Glycomimetic inhibitors of tandem-repeat galectins: Simple and efficient

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61388971%3A_____%2F24%3A00585278" target="_blank" >RIV/61388971:_____/24:00585278 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/68407700:21460/24:00373340 RIV/00216208:11310/24:10479581

Výsledek na webu

<a href="https://www.sciencedirect.com/science/article/pii/S0045206824001366?via%3Dihub" target="_blank" >https://www.sciencedirect.com/science/article/pii/S0045206824001366?via%3Dihub</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1016/j.bioorg.2024.107231" target="_blank" >10.1016/j.bioorg.2024.107231</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Glycomimetic inhibitors of tandem-repeat galectins: Simple and efficient

Popis výsledku v původním jazyce

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 3,3-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.

Název v anglickém jazyce

Glycomimetic inhibitors of tandem-repeat galectins: Simple and efficient

Popis výsledku anglicky

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 3,3-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.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

10608 - Biochemistry and molecular biology

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

Bioorganic Chemistry

ISSN

0045-2068

e-ISSN

1090-2120

Svazek periodika

145

Číslo periodika v rámci svazku

April 24

Stát vydavatele periodika

NL - Nizozemsko

Počet stran výsledku

13

Strana od-do

107231

Kód UT WoS článku

001197668500001

EID výsledku v databázi Scopus

2-s2.0-85186065776