Less cytotoxic protoflavones as antiviral agents: Protoapigenone 1′-O-isopropyl Ether shows improved selectivity against the Epstein-Barr Virus lytic cycle.

  • HIV Clinical and Translational Research
December 04, 2019 By:
  • Vagvolgyi M
  • Girst G
  • Kusz N
  • Otvos SB
  • Fulop F
  • Hohmann J
  • Servais JY
  • Seguin-Devaux C
  • Chang FR
  • Chen MS
  • Chang LK
  • Hunyadi A.

Protoflavones, a rare group of natural flavonoids with a non-aromatic B-ring, are best known for their antitumor properties. The protoflavone B-ring is a versatile moiety that might be explored for various pharmacological purposes, but the common cytotoxicity of these compounds is a limitation to such efforts. Protoapigenone was previously found to be active against the lytic cycle of Epstein-Barr virus (EBV). Further, the 5-hydroxyflavone moiety is a known pharmacophore against HIV-integrase. The aim of this work was to prepare a series of less cytotoxic protoflavone analogs and study their antiviral activity against HIV and EBV. Twenty-seven compounds, including 18 new derivatives, were prepared from apigenin through oxidative de-aromatization and subsequent continuous-flow hydrogenation, deuteration, and/or 4'-oxime formation. One compound was active against HIV at the micromolar range, and three compounds showed significant activity against the EBV lytic cycle at the medium-low nanomolar range. Among these derivatives, protoapigenone 1'-O-isopropyl ether (6) was identified as a promising lead that had a 73-times selectivity of antiviral over cytotoxic activity, which exceeds the selectivity of protoapigenone by 2.4-times. Our results open new opportunities for designing novel potent and safe anti-EBV agents that are based on the natural protoflavone moiety.

2019 Dec. Int J Mol Sci.20(24):6269.
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