2. Academic Validation
  3. Discovery of 1,8-naphthalidine derivatives as potent anti-hepatic fibrosis agents via repressing PI3K/AKT/Smad and JAK2/STAT3 pathways

Discovery of 1,8-naphthalidine derivatives as potent anti-hepatic fibrosis agents via repressing PI3K/AKT/Smad and JAK2/STAT3 pathways

  • Bioorg Med Chem. 2021 Nov 1:49:116438. doi: 10.1016/j.bmc.2021.116438.
Zhen-Ning Lu 1,  Qi Shan 1,  Shang-Jiu Hu 1,  Yue Zhao 2,  Guo-Ning Zhang 1,  Mei Zhu 1,  Dong-Ke Yu 3,  Ju-Xian Wang 4,  Hong-Wei He 5
Affiliations

Affiliations

  • 1 Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China.
  • 2 Beijing Changping Technology Innodevelop Group, Beijing 102200, China.
  • 3 Personalized Drug Therapy Key Laboratory of Sichuan Province, Department of Pharmacy, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610072, China.
  • 4 Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China. Electronic address: wangjuxian@imb.cams.cn.
  • 5 Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China. Electronic address: hehwei@imb.pumc.edu.cn.
PMID: 34610571 DOI: 10.1016/j.bmc.2021.116438
Abstract

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.

Keywords

Bile duct ligation; COL1A1; JAK2/STAT3 pathway; Liver fibrosis; Naphthalidine; PI3K/AKT/Smad pathway; Structure-activity relationship.

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