Synthesis of a Heparan Sulfate Mimetic Library Targeting FGF and VEGF via Click Chemistry on a Monosaccharide Template
| Autor: | Cai Ping Li, Siska Cochran, Vito Ferro, Ligong Liu, Shane Jimmink |
|---|---|
| Rok vydání: | 2012 |
| Předmět: |
Vascular Endothelial Growth Factor A
Stereochemistry Biochemistry Small Molecule Libraries Structure-Activity Relationship chemistry.chemical_compound Drug Discovery Structure–activity relationship General Pharmacology Toxicology and Pharmaceutics Surface plasmon resonance Pharmacology Dose-Response Relationship Drug Molecular Structure Chemistry Molecular Mimicry Monosaccharides Organic Chemistry Stereoisomerism Heparan sulfate Propargyl alcohol Combinatorial chemistry Cycloaddition Click chemistry Fibroblast Growth Factor 1 Molecular Medicine Click Chemistry Fibroblast Growth Factor 2 Heparan sulfate binding Heparitin Sulfate Lead compound |
| Zdroj: | ChemMedChem. 7:1267-1275 |
| ISSN: | 1860-7179 |
| DOI: | 10.1002/cmdc.201200151 |
| Popis: | 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). |
| Databáze: | OpenAIRE |
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