Abstract
Heparin and heparan sulfate represent key members of the glycosaminoglycan family of carbohydrates and underpin considerable repertoires of biological importance. As such, their efficiency of synthesis represents a key requirement, to further understand and exploit the H/HS structure-to-biological function axis. In this review we focus on chemical approaches to and methodology improvements for the synthesis of these essential sugars (from 2015 onwards). We first consider advances in accessing the heparin-derived pentasaccharide anticoagulant fondaparinux. This is followed by heparan sulfate targets, including key building block synthesis, oligosaccharide construction and chemical sulfation techniques. We end with a consideration of technological improvements to traditional, solution-phase synthesis approaches that are increasingly being utilised.
Highlights
Carbohydrates are indispensable to glycoconjugate biological function; this is typified by the glycosaminoglycans (GAGs)
One GAG in particular, heparan sulfate (HS) is involved in mediating mammalian cell function, exemplified by its interaction with growth factors such as fibroblast growth factors (FGFs), a protein family involved in cell proliferation, differentiation, and angiogenesis.[1]
In this review we focus on chemical approaches to and methodology improvements for the synthesis of H/HS from 2015 onwards
Summary
Carbohydrates are indispensable to glycoconjugate biological function; this is typified by the glycosaminoglycans (GAGs). GAGs are present on most animal cell surfaces and in the surrounding extracellular matrix They are extremely diverse, containing a linear and structurally heterogeneous anionic glycan chain and impart important biological functions by binding to different growth factors, enzymes, morphogens, cell adhesion molecules, and cytokines. HS chains have an average molecular weight of 30 kDa and this, taken in context with the possibilities for functional group variation, presents a huge structural microheterogeneity and enormous scientific challenge in unravelling and understanding the HS structure-tofunction paradigm. Due to their structural complexity and biological importance, the synthetic challenge surrounding access to (and application of) structurally defined H and HS fragments is significant and of continued interest. We first discuss recent efforts to develop more efficient synthetic routes to 1 using traditional modular synthetic routes and explore one-pot, programmable methodologies.[13]
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