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

Tsurng Juhn Huang, Cheng Lin Yang, Yu Cheng Kuo, Yi Chih Chang, Li Ming Yang, Bo Hon Chou, Shwu Jiuan Lin

Research output: Contribution to journalArticle

13 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)720-728
Number of pages9
JournalBioorganic and Medicinal Chemistry
Volume23
Issue number4
DOIs
Publication statusPublished - Feb 15 2015

Fingerprint

Viruses
Hepatitis B virus
Amides
Derivatives
DNA
Antiviral Agents
Viral Genes
DNA Replication
Gene expression
RNA
Hepatitis B e Antigens
Viral DNA
Viral RNA
Hepatitis B Surface Antigens
Virus Replication
isosteviol
Transfection
Proteins
Plasmids
Down-Regulation

Keywords

  • Antiviral effect
  • Hepatitis B virus
  • Isosteviol derivative
  • NF-κB

ASJC Scopus subject areas

  • Biochemistry
  • Clinical Biochemistry
  • Molecular Biology
  • Molecular Medicine
  • Organic Chemistry
  • Drug Discovery
  • Pharmaceutical Science

Cite this

Synthesis and anti-hepatitis B virus activity of C4 amide-substituted isosteviol derivatives. / Huang, Tsurng Juhn; Yang, Cheng Lin; Kuo, Yu Cheng; Chang, Yi Chih; Yang, Li Ming; Chou, Bo Hon; Lin, Shwu Jiuan.

In: Bioorganic and Medicinal Chemistry, Vol. 23, No. 4, 15.02.2015, p. 720-728.

Research output: Contribution to journalArticle

Huang, Tsurng Juhn ; Yang, Cheng Lin ; Kuo, Yu Cheng ; Chang, Yi Chih ; Yang, Li Ming ; Chou, Bo Hon ; Lin, Shwu Jiuan. / Synthesis and anti-hepatitis B virus activity of C4 amide-substituted isosteviol derivatives. In: Bioorganic and Medicinal Chemistry. 2015 ; Vol. 23, No. 4. pp. 720-728.
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