A New Strategy for the Solid-Phase Synthesis of Glycoconjugate Biomolecules

Abstract

A simple and efficient bidirectional solid-phase synthe- sis, based the use of a Tentagel solid support, functionaiized with a suitably protected 2-amino sugar residue, is proposed for the prep- aration ofa variety ofglycoconjugates, including glycopeptides and nucleo- glycopeptides. Since the biomedical potential of oligosaccharides and re- lated glycoconjugates has been well recognizedl-5 the de- velopment of effective methodologies for their rapid assembly is attracting current attention. Glycoconjugates are among the most functionally and structurally diverse molecules in nature and it is now well established that pro- tein- and lipid-bound saccharides play essential roles in many molecular processes impacting eukaryotic bioiogy and disease. The presence of a sugar moiety is believed to influence the transport of the drug through biological membranes as well as to increase its resistance to hydro- lytic enzymes. The synthesis and modification of oligosaccharide units and their coupling with appropriate lipids, phospholipids, oligonucleotides and proteins are essential to extend the knowledge the molecular mode of action of glycocon- jugates and, furthermore, to get a further insight into their physiological activity. In this context the polymer sup- ported approach is particularly promising in principie. A iarge number of studies the solid-phase synthesis of glycopeptides have been reported6'7 and since the polymer supported synthesis of peptides is a weli established pro- cess,8 the majority of progress in the synthesis of glyco- peptides has involved the linkage of the giycopeptide to the polymer support via the peptide moiety rather than via the carbohydrate moiety. Recentiy several papers have been reported in the literature dealing with the synthesis of giyco-oligonucleotide conjugates in which the sugar residue is either attached to the nucleotide base before the oligonucleotide assembiy,e or used as separate building block in an on iine solid phase strategy.i0-12