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Glycopolymers Decorated with 3-O-Substituted Thiodigalactosides as Potent Multivalent Inhibitors of Galectin-3

  • David Vrbata
    David Vrbata
    Institute of Microbiology of the Czech Academy of Sciences, Vídeňská 1083, CZ-142 20 Prague 4, Czech Republic
    More by David Vrbata
  • Marcela Filipová
    Marcela Filipová
    Institute of Macromolecular Chemistry of the Czech Academy of Sciences, Heyrovského nám. 2, CZ-162 06 Prague 6, Czech Republic
  • Marina R. Tavares
    Marina R. Tavares
    Institute of Macromolecular Chemistry of the Czech Academy of Sciences, Heyrovského nám. 2, CZ-162 06 Prague 6, Czech Republic
  • Jakub Červený
    Jakub Červený
    Institute of Microbiology of the Czech Academy of Sciences, Vídeňská 1083, CZ-142 20 Prague 4, Czech Republic
    Department of Analytical Chemistry, Faculty of Science, Charles University, Albertov 6, CZ-128 43 Prague 2, Czech Republic
  • Miluše Vlachová
    Miluše Vlachová
    Institute of Microbiology of the Czech Academy of Sciences, Vídeňská 1083, CZ-142 20 Prague 4, Czech Republic
  • Milada Šírová
    Milada Šírová
    Institute of Microbiology of the Czech Academy of Sciences, Vídeňská 1083, CZ-142 20 Prague 4, Czech Republic
  • Helena Pelantová
    Helena Pelantová
    Institute of Microbiology of the Czech Academy of Sciences, Vídeňská 1083, CZ-142 20 Prague 4, Czech Republic
  • Lucie Petrásková
    Lucie Petrásková
    Institute of Microbiology of the Czech Academy of Sciences, Vídeňská 1083, CZ-142 20 Prague 4, Czech Republic
  • Ladislav Bumba
    Ladislav Bumba
    Institute of Microbiology of the Czech Academy of Sciences, Vídeňská 1083, CZ-142 20 Prague 4, Czech Republic
  • Rafał Konefał
    Rafał Konefał
    Institute of Macromolecular Chemistry of the Czech Academy of Sciences, Heyrovského nám. 2, CZ-162 06 Prague 6, Czech Republic
  • Tomáš Etrych
    Tomáš Etrych
    Institute of Macromolecular Chemistry of the Czech Academy of Sciences, Heyrovského nám. 2, CZ-162 06 Prague 6, Czech Republic
  • Vladimír Křen
    Vladimír Křen
    Institute of Microbiology of the Czech Academy of Sciences, Vídeňská 1083, CZ-142 20 Prague 4, Czech Republic
  • Petr Chytil
    Petr Chytil
    Institute of Macromolecular Chemistry of the Czech Academy of Sciences, Heyrovského nám. 2, CZ-162 06 Prague 6, Czech Republic
    More by Petr Chytil
  • , and 
  • Pavla Bojarová*
    Pavla Bojarová
    Institute of Microbiology of the Czech Academy of Sciences, Vídeňská 1083, CZ-142 20 Prague 4, Czech Republic
    Department of Health Care Disciplines and Population Protection, Faculty of Biomedical Engineering, Czech Technical University in Prague, nám. Sítná 3105, CZ-272 01 Kladno, Czech Republic
    *Email: [email protected]. Phone: (+420)296 442 360.
Cite this: J. Med. Chem. 2022, 65, 5, 3866–3878
Publication Date (Web):February 14, 2022
https://doi.org/10.1021/acs.jmedchem.1c01625
Copyright © 2022 American Chemical Society

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    Abstract

    Abstract Image

    Galectin-3 (Gal-3) participates in many cancer-related metabolic processes. The inhibition of overexpressed Gal-3 by, e.g., β-galactoside-derived inhibitors is hence promising for cancer treatment. The multivalent presentation of such inhibitors on a suitable biocompatible carrier can enhance the overall affinity to Gal-3 and favorably modify the interaction with Gal-3-overexpressing cells. We synthesized a library of C-3 aryl-substituted thiodigalactoside inhibitors and their multivalent N-(2-hydroxypropyl)methacrylamide (HPMA)-based counterparts with two different glycomimetic contents. Glycopolymers with a higher content of glycomimetic exhibited a higher affinity to Gal-3 as assessed by ELISA and biolayer interferometry. Among them, four candidates (with 4-acetophenyl, 4-cyanophenyl, 4-fluorophenyl, and thiophen-3-yl substitution) were selected for further evaluation in cancer-related experiments in cell cultures. These glycopolymers inhibited Gal-3-induced processes in cancer cells. The cyanophenyl-substituted glycopolymer exhibited the strongest antiproliferative, antimigratory, antiangiogenic, and immunoprotective properties. The prepared glycopolymers appear to be prospective modulators of the tumor microenvironment applicable in the therapy of Gal-3-associated cancers.

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    The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.jmedchem.1c01625.

    • Synthetic procedures, compound characterization, binding and inhibition assays, and cell culture studies (PDF)

    • Molecular formula strings for the synthesized compounds (CSV)

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    Cited By

    This article is cited by 6 publications.

    1. Dorota Konvalinková, František Dolníček, Michaela Hovorková, Jakub Červený, Ondřej Kundrát, Helena Pelantová, Lucie Petrásková, Josef Cvačka, Margarita Faizulina, Beena Varghese, Petr Kovaříček, Vladimír Křen, Pavel Lhoták, Pavla Bojarová. Glycocalix[4]arenes and their affinity to a library of galectins: the linker matters. Organic & Biomolecular Chemistry 2023, 21 (6) , 1294-1302. https://doi.org/10.1039/D2OB02235D
    2. Michaela Hovorková, Jakub Červený, Ladislav Bumba, Helena Pelantová, Josef Cvačka, Vladimír Křen, Olivier Renaudet, David Goyard, Pavla Bojarová. Advanced high-affinity glycoconjugate ligands of galectins. Bioorganic Chemistry 2023, 131 , 106279. https://doi.org/10.1016/j.bioorg.2022.106279
    3. Domenica Capasso, Luciano Pirone, Sonia Di Gaetano, Rita Russo, Michele Saviano, Valeria Frisulli, Amina Antonacci, Emilia Pedone, Viviana Scognamiglio. Galectins detection for the diagnosis of chronic diseases: An emerging biosensor approach. TrAC Trends in Analytical Chemistry 2023, 159 , 116952. https://doi.org/10.1016/j.trac.2023.116952
    4. Macarena Martínez-Bailén, Javier Rojo, Javier Ramos-Soriano. Multivalent glycosystems for human lectins. Chemical Society Reviews 2023, 52 (2) , 536-572. https://doi.org/10.1039/D2CS00736C
    5. Sjors van Klaveren, Jaka Dernovšek, Žiga Jakopin, Marko Anderluh, Hakon Leffler, Ulf J. Nilsson, Tihomir Tomašič. Design and synthesis of novel 3-triazolyl-1-thiogalactosides as galectin-1, -3 and -8 inhibitors. RSC Advances 2022, 12 (29) , 18973-18984. https://doi.org/10.1039/D2RA03163A
    6. Angelica Pace, Fabio Scirocchi, Chiara Napoletano, Ilaria Grazia Zizzari, Luca D’Angelo, Antonio Santoro, Marianna Nuti, Hassan Rahimi, Aurelia Rughetti. Glycan-Lectin Interactions as Novel Immunosuppression Drivers in Glioblastoma. International Journal of Molecular Sciences 2022, 23 (11) , 6312. https://doi.org/10.3390/ijms23116312

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