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Ferrocene- and ruthenium arene-containing glycomimetics as selective inhibitors of human galectin-1 and -3
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SYSNO ASEP 0599696 Document Type J - Journal Article R&D Document Type Journal Article Subsidiary J Článek ve WOS Title Ferrocene- and ruthenium arene-containing glycomimetics as selective inhibitors of human galectin-1 and -3 Author(s) Hamala, Vojtěch (UCHP-M) RID, SAI, ORCID
Kurfiřt, Martin (UCHP-M) RID, ORCID, SAI
Červenková Šťastná, Lucie (UCHP-M) RID, ORCID, SAI
Hujerová, Hedvika (UCHP-M)
Bernášková, Jana (UCHP-M) RID, SAI
Parkan, Kamil (UOCHB-X) ORCID
Kaminský, Jakub (UOCHB-X) RID, ORCID
Habanová, Nina (UOCHB-X) ORCID
Kozák, Jaroslav (UOCHB-X) RID, ORCID
Magdolenová, Alžbeta (UOCHB-X)
Zavřel, Martin (UOCHB-X) ORCID
Staroňová, Tatiana (BFU-R)
Ostatná, Veronika (BFU-R) RID, ORCID
Žaloudková, Lucie (BFU-R)
Daňhel, Aleš (BFU-R) RID, ORCID
Holčáková, J. (CZ)
Voňka, P. (CZ)
Hrstka, R. (CZ)
Karban, Jindřich (UCHP-M) RID, ORCID, SAISource Title Inorganic Chemistry Frontiers. - : Royal Society of Chemistry - ISSN 2052-1553
Roč. 11, č. 21 (2024), s. 7588-7609Number of pages 22 s. Language eng - English Country GB - United Kingdom Keywords digit NM affinity ; therapeutic targer ; crystal-structure ; ligant ; derivatives OECD category Inorganic and nuclear chemistry R&D Projects GA23-06115S GA ČR - Czech Science Foundation (CSF) LX22NPO5102 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) Research Infrastructure e-INFRA CZ II - 90254 - CESNET, zájmové sdružení právnických osob
ELIXIR CZ III - 90255 - Ústav organické chemie a biochemie AV ČR, v. v. i.Method of publishing Open access Institutional support UCHP-M - RVO:67985858 ; UOCHB-X - RVO:61388963 ; BFU-R - RVO:68081707 UT WOS 001319761900001 EID SCOPUS 85205443201 DOI https://doi.org/10.1039/D4QI01555J Annotation Galectins are a family of β-galactoside-binding proteins with an evolutionarily conserved carbohydrate recognition domain. Their dysregulation has been implicated in physiological and pathological processes, including fibrotic disorders, inflammation, and cancer. For example, elevated levels of galectin-1 contribute to tumor cell migration and immune evasion, whereas overexpression of galectin-3 is associated with increased invasiveness and the formation of metastasis. Pharmacological inhibition of these galectins is a promising therapeutic strategy to counteract their oncogenic effects. In this study, we synthesized a novel series of galectin inhibitors with ferrocene and ruthenium arene motifs attached to lactose, N-acetyllactosamine, or thiodigalactoside scaffolds. We determined their binding affinity toward human galectin-1 (hgal-1) and the CRD domain of human galectin-3 (hgal-3-CRD) using fluorescence polarization, intrinsic fluorescence of galectin tryptophan residues, and isothermal titration calorimetry. The ferrocene analogs exhibited superior affinity for both hgal-1 and hgal-3-CRD compared with ruthenium arenes. In particular, a symmetrical diferrocene thiodigalactoside complex exhibited low nanomolar affinity for hgal-1 and selectivity over hgal-3-CRD. Asymmetrical monoferrocene thiodigalactoside complexes exhibited nanomolar affinity and good selectivity for hgal-3-CRD. Chronopotentiometric stripping analysis demonstrated that the inhibitors stabilized hgal-1 against destabilization by electric field effects.19F{ 1H} NMR experiments and molecular dynamics simulations suggested that the incorporation of the
ferrocene motif limited the accessible binding modes to hgal-3-CRD whereas binding to hgal-1 remained unrestricted, resulting in attenuated binding affinities to hgal-3-CRD and selectivity for hgal-1. These results open new possibilities for the design and optimization of therapeutic organometallic galectin inhibitors.Workplace Institute of Chemical Process Fundamentals Contact Eva Jirsová, jirsova@icpf.cas.cz, Tel.: 220 390 227 Year of Publishing 2025 Electronic address https://pubs.rsc.org/en/content/articlepdf/2024/qi/d4qi01555j
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