Less cytotoxic protoflavones as antiviral agents: Protoapigenone 1-O-isopropyl ether shows improved selectivity against the epstein–barr virus lytic cycle

Máté Vágvölgyi, Gábor Girst, Norbert Kúsz, Sándor B. Ötvös, Ferenc Fülöp, Judit Hohmann, Jean Yves Servais, Carole Seguin-Devaux, Fang Rong Chang, Michael S. Chen, Li Kwan Chang, Attila Hunyadi*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

6 Citations (Scopus)

Abstract

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.

Original languageEnglish
Article number6269
JournalInternational Journal of Molecular Sciences
Volume20
Issue number24
DOIs
Publication statusPublished - 2 Dec 2019

Keywords

  • Antitumor
  • Antiviral
  • Barr virus
  • Continuous-flow chemistry
  • Drug discovery
  • Epstein
  • Lytic cycle
  • Natural product
  • Oxime
  • Protoflavonoid

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