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

研究成果: 雜誌貢獻文章同行評審

20 引文 斯高帕斯(Scopus)


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.

頁(從 - 到)720-728
期刊Bioorganic and Medicinal Chemistry
出版狀態已發佈 - 2月 15 2015

ASJC Scopus subject areas

  • 生物化學
  • 臨床生物化學
  • 分子生物學
  • 分子醫學
  • 有機化學
  • 藥物發現
  • 藥學科學


深入研究「Synthesis and anti-hepatitis B virus activity of C4 amide-substituted isosteviol derivatives」主題。共同形成了獨特的指紋。