Design, synthesis and biological evaluation of seco-A-pentacyclic triterpenoids-3,4-lactone as potent non-nucleoside HBV inhibitors

Bioorg Med Chem Lett. 2018 May 15;28(9):1501-1506. doi: 10.1016/j.bmcl.2018.03.076. Epub 2018 Mar 29.

Abstract

A series of seco-A-pentacyclic triterpenoids-3,4-lactone were synthesized and the anti-HBV activities were evaluated in vitro. Several compounds inhibited the secretion of HBV antigen and the replication of HBV DNA in micromolar level. Compounds D7 and D10, seco-A-oleanane-3,4-lactone, suppressed the HBeAg secretion with IC50 values of 0.14 μM and 0.86 μM respectively, and the inhibitory activities were also confirmed by detecting the fluorescence intensity of FITC-labeled monoclonal mouse HBeAg antibody via flow cytometry. Compounds D7 and D10 as well as B4, ring-A cleaved 3,30-dioic acid, also displayed remarkable inhibition on both HBV DNA replication at the concentration of 25 μM and HBV cccDNA (covalently closed circularDNA) replication with IC50 values of 33.5 μM, 32.7 μM and 12.3 μM respectively.

Keywords: HBV cccDNA replication; HBeAg secretion inhibition; seco-A-triterpenoid-3,4-lactone.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antiviral Agents / chemical synthesis
  • Antiviral Agents / chemistry
  • Antiviral Agents / pharmacology*
  • DNA Replication / drug effects
  • Dose-Response Relationship, Drug
  • Drug Design*
  • Hepatitis B Surface Antigens / drug effects
  • Hepatitis B Surface Antigens / immunology
  • Hepatitis B virus / drug effects*
  • Hepatitis B virus / immunology
  • Microbial Sensitivity Tests
  • Molecular Structure
  • Structure-Activity Relationship
  • Triterpenes / chemical synthesis
  • Triterpenes / chemistry
  • Triterpenes / pharmacology*

Substances

  • Antiviral Agents
  • Hepatitis B Surface Antigens
  • Triterpenes