissues, is greatly increased on cancer cells as a result of aberrant glycosylation. It is considered to be an important cancer marker. The high incidence of these carcinomas to invade other tissues such as lymph nodes, lung, and liver by metastasis was one of the arguments raised to generate T-antigen dendrimers that might have the potential to block the receptor sites following surgery. The synthesis of the T-antigen disaccharide will be briefly described, followed by the elaboration of neoglycoproteins and glycopolymers used to raise monoclonal antibodies against the T-antigen and for screening purpose, respectively. Scaffolds made of poly(amidoamine) (PAMAM), poly(propylene imine), N,N′-bis(acrylamido)acetic acid, and finally hyperbranched l-lysine were used to construct relatively small glycodendrimers bearing T-antigen moieties. Few glycodendrimers were also linked to fluorescein and biotin probes to generate ligands that can be used to detect T-Ag receptor sites.