Synthesis of a Heparan Sulfate Mimetic Library Targeting FGF and VEGF via Click Chemistry on a Monosaccharide Template

ChemMedChem - Tập 7 Số 7 - Trang 1267-1275 - 2012
Ligong Liu1,2, Caiping Li1, Siska Cochran1, Shane Jimmink1, Vito Ferro1,3
1Drug Design Group, Progen Pharmaceuticals Limited, 2806 Ipswich Road, Darra, QLD 4076 (Australia)
2Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia
3School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, QLD 4072, Australia

Tóm tắt

AbstractA 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 CuI‐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 (Kd=84 and 49 μM, respectively) and good selectivity over FGF‐2 (29‐ and 51‐fold, respectively).

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ChemMedChem

Tập 7 Số 7

1267-1275

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