Modulation of aryl hydrocarbon receptor activity by halogenated indoles
Language English Country Great Britain, England Media print-electronic
Document type Journal Article
PubMed
39454560
DOI
10.1016/j.bmc.2024.117964
PII: S0968-0896(24)00378-X
Knihovny.cz E-resources
- Keywords
- Aryl hydrocarbon receptor, Halogen, Indole derivatives, Inflammation,
- MeSH
- Cytochrome P-450 CYP1A1 metabolism MeSH
- Halogenation MeSH
- Indoles * chemistry pharmacology MeSH
- Humans MeSH
- Molecular Structure MeSH
- Receptors, Aryl Hydrocarbon * metabolism chemistry MeSH
- Molecular Docking Simulation * MeSH
- Basic Helix-Loop-Helix Transcription Factors MeSH
- Cell Survival drug effects MeSH
- Dose-Response Relationship, Drug MeSH
- Structure-Activity Relationship MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Names of Substances
- AHR protein, human MeSH Browser
- Cytochrome P-450 CYP1A1 MeSH
- Indoles * MeSH
- Receptors, Aryl Hydrocarbon * MeSH
- Basic Helix-Loop-Helix Transcription Factors MeSH
The aryl hydrocarbon receptor (AhR) is a cytosolic ligand-activated transcription factor integral to various physiological and pathological processes. Among its diverse ligands, indole-based compounds have garnered attention due to their significant biological activity and potential therapeutic applications. This study explores the activation of AhR by structurally diverse halogenated indoles. We evaluated the transcriptional activity of AhR and cell viability in the human LS174T-AhR-luc reporter cell line. Among the tested compounds, 4-FI, 7-FI, 6-BrI, 7-BrI, 6-Cl-2-ox, 5-Br-2-ox, and 6-Br-2-ox activated AhR in a concentration-dependent manner, displaying high efficacy and potency. Molecular docking analysis revealed moderate binding affinities of these compounds to the PAS-B domain of AhR, corroborated by competitive radioligand binding assays. Functional assays showed that halogenated indoles induce the formation of AhR-ARNT heterodimer and enhance the binding of the AhR to the CYP1A1 promoter. Additionally, 4-FI and 7-FI exhibited anti-inflammatory properties in Caco-2 cell models, highlighting their potential for therapeutic applications. This study underscores the significance of the type and position of halogen moiety in indole scaffold, suggesting their potential as candidates for developing therapeutics drugs to treat conditions such as inflammatory bowel disease via AhR activation.
Department of Biochemistry Faculty of Science Palacky University Olomouc Czech Republic
Department of Cell Biology and Genetics Faculty of Science Palacky University Olomouc Czech Republic
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