Solid-phase synthesis of glicosaminoglycans

Abstract

Glycosaminoglycans (GAGs) are highly charged and linear polysaccharide repeating units (with the exception of keratin sulfate), which are further classified according their monosaccharide composition and glycosidic linkage. They are present on most animal cell surfaces and in the extracellular matrix, where they engage through ionic interactions with a large number of proteins, including growth factors and their receptors. In this Thesis, we have developed an effective solid phase strategy for synthesis glycosaminogycans (GAGs). This strategy was applied for the assembly of monosaccharide building blocks into advanced oligosaccharide precursors up to the size of an octasaccharide with high yield and stereo-selectivity. A novel ester type linker was developed that incorporated a stable carbamate protected C5-spacer for later ligand immobilization. The carbamate function proved stable throughout the synthesis and was easily cleaved from the resin by a choice of two complementary methods. In addition a systematic evaluation of iduronic acid (IdoA) and Idose (Ido) glycosyl donors was carried out. In particular we evaluated a new class of highly reactive IdoA n-pentenyl orthoesters (NPOEs), with variation in protecting group pattern and the leaving group, for the sequential solution and solid-phase synthesis of glycosaminoglycans precursors.