Design, synthesis, and biological evaluation of (E)-2-benzylidene-1-indanones derivatized by bioisosteric replacement of aurones
Abstract 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 ef...
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2024-12-01
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| Series: | Applied Biological Chemistry |
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| Online Access: | https://doi.org/10.1186/s13765-024-00973-9 |
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| author | Youngshim Lee Seunghyun Ahn Euitaek Jung Dongsoo Koh Yoongho Lim Young Han Lee Soon Young Shin |
| author_facet | Youngshim Lee Seunghyun Ahn Euitaek Jung Dongsoo Koh Yoongho Lim Young Han Lee Soon Young Shin |
| author_sort | Youngshim Lee |
| collection | DOAJ |
| description | Abstract 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-1H-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. |
| format | Article |
| id | doaj-art-cba7278e73724219a9e8b1d804ca4067 |
| institution | DOAJ |
| issn | 2468-0842 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | SpringerOpen |
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| series | Applied Biological Chemistry |
| spelling | doaj-art-cba7278e73724219a9e8b1d804ca40672025-08-20T03:18:32ZengSpringerOpenApplied Biological Chemistry2468-08422024-12-0167111510.1186/s13765-024-00973-9Design, synthesis, and biological evaluation of (E)-2-benzylidene-1-indanones derivatized by bioisosteric replacement of auronesYoungshim Lee0Seunghyun Ahn1Euitaek Jung2Dongsoo Koh3Yoongho Lim4Young Han Lee5Soon Young Shin6Division of Bioscience and Biotechnology, Konkuk UniversityDepartment of Applied Chemistry, Dongduk Women’s UniversityDepartment of Biological Sciences, Sanghuh College of Life Science, Konkuk UniversityDepartment of Applied Chemistry, Dongduk Women’s UniversityDivision of Bioscience and Biotechnology, Konkuk UniversityDepartment of Biological Sciences, Sanghuh College of Life Science, Konkuk UniversityDepartment of Biological Sciences, Sanghuh College of Life Science, Konkuk UniversityAbstract 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-1H-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.https://doi.org/10.1186/s13765-024-00973-9AuroneBioisosteric replacement(E)-2-benzylidene-1-indanonesThymic stromal lymphopoietinMitogen-activated protein kinase |
| spellingShingle | Youngshim Lee Seunghyun Ahn Euitaek Jung Dongsoo Koh Yoongho Lim Young Han Lee Soon Young Shin Design, synthesis, and biological evaluation of (E)-2-benzylidene-1-indanones derivatized by bioisosteric replacement of aurones Applied Biological Chemistry Aurone Bioisosteric replacement (E)-2-benzylidene-1-indanones Thymic stromal lymphopoietin Mitogen-activated protein kinase |
| title | Design, synthesis, and biological evaluation of (E)-2-benzylidene-1-indanones derivatized by bioisosteric replacement of aurones |
| title_full | Design, synthesis, and biological evaluation of (E)-2-benzylidene-1-indanones derivatized by bioisosteric replacement of aurones |
| title_fullStr | Design, synthesis, and biological evaluation of (E)-2-benzylidene-1-indanones derivatized by bioisosteric replacement of aurones |
| title_full_unstemmed | Design, synthesis, and biological evaluation of (E)-2-benzylidene-1-indanones derivatized by bioisosteric replacement of aurones |
| title_short | Design, synthesis, and biological evaluation of (E)-2-benzylidene-1-indanones derivatized by bioisosteric replacement of aurones |
| title_sort | design synthesis and biological evaluation of e 2 benzylidene 1 indanones derivatized by bioisosteric replacement of aurones |
| topic | Aurone Bioisosteric replacement (E)-2-benzylidene-1-indanones Thymic stromal lymphopoietin Mitogen-activated protein kinase |
| url | https://doi.org/10.1186/s13765-024-00973-9 |
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