Preprint Article Version 1 This version is not peer-reviewed

Less Cytotoxic Protoflavones as Antiviral Agents: Protoapigenone 1′-O-isopropyl Ether Shows Improved Selectivity Against the Epstein-Barr Virus Lytic Cycle

Version 1 : Received: 3 December 2019 / Approved: 4 December 2019 / Online: 4 December 2019 (11:40:33 CET)

A peer-reviewed article of this Preprint also exists.

Vágvölgyi, M.; Girst, G.; Kúsz, N.; Ötvös, S.B.; Fülöp, F.; Hohmann, J.; Servais, J.-Y.; Seguin-Devaux, C.; Chang, F.-R.; Chen, M.S.; Chang, L.-K.; Hunyadi, A. Less Cytotoxic Protoflavones as Antiviral Agents: Protoapigenone 1′-O-isopropyl ether Shows Improved Selectivity Against the Epstein–Barr Virus Lytic Cycle. Int. J. Mol. Sci. 2019, 20, 6269. Vágvölgyi, M.; Girst, G.; Kúsz, N.; Ötvös, S.B.; Fülöp, F.; Hohmann, J.; Servais, J.-Y.; Seguin-Devaux, C.; Chang, F.-R.; Chen, M.S.; Chang, L.-K.; Hunyadi, A. Less Cytotoxic Protoflavones as Antiviral Agents: Protoapigenone 1′-O-isopropyl ether Shows Improved Selectivity Against the Epstein–Barr Virus Lytic Cycle. Int. J. Mol. Sci. 2019, 20, 6269.

Journal reference: Int. J. Mol. Sci. 2019, 20, 6269
DOI: 10.3390/ijms20246269

Abstract

Protoflavones, a rare group of natural flavonoids with a non-aromatic B-ring, are best known of their antitumor properties. The protoflavone B-ring is a versatile moiety that may be explored for other pharmacological purposes, but 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 to 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 3 compounds showed significant activity against the EBV lytic cycle at the medium-low nanomolar range. Among these, protoapigenone 1′-O-isopropyl ether (6) was identified as a promising lead due to its 73-times selectivity of its antiviral over its cytotoxic effect, which exceeds that of protoapigenone by 2.4-times. Our results open new opportunities to design new, potent and safe anti-EBV agents based on the natural protoflavone moiety.

Subject Areas

natural product; drug discovery; protoflavonoid; continuous-flow chemistry; oxime; antitumor; antiviral; epstein-barr virus; lytic cycle

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