Discovery of 1,8-naphthalidine derivatives as potent anti-hepatic fibrosis agents via repressing PI3K/AKT/Smad and JAK2/STAT3 pathways
| Autor: | Hongwei He, Mei Zhu, Qi Shan, Guoning Zhang, Zhen-Ning Lu, Zhao Yue, Shang-Jiu Hu, Juxian Wang, Dong‐ke Yu |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
Liver Cirrhosis
STAT3 Transcription Factor Clinical Biochemistry Pharmaceutical Science Smad Proteins SMAD Biochemistry Phosphatidylinositol 3-Kinases Structure-Activity Relationship Fibrosis Drug Discovery medicine Humans Molecular Biology Protein kinase B PI3K/AKT/mTOR pathway Cells Cultured Cell Proliferation Dose-Response Relationship Drug Molecular Structure Chemistry Organic Chemistry Janus Kinase 2 medicine.disease CTGF 1-Naphthylamine Hepatic stellate cell Cancer research Molecular Medicine Hepatic fibrosis Proto-Oncogene Proteins c-akt Transforming growth factor |
| Zdroj: | Bioorganicmedicinal chemistry. 49 |
| ISSN: | 1464-3391 |
| Popis: | Liver fibrosis is one of the most common pathological consequences of chronic liver diseases (CLD). To develop effective antifibrotic strategies, a novel class of 1-(substituted phenyl)-1,8-naphthalidine-3-carboxamide derivatives were designed and synthesized. By means of the collagen type I α 1 (COL1A1)-based screening and cytotoxicity assay in human hepatic stellate cell (HSC) line LX-2, seven compounds were screened out from total 60 derivatives with high inhibitory effect and relatively low cytotoxicity for further COL1A1 mRNA expression analysis. It was found that compound 17f and 19g dose-dependently inhibited the expression of fibrogenic markers, including α-smooth muscle actin (α-SMA), matrix metalloprotein 2 (MMP-2), connective tissue growth factor (CTGF) and transforming growth factor β1 (TGFβ1) on both mRNA and protein levels. Further mechanism studies indicated that they might suppress the hepatic fibrogenesis via inhibiting both PI3K/AKT/Smad and non-Smad JAK2/STAT3 signaling pathways. Furthermore, 19g administration attenuated hepatic histopathological injury and collagen accumulation, and reduced fibrogenesis-associated protein expression in liver tissues of bile duct ligation (BDL) rats, showing significant antifibrotic effect in vivo. These findings identified 1,8-naphthalidine derivatives as potent anti-hepatic fibrosis agents, and provided valuable information for further structure optimization. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full Text from ScienceDirect