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

Hansen, Steen U.; Miller, Gavin J.; Cole, Claire; Rushton, Graham; Avizienyte, Egle; Jayson, Gordon C.; Gardiner, John M.

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.

Citation

Hansen, S. U., Miller, G. J., Cole, C., Rushton, G., Avizienyte, E., Jayson, G. C., & Gardiner, J. M. (2013). Tetrasaccharide iteration synthesis of a heparin-like dodecasaccharide and radiolabelling for in vivo tissue distribution studies. Nature communications, 4, Article 2016. https://doi.org/10.1038/ncomms3016

• Journal Article Type: Article
• Acceptance Date: May 16, 2013
• Publication Date: Jul 5, 2013
• Journal: Nature Communications
• Print ISSN: 2041-1723
• Peer Reviewed: Peer Reviewed
• Volume: 4
• Article Number: 2016
• DOI: https://doi.org/10.1038/ncomms3016
• Keywords: Kidney, Animals, Mice, Mice, SCID, Tritium, Heparin, Oligosaccharides, Chromatography, Gel, Chromatography, High Pressure Liquid, Magnetic Resonance Spectroscopy, Reproducibility of Results, Isotope Labeling, Tissue Distribution, Female
• Publisher URL: http://dx.doi.org/10.1038/ncomms3016