2. Academic Validation
  3. Synthesis and anti-hepatitis B virus activity of C4 amide-substituted isosteviol derivatives

Synthesis and anti-hepatitis B virus activity of C4 amide-substituted isosteviol derivatives

  • Bioorg Med Chem. 2015 Feb 15;23(4):720-8. doi: 10.1016/j.bmc.2014.12.064.
Tsurng-Juhn Huang 1,  Cheng-Lin Yang 2,  Yu-Cheng Kuo 3,  Yi-Chih Chang 4,  Li-Ming Yang 5,  Bo-Hon Chou 6,  Shwu-Jiuan Lin 7
Affiliations

Affiliations

  • 1 School of Medicine, China Medical University, Taichung 404, Taiwan.
  • 2 Graduate Institute of Biomedical Sciences, National Chung Hsing University, Taichung 402, Taiwan.
  • 3 Department of Radiation Oncology, China Medical University Hospital, Taichung 404, Taiwan; Department of Biomedical Imaging and Radiological Science, China Medical University, Taichung 404, Taiwan.
  • 4 Department of Medical Laboratory Science and Biotechnology, China Medical University, Taichung 404, Taiwan.
  • 5 Division of Chinese Medicinal Chemistry, National Research Institute of Chinese Medicine, Ministry of Health and Welfare, Taipei 112, Taiwan; Department of Pharmaceutical Sciences, School of Pharmacy, Taipei Medical University, Taipei 110, Taiwan.
  • 6 Department of Pharmaceutical Sciences, School of Pharmacy, Taipei Medical University, Taipei 110, Taiwan.
  • 7 Department of Pharmaceutical Sciences, School of Pharmacy, Taipei Medical University, Taipei 110, Taiwan; Ph.D. Program for the Clinical Drug Discovery from Botanical Herbs, College of Pharmacy, Taipei Medical University, Taipei 110, Taiwan. Electronic address: shwu-lin@tmu.edu.tw.
PMID: 25600408 DOI: 10.1016/j.bmc.2014.12.064
Abstract

A series of novel isosteviol derivatives having C4-amide substituents were synthesized in order to test for Antiviral effects against the hepatitis B virus (HBV) in vitro. Among them, IN-4 [N-(propylcarbonyl)-4α-amino-19-nor-ent-16-ketobeyeran] (5) exhibited inhibitory activity against secretion of HBsAg and HBeAg as well as inhibition of HBV DNA replication. Therefore, the mechanism of its Antiviral activity was further analyzed using HBV-transfected Huh7 cells. Exposure to IN-4 produced minimal inhibitory effects on viral precore/pregenomic RNA expression. However, expression levels of the 2.4/2.1-kb preS/major S RNA of the viral surface gene significantly decreased, along with intracellular levels of HBV DNA. A promoter activity analysis demonstrated that IN-4 significantly inhibited viral X, S, and preS expression levels but not viral core promoter activities. In particular, IN-4 was observed to significantly inhibit HBV gene regulation by disrupting nuclear factor (NF)-κB-associated promoter activity. In addition, the nuclear expression of p65/p50 NF-κB member proteins was attenuated following IN-4 treatment, while cytoplasmic IκBα protein levels were enhanced. Meanwhile, IN-4 was observed to inhibit the binding activity of NF-κB to putative DNA elements. Furthermore, transfection of a p65 expression plasmid into Huh7 cells significantly reversed the inhibitory effect of IN-4 on HBV DNA levels, providing further evidence of the central role of NF-κB in its Antiviral mechanism. It is therefore suggested that IN-4 inhibits HBV by interfering with the NF-κB signaling pathway, resulting in downregulation of viral gene expression and DNA replication.

Keywords

Antiviral effect; Hepatitis B virus; Isosteviol derivative; NF-κB.

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