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Glycomimetic inhibitors of tandem-repeat galectins: Simple and efficient
D. Vrbata, J. Červený, N. Kulik, M. Hovorková, S. Balogová, M. Vlachová, H. Pelantová, V. Křen, P. Bojarová
Jazyk angličtina Země Spojené státy americké
Typ dokumentu časopisecké články
- MeSH
- galektiny * metabolismus MeSH
- lidé MeSH
- sacharidy chemie MeSH
- thiogalaktosidy * chemie MeSH
- vazba proteinů MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
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.
Citace poskytuje Crossref.org
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- $a 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.
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- $a Hovorková, Michaela $u 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
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- $a Balogová, Soňa $u 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
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- $a Bojarová, Pavla $u 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 in Prague, nám. Sítná 3105, CZ-272 01 Kladno, Czech Republic. Electronic address: bojarova@biomed.cas.cz
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