Synthesis and applications of heparin-like oligosaccharide fragments

S9.4 GAG synthesis
Location (hall): 
Start/end time: 
Thursday, July 4, 2019 - 15:00 to 15:30
Speaker reference: 

John Gardiner1, Gavin Miller1,2, Steen Hansen1, Robin Jeanneret1, Charlotte Dalton1, Marek Barath1,3

1University of Manchester, Manchester, United Kingdom, 2University of Keele, Keele, United Kingdom, 3Slovak Academy of Sciences, Bratislava, Slovakia

Heparin/heparan sulfates (H/HS) are linear glycosaminoglycan (GAG) oligosaccharides typically occurring with the backbone modified by a variety of different sulfation patterns. They play diverse regulatory roles in biology. Synthesis of defined HS-like fragments has seen extensive interest from a a range of labs, both for defining new activities, including synthetic anti-coagulants, but also as tools to investigate chemical biology with defined microhetereogeneity. Improved strategies that shorten syntheses are important, as are applications to site-specific diversity, scalability and modifications for conjugation. Here we will describe synthetic entry to long H/HS-like backbones, contributing to expanding the synthetic heparanome, and show how programed synthesis can provide insights into micro-structure specific regulatory effects on HS-dependent biology, and also how synthetic design can afford scalable access to long bioactive oligosaccharides. 

This presentation will describe enabling gram-scale syntheses of HS-type dodecasaccharides,1 based on scalable processes for iduronate bulding blocks, and efficient block-style syntheses. Synthetic access to these structurally-varied long HS targets has enabled identification of a structure-specific orthogonal regulation on chemokine-mediated biology1a,3 and evidence for enhanced tumour sensitization in combination therapy,4 and provided tools for PK. Block-synthesis strategy also enables synthetic access to substantially loner H/HS-related oligosaccharides (up to 40-mer backbone).5 This contributes to help establish that that longer HS fragments are viable synthetic targets for biomedical targets and the pursuit in many labs now of designer HS synthesis to identify new structure-specific chemical biology to potentially underpin new glycotherapeutics.

New conformationally-controlled glycosylations using a bicyclic iduronate lactone2 is  also described. This facilitates reversing the order of GAG fragment syntheses from the traditional reducing terminal to non-reducing terminal direction. This has also been deployed now to intercept prior H/HS-like fragments, but also as a viable unit for synthesis of Dermatan Sulfate GAG fragments also,6 and so hopefully reagents and strategies here may contribute to providing availability of ranges of synthetic GAG fragments.

  1. (a) Jayson, G. C.; Hansen, S. U.; Miller, G. J.; Cole, C. L.; Rushton, G.; Avizienyte, E.; Gardiner, J. M. Chem. Commun. 2015, 51, 13846-13849. (b) Hansen, S. U.; Miller, G. J.; Jayson, G. C.; Gardiner, J. M. OrgLett, 2013, 15, 88–91.  
  2. Hansen, S. U.; Dalton, C. E.; Raftery, J.; Kwan, G.; Jayson, G. C.; Miller, G. J.; Gardiner, J. M. J. Org. Chem, 2015, 80, 3777-3789.   
  3. (a) Miller, G. J.; Hansen, S. U.; Rushton, G.; Avizienyte, E.; Cole. C.; Jayson, G. C.; Gardiner, J. M. Nature Communications 2013, 4, 2016. (b) Miller, G. J.; Hansen, S. U.; Cole. C.; Avizienyte, E.; Rushton, G.; Jayson, G. C.; Gardiner, J. M. Chemical Science 2013, 4, 3218-3222. 
  4. Avizienyte, E.; Cole, C. L.; Rushton, G.; Miller, G. J.; Bugatti, A.; Presta, M.; Gardiner, J. M.; Jayson, G. C. PLOSOne 2016, 11(8), e0159739. 
  5. Hansen, S. U.; Miller, G. J.; Cliff, M. J.; Jayson, G. C.; Gardiner, J. M. Chemical Science 2015, 6, 6158-6164.
  6. Jeanneret, R. A.; Dalton, C. E.; Gardiner, J. M. 2019 submitted