title: Tetrasaccharide iteration synthesis of a heparin-like dodecasaccharide and radiolabelling for in vivo tissue distribution studies.
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 (3)H 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.
authors.affiliation: Faculty of EPS, School of Chemistry, Manchester Institute of Biotechnology, The University of Manchester, 131 Princess Street, Manchester M1 7DN, UK.
authors.forename: Steen U
authors.initials: SU
authors.lastname: Hansen
authors.forename: Gavin J
authors.initials: GJ
authors.lastname: Miller
authors.forename: Claire
authors.initials: C
authors.lastname: Cole
authors.forename: Graham
authors.initials: G
authors.lastname: Rushton
authors.forename: Egle
authors.initials: E
authors.lastname: Avizienyte
authors.forename: Gordon C
authors.initials: GC
authors.lastname: Jayson
authors.forename: John M
authors.initials: JM
authors.lastname: Gardiner
mesh_terms: D000818:Animals; D002850:Chromatography, Gel; D002851:Chromatography, High Pressure Liquid; D005260:Female; D006493:Heparin; D007553:Isotope Labeling; D007668:Kidney / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D016513:Mice, SCID; D009844:Oligosaccharides / Q000138:chemical synthesis* / Q000737:chemistry; D015203:Reproducibility of Results; D014018:Tissue Distribution; D014316:Tritium / Q000378:metabolism*
chemical_list: D009844:Oligosaccharides; D014316:Tritium; D006493:Heparin