Ferrocene- and ruthenium arene-containing glycomimetics as selective inhibitors of human galectin-1 and -3

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F67985858%3A_____%2F24%3A00599696" target="_blank" >RIV/67985858:_____/24:00599696 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/68081707:_____/24:00599696 RIV/61388963:_____/24:00599696 RIV/00216224:14310/24:00137750 RIV/00209805:_____/24:00080118 a 2 dalších

Výsledek na webu

<a href="https://pubs.rsc.org/en/content/articlepdf/2024/qi/d4qi01555j" target="_blank" >https://pubs.rsc.org/en/content/articlepdf/2024/qi/d4qi01555j</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1039/D4QI01555J" target="_blank" >10.1039/D4QI01555J</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Ferrocene- and ruthenium arene-containing glycomimetics as selective inhibitors of human galectin-1 and -3

Popis výsledku v původním jazyce

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 thenferrocene 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.

Název v anglickém jazyce

Ferrocene- and ruthenium arene-containing glycomimetics as selective inhibitors of human galectin-1 and -3

Popis výsledku anglicky

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 thenferrocene 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.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

10402 - Inorganic and nuclear chemistry

Projekt

Výsledek vznikl pri realizaci vícero projektů. Více informací v záložce Projekty.

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2024

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

Inorganic Chemistry Frontiers

ISSN

2052-1553

e-ISSN

2052-1553

Svazek periodika

11

Číslo periodika v rámci svazku

21

Stát vydavatele periodika

GB - Spojené království Velké Británie a Severního Irska

Počet stran výsledku

22

Strana od-do

7588-7609

Kód UT WoS článku

001319761900001

EID výsledku v databázi Scopus

2-s2.0-85205443201