Tetrasaccharide iteration synthesis of a heparin-like dodecasaccharide and radiolabelling for in vivo tissue distribution studies

Steen U. Hansen, Gavin J. Miller, Claire Cole, Graham Rushton, Egle Avizienyte, Gordon C. Jayson and John M. Gardiner ()
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Steen U. Hansen: Faculty of EPS, School of Chemistry, Manchester Institute of Biotechnology, The University of Manchester
Gavin J. Miller: Faculty of EPS, School of Chemistry, Manchester Institute of Biotechnology, The University of Manchester
Claire Cole: School of Cancer and Enabling Sciences, The University of Manchester
Graham Rushton: School of Cancer and Enabling Sciences, The University of Manchester
Egle Avizienyte: School of Cancer and Enabling Sciences, The University of Manchester
Gordon C. Jayson: School of Cancer and Enabling Sciences, The University of Manchester
John M. Gardiner: Faculty of EPS, School of Chemistry, Manchester Institute of Biotechnology, The University of Manchester

Nature Communications, 2013, vol. 4, issue 1, 1-9

Abstract: Abstract Heparin-like oligosaccharides mediate numerous important biological interactions, of which many are implicated in various diseases. Synthetic improvements are central to the development of such oligosaccharides as therapeutics and, in addition, there are no methods to elucidate the pharmacokinetics of structurally defined heparin-like oligosaccharides. Here we report an efficient two-cycle [4+4+4] tetrasaccharide-iteration-based approach for rapid chemical synthesis of a structurally defined heparin-related dodecasaccharide, combined with the incorporation of a latent aldehyde tag, unmasked in the final step of chemical synthesis, providing a generic end group for labelling/conjugation. We exploit this latent aldehyde tag for 3H radiolabelling to provide the first example of this kind of agent for monitoring in vivo tissue distribution and in vivo stability of a biologically active, structurally defined heparin related dodecasaccharide. Such studies are critical for the development of related saccharide therapeutics, and the data here establish that a biologically active, synthetic, heparin-like dodecasaccharide provides good organ distribution, and serum lifetimes relevant to developing future oligosaccharide therapeutics.

Date: 2013
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DOI: 10.1038/ncomms3016

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