Design, synthesis, and biological evaluation of (E)-2-benzylidene-1-indanones derivatized by bioisosteric replacement of aurones

Thymic stromal lymphopoietin (TSLP) is a cytokine derived from epithelial cells and plays an essential role in the onset and activation of Th2-derived allergic inflammatory conditions, including atopic dermatitis. Despite their potential as drug targets, well-defined small molecules that effectively...

Full description

Saved in:
Bibliographic Details
Published in:Applied biological chemistry 2024, 67(0), , pp.1-15
Main Authors: Lee, Youngshim, Ahn, Seunghyun, Jung, Euitaek, Koh, Dongsoo, Lim, Yoongho, Lee, Young Han, Shin, Soon Young
Format: Article
Language:English
Subjects:
(E)-2-benzylidene-1-indanones
Applied Microbiology
Atopic dermatitis
Aurone
Bioisosteric replacement
Biological activity
Biological Techniques
Bioorganic Chemistry
Cell activation
Chemistry
Chemistry and Materials Science
Dermatitis
EGR-1 protein
Epithelial cells
Epithelium
Gene expression
Interleukin 4
Keratinocytes
Kinases
Lymphocytes T
Magnetic resonance spectroscopy
MAP kinase
Mass spectrometry
Mass spectroscopy
Metabolites
Mitogen-activated protein kinase
NMR spectroscopy
Phosphorylation
Plants
Polymerase chain reaction
Real time
Signal transduction
Therapeutic targets
Thymic stromal lymphopoietin
Thymus
농학
Citations: Items that this one cites
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Thymic stromal lymphopoietin (TSLP) is a cytokine derived from epithelial cells and plays an essential role in the onset and activation of Th2-derived allergic inflammatory conditions, including atopic dermatitis. Despite their potential as drug targets, well-defined small molecules that effectively block TSLP expression are still lacking. A plant-derived secondary metabolite, aurone, was derivatized based on bioisosteric replacement to identify compounds that inhibit the promoter activity of TSLP. Thirteen ( E )-2-benzylidene-1-indanones were designed and synthesized, and their structures were identified using NMR spectroscopy and mass spectrometry. Inhibition of the expression of TSLP triggered by interleukin-4 (IL-4) caused by ( E )-2-benzylidene-1-indanones was measured using a TSLP gene promoter-reporter activity assay. Because compound 12 , ( E )-5-methoxy-2-(3-methoxybenzylidene)-2,3-dihydro-1 H -inden-1-one, showed the best activity, further biological experiments, including RT-PCR analysis, quantitative real-time PCR, and inhibitory effects on IL-4-induced early growth response-1 (EGR-1) expression, EGR-1 DNA-binding activity, and IL-4-induced phosphorylation of the mitogen-activated protein kinase (MAPK) signaling cascade were performed. This study demonstrated that compound 12 acts on MAPK to block IL-4-triggered mRNA expression of TSLP via the MAPK-EGR-1 signaling pathway in HaCaT keratinocytes.
ISSN:2468-0842
2468-0834
2468-0842
DOI:10.1186/s13765-024-00973-9