Towards the synthesis of specific heparan sulfate sequences

Session: 
S9.4 GAG synthesis
Code: 
OL9.4.1
Location (hall): 
Fucose
Start/end time: 
Thursday, July 4, 2019 - 15:30 to 15:45
Daniel
Sheppard

Daniel Sheppard1, Ralf Schwoerer1, Karl Shaffer1, Peter Tyler1

1Ferrier Research Institute, Lower Hutt, New Zealand

Sulfated polysaccharides such as heparan sulfates (HS) have many roles in mammalian cells. One of these roles is as factors in cell signalling cascades, regulating processes including haemostasis and angiogenesis¹. They are often found as heparan sulfate proteoglycans (HSPG) on the outer surface of a cell, and present in the extracellular matrix². Their ubiquity and specificity make them potential pharmaceutical targets, but there has been relatively limited development in this space. This is primarily a result of synthetic challenges in accessing specific HS sequences, as such a synthesis requires absolute regio- and stereospecific control in reactions. 

In this presentation, we will discuss synthetic strategies used to access novel polysaccharides with specific functionality. A major factor in our plan is the use of disaccharide building blocks with a robust, orthogonal protecting group strategy³. Following glycosylation of disaccharide building blocks to the required length, these protecting groups allow access to specific sites on the polysaccharide for functionalisation. This includes the recent incorporation of the acetoxymethyl benzoate (AMB) protecting group, allowing access to a new position of interest within our existing strategy. 

We will discuss some of the successes and challenges encountered during our synthetic approach, and the recent adaption of AMB to access new positions for sulfation.

A figure showing the use of an orthogonal protecting group strategy on disaccharide building blocks to generate specific sulfated oligosaccharide sequences.

References: 
  1. van Wijk, X. M.; van Kuppevelt, T. H. Angiogenesis 2014, 17, 443.
  2. Bernfield, M.; Götte, M.; Park, P. W.; Reizes, O.; Fitzgerald, M. L.; Lincecum, J.; Zako, M. Annual Review of Biochemistry 1999, 68, 729.
  3. Schwoerer, R.; Zubkova, O. V.; Turnbull, J. E.; Tyler, P. C. Chem. Eur. J. 2013, 19, 6817.

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