title: Synthesis of a heparan sulfate mimetic library targeting FGF and VEGF via click chemistry on a monosaccharide template.
abstract: A disulfated methyl 6-azido-6-deoxy-α-D-mannopyranoside template was used as a core structure for binding to the angiogenic growth factors FGF-1, FGF-2, and VEGF. The core structure was diversified in a rapid, parallel manner by employing the Cu(I)-catalyzed Huisgen azide-alkyne cycloaddition ("click") reaction. The diversity was further extended by incorporating a Swern oxidation-Wittig reaction sequence on a click adduct of propargyl alcohol. Thus, the sulfated core was linked by various spacers to selected hydrophobic or polar motifs, which were designed to probe the protein surface surrounding the cationic heparan sulfate binding sites of the growth factors in order to improve affinity and selectivity. The affinities of the compounds for the growth factors were measured by surface plasmon resonance solution affinity assays. A lead compound was identified with micromolar binding affinity toward both FGF-1 and VEGF (K(d)=84 and 49 μM, respectively) and good selectivity over FGF-2 (29- and 51-fold, respectively).
authors.affiliation: Drug Design Group, Progen Pharmaceuticals Limited, 2806 Ipswich Road, Darra, QLD 4076, Australia. l.liu@imb.uq.edu.au
authors.forename: Ligong
authors.initials: L
authors.lastname: Liu
authors.forename: Caiping
authors.initials: C
authors.lastname: Li
authors.forename: Siska
authors.initials: S
authors.lastname: Cochran
authors.forename: Shane
authors.initials: S
authors.lastname: Jimmink
authors.forename: Vito
authors.initials: V
authors.lastname: Ferro
mesh_terms: D057930:Click Chemistry; D004305:Dose-Response Relationship, Drug; D016220:Fibroblast Growth Factor 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016222:Fibroblast Growth Factor 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006497:Heparan Sulfate / Q000737:chemistry / Q000494:pharmacology; D018716:Molecular Mimicry; D015394:Molecular Structure; D009005:Monosaccharides / Q000737:chemistry*; D054852:Small Molecule Libraries / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D016220:Fibroblast Growth Factor 1; D016222:Fibroblast Growth Factor 2; D006497:Heparan Sulfate; D009005:Monosaccharides; D054852:Small Molecule Libraries; D042461:Vascular Endothelial Growth Factor A