Synthesis of disaccharides derived from heparin and evaluation of effects on endothelial cell growth and on binding of heparin to FGF-2.
The disaccharide beta-D-GlcA-(1-->4)-alpha-D-GlcNAc-1-->OMe and other small nonsulfated oligosaccharides related to heparin/heparan sulfate have been shown to bind to FGF and activated the fibroblast growth factor (FGF) signalling pathway in (F32) cells expressing the FGF receptor. Synthetic routes to beta-D-GlcA-(1-->4)-alpha-D-GlcNAc-1-->OMe and a glucose analogue beta-D-Glc-(1-->4)-alpha-D-GlcNAc-1-->OMe are described. The effects of these disaccharides on endothelial cell growth, which is relevant to angiogenesis, were evaluated and it was found they did not mimic the inhibitory effects that were observed for heparin albumin (HA) and that have also been observed by monosaccharide conjugates. They did not alter bovine aortic endothelial cell (BAEC) proliferation, in the presence of FGF-2 in serum free medium or in absence of FGF-2 in serum free and complete medium. Disaccharides (10 microg/mL) reduced by 25-31% the inhibition caused by HA (10 microg/mL) on BAEC growth in serum-free medium but had no effect in complete medium. There was no evidence obtained for the binding of these oligosaccharides to FGF-2 in competition with HA by ELISA.
O'Brien
Alan
A
Centre for Synthesis and Chemical Biology, Department of Chemistry, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin 4, Ireland.
Lynch
Ciaran
C
O'Boyle
Kathy M
KM
Murphy
Paul V
PV
D020533:Angiogenesis Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000502:physiology*; D000818:Animals; D001011:Aorta / Q000166:cytology; D001667:Binding, Competitive; D002417:Cattle; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D004187:Disaccharides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects*; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism* / Q000494:pharmacology; D006493:Heparin / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D006494:Heparin Antagonists / Q000138:chemical synthesis; D018716:Molecular Mimicry; D018919:Neovascularization, Physiologic
D020533:Angiogenesis Inhibitors; D004187:Disaccharides; D006494:Heparin Antagonists; C498068:methyl glucopyranosyl-1-4-N-acetyl-2-amino-2-deoxyglucopyranoside; C498067:methyl glucuronopyranosyl-1-4-N-acetyl-2-amino-2-deoxyglucopyranoside; D016222:Fibroblast Growth Factor 2; D006493:Heparin