Decoding structural determinants of aryl hydrocarbon receptor antagonism by monoterpenoids

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F68081707%3A_____%2F25%3A00618580" target="_blank" >RIV/68081707:_____/25:00618580 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/61989592:15310/25:73631569

Výsledek na webu

<a href="https://www.sciencedirect.com/science/article/pii/S0045206825001452?via%3Dihub" target="_blank" >https://www.sciencedirect.com/science/article/pii/S0045206825001452?via%3Dihub</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1016/j.bioorg.2025.108265" target="_blank" >10.1016/j.bioorg.2025.108265</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Decoding structural determinants of aryl hydrocarbon receptor antagonism by monoterpenoids

Popis výsledku v původním jazyce

Monocyclic monoterpenoids carvones have been recently identified as atypical negative allosteric modulators of aryl hydrocarbon receptor (AhR). In the current work, we performed AhR antagonist activity screening of 100 natural and synthetic monoterpenoids, and their analogues. Using SAR approach, structural determinants of AhR antagonist activity were assigned, including C--O presence/position, planarity, and C3/C5-alkylation. Applying pyramidal selection criteria, including absence of residual agonist activity, no cytotoxicity, strong antagonist potency, and pan-antagonism against diverse AhR agonists, we distilled four lead AhR antagonists (carvacrol, ocresol, 3-methyl-S-carvone, EN-2). Whereas 3-methyl-S-carvone and EN-2 were non-competitive AhR panantagonists, carvacrol and o-cresol were ligand-selective AhR antagonists acting by unclear mechanism. We characterized in detail the effects of lead compounds at cellular functions of AhR, including AhR nuclear translocation, AhR dimerization with ARNT, and the expression of AhR-regulated genes. As a proof of concept, effects of monoterpenoids in the murine macrophages were investigated.

Název v anglickém jazyce

Decoding structural determinants of aryl hydrocarbon receptor antagonism by monoterpenoids

Popis výsledku anglicky

Monocyclic monoterpenoids carvones have been recently identified as atypical negative allosteric modulators of aryl hydrocarbon receptor (AhR). In the current work, we performed AhR antagonist activity screening of 100 natural and synthetic monoterpenoids, and their analogues. Using SAR approach, structural determinants of AhR antagonist activity were assigned, including C--O presence/position, planarity, and C3/C5-alkylation. Applying pyramidal selection criteria, including absence of residual agonist activity, no cytotoxicity, strong antagonist potency, and pan-antagonism against diverse AhR agonists, we distilled four lead AhR antagonists (carvacrol, ocresol, 3-methyl-S-carvone, EN-2). Whereas 3-methyl-S-carvone and EN-2 were non-competitive AhR panantagonists, carvacrol and o-cresol were ligand-selective AhR antagonists acting by unclear mechanism. We characterized in detail the effects of lead compounds at cellular functions of AhR, including AhR nuclear translocation, AhR dimerization with ARNT, and the expression of AhR-regulated genes. As a proof of concept, effects of monoterpenoids in the murine macrophages were investigated.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

10608 - Biochemistry and molecular biology

Projekt

<a href="/cs/project/GA23-04662S" target="_blank" >GA23-04662S: Monoterpenoidy jako nová třída negativních alosterických modulátorů aryl uhlovodíkového receptoru v terapii kolorektálního karcinomu</a><br>

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2025

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

157

Číslo periodika v rámci svazku

APR 2025

Stát vydavatele periodika

NL - Nizozemsko

Počet stran výsledku

12

Strana od-do

108265

Kód UT WoS článku

001427804300001

EID výsledku v databázi Scopus

2-s2.0-85217671468