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

Authors

  • Dr. Ligong Liu,

    Corresponding author
    1. Drug Design Group, Progen Pharmaceuticals Limited, 2806 Ipswich Road, Darra, QLD 4076 (Australia)
    2. Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072 (Australia)
    • Drug Design Group, Progen Pharmaceuticals Limited, 2806 Ipswich Road, Darra, QLD 4076 (Australia)
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  • Dr. Caiping Li,

    1. Drug Design Group, Progen Pharmaceuticals Limited, 2806 Ipswich Road, Darra, QLD 4076 (Australia)
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  • Dr. Siska Cochran,

    1. Drug Design Group, Progen Pharmaceuticals Limited, 2806 Ipswich Road, Darra, QLD 4076 (Australia)
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  • Shane Jimmink,

    1. Drug Design Group, Progen Pharmaceuticals Limited, 2806 Ipswich Road, Darra, QLD 4076 (Australia)
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  • Dr. Vito Ferro

    Corresponding author
    1. Drug Design Group, Progen Pharmaceuticals Limited, 2806 Ipswich Road, Darra, QLD 4076 (Australia)
    2. School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, QLD 4072 (Australia)
    • Drug Design Group, Progen Pharmaceuticals Limited, 2806 Ipswich Road, Darra, QLD 4076 (Australia)
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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 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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