The binding of human galectins by glycomimetic inhibitors is a promising therapeutic approach. The structurally distinct group of tandem-repeat galectins has scarcely been studied so far, and there is hardly any knowledge on their ligand specificity or their inhibitory potential, particularly concerning non-natural carbohydrates. Here, we present the synthesis of a library of seven 3-O-disubstituted thiodigalactoside-derived glycomimetics and their affinity to two tandem-repeat galectins, Gal-8 and Gal-9. The straightforward synthesis of these glycomimetics involved dibutyltin oxide-catalyzed 3,3́-O-disubstitution of commercially available unprotected thiodigalactoside, and conjugation of various aryl substituents by copper-catalyzed Huisgen azide-alkyne cycloaddition (CuAAC). The inhibitory potential of the prepared glycomimetics for Gal-8 and Gal-9 was assessed, and compared with the established galectins Gal-1 and Gal-3. The introduction of C-3 substituents resulted in an over 40-fold increase in affinity compared with unmodified TDG. The structure-affinity relations within the studied series were discussed using molecular modeling. Furthermore, the prepared glycomimetics were shown to scavenge Gal-8 and Gal-9 from the surface of cancer cells. This pioneering study on the synthetic inhibitors especially of Gal-9 identified lead compounds that may be used in further biomedical research.

Institute of Microbiology of the Czech Academy of Sciences Vídeňská 1083 CZ 142 00 Prague 4 Czech Republic

Institute of Microbiology of the Czech Academy of Sciences Vídeňská 1083 CZ 142 00 Prague 4 Czech Republic; Department of Analytical Chemistry Faculty of Science Charles University Hlavova 8 CZ 128 43 Prague 2 Czech Republic

Institute of Microbiology of the Czech Academy of Sciences Vídeňská 1083 CZ 142 00 Prague 4 Czech Republic; Department of Biochemistry Faculty of Science Charles University Hlavova 8 CZ 128 43 Prague 2 Czech Republic

Institute of Microbiology of the Czech Academy of Sciences Vídeňská 1083 CZ 142 00 Prague 4 Czech Republic; Department of Genetics and Microbiology Faculty of Science Charles University Viničná 5 CZ 128 43 Prague 2 Czech Republic

Institute of Microbiology of the Czech Academy of Sciences Vídeňská 1083 CZ 142 00 Prague 4 Czech Republic; Department of Health Care Disciplines and Population Protection Faculty of Biomedical Engineering Czech Technical University Prague nám Sítná 3105 CZ 272 01 Kladno Czech Republic

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Human Milk Oligosaccharides Multivalently Presented on Defined Synthetic Neo-Glycoproteins Are Nanomolar Ligands of Tandem-Repeat Galectins