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Rational Design and Synthesis of Methyl-β-d-galactomalonyl Phenyl Esters as Potent Galectin-8N Antagonists

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    Rational Design and Synthesis of Methyl-β-d-galactomalonyl Phenyl Esters as Potent Galectin-8N Antagonists
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    • Brijesh Patel
      Brijesh Patel
      Institute for Glycomics, Griffith University, Gold Coast Campus, Southport, Queensland 4222, Australia
      More by Brijesh Patel
      Orcidhttp://orcid.org/0000-0002-8029-0356
    • Chandan Kishor
      Chandan Kishor
      Institute for Glycomics, Griffith University, Gold Coast Campus, Southport, Queensland 4222, Australia
      School of Chemistry and Molecular Bioscience, and Molecular Horizons, University of Wollongong, Wollongong, New South Wales 2522, Australia
      More by Chandan Kishor
      Orcidhttp://orcid.org/0000-0002-6328-1116
    • Todd. A. Houston
      Todd. A. Houston
      Institute for Glycomics, Griffith University, Gold Coast Campus, Southport, Queensland 4222, Australia
      More by Todd. A. Houston
    • Hadas Shatz-Azoulay
      Hadas Shatz-Azoulay
      Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 76100, Israel
      More by Hadas Shatz-Azoulay
    • Yehiel Zick
      Yehiel Zick
      Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 76100, Israel
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    • Yaron Vinik*
      Yaron Vinik
      Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 76100, Israel
      *Y.V. email: [email protected]
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    • Helen Blanchard*
      Helen Blanchard
      Institute for Glycomics, Griffith University, Gold Coast Campus, Southport, Queensland 4222, Australia
      School of Chemistry and Molecular Bioscience, and Molecular Horizons, University of Wollongong, Wollongong, New South Wales 2522, Australia
      *H.B. email: [email protected]
      More by Helen Blanchard
      Orcidhttp://orcid.org/0000-0003-3372-5027
    Other Access OptionsSupporting Information (7)

    Journal of Medicinal Chemistry

    Cite this: J. Med. Chem. 2020, 63, 20, 11573–11584
    Click to copy citationCitation copied!
    https://doi.org/10.1021/acs.jmedchem.0c00602
    Published August 18, 2020
    Copyright © 2020 American Chemical Society
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    Abstract

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    Galectin-8 is a β-galactoside-recognizing protein having an important role in the regulation of bone remodeling and cancer progression and metastasis. Methyl β-d-galactopyranoside malonyl aromatic esters have been designed to target and engage with particular amino acid residues of the galectin-8N extended carbohydrate-binding site. The chemically synthesized compounds had in vitro binding affinity toward galectin-8N in the range of 5–33 μM, as evaluated by isothermal titration calorimetry. This affinity directly correlated with the compounds’ ability to inhibit galectin-8-induced expression of chemokines and proinflammatory cytokines in the SUM159 breast cancer cell line. X-ray crystallographic structure determination revealed that these monosaccharide-based compounds bind galectin-8N by engaging its unique arginine (Arg59) and simultaneously cross-linking to another arginine (Arg45) located across the carbohydrate-binding site. This structure-based drug design approach has led to the discovery of novel monosaccharide galactose-based antagonists, with the strongest-binding compound (Kd 5.72 μM) holding 7-fold tighter than the disaccharide lactose.

    Copyright © 2020 American Chemical Society

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    Supporting Information

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    The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.jmedchem.0c00602.

    • Additional figures illustrating the ITC graphs of reference compounds, molecular docking analysis of key compounds, chemical intermediate synthetic scheme and procedure, 1H and 13C NMR spectra, HRMS spectra, and chromatography analysis of key compounds (PDF)

    • Molecular formula strings of compounds 8−13, 15, and 17 with Kd values (CSV)

    • Galectin-8N-10 molecular docking coordinate file (PDB)

    • Galectin-8N-11 molecular docking coordinate file (PDB)

    • Galectin-8N-12 molecular docking coordinate file (PDB)

    • Galectin-8N-13 molecular docking coordinate file (PDB)

    • Galectin-8N-17 molecular docking coordinate file (PDB)

    Accession Codes

    The PDB code for galectin-8N–methyl 3-O-[(3′-O-benzyl)malonyl]-β-d-galactopyranoside 13 complex is 6W4Z. The authors will release the atomic coordinates and experimental data upon article publication.

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    Most electronic Supporting Information files are available without a subscription to ACS Web Editions. Such files may be downloaded by article for research use (if there is a public use license linked to the relevant article, that license may permit other uses). Permission may be obtained from ACS for other uses through requests via the RightsLink permission system: http://pubs.acs.org/page/copyright/permissions.html.

    Cited By

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    This article is cited by 17 publications.

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    Journal of Medicinal Chemistry

    Cite this: J. Med. Chem. 2020, 63, 20, 11573–11584
    Click to copy citationCitation copied!
    https://doi.org/10.1021/acs.jmedchem.0c00602
    Published August 18, 2020
    Copyright © 2020 American Chemical Society
    Request reuse permissions

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