CHEMICAL SYNTHESIS, SITE-SPECIFIC LABELLING AND BIOLOGICAL EVALUATION/PK OF HEPARAN SULPHATE OLIGOSACCHARIDES

Heparin and heparan sulfate (H/HS) are highly charged, ubiquitous, naturally occurring glycosaminoglycans (GAGs) which are involved in regulating a wide range of biologically important cellular signalling events that control a variety of biological functions.¹ Despite advances in separation techniques,² the complex heterogeneity of natural H/HS oligosaccharides means that defining the roles of specific sequences is best addressed by precise chemical synthesis of a diversity of structurally defined sequences.

We describe here our syntheses of a range of oligosaccharides (up to dodecasaccharide length) with key, pre-installed diversity to investigate alternating sulfation patterns, underpinned by our recently reported new routes to heparin-related disaccharide and oligosaccharide modules.³ The synthesis provides a modular approach to these different targets, which has enabled biological evaluation (in vitro and in vivo) of a range of synthetic oligosaccharides for FGF binding, cell proliferation and migration experiments. The structure-biological effect information regarding length and specific sulfation effects, we have thus been able to obtain from a matrix of synthetic compounds will be presented here. We have also developed syntheses to provide versatile new end-labellable oligosaccharides, applicable to a range of conjugation and labelling strategies. This includes using a tetrasaccharide-module approach to rapidly access an end-modified bioactive dodecasaccharide then employed for specific ³H-labelling enabling us to conduct in vivo monitoring and PK studies.