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Open AccessArticle

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

1
Institute of Pharmacognosy, Interdisciplinary Excellence Centre, University of Szeged, 6720 Szeged, Hungary
2
Institute of Pharmaceutical Chemistry, University of Szeged, 6720 Szeged, Hungary
3
MTA-SZTE Stereochemistry Research Group, Hungarian Academy of Sciences, 6720 Szeged, Hungary
4
Interdisciplinary Centre for Natural Products, University of Szeged, 6720 Szeged, Hungary
5
Department of Infection and Immunity, Luxembourg Institute of Health, L-4354 Esch-sur-Alzette, Luxemburg
6
Graduate Institute of Natural Products, Kaohsiung Medical University, Kaohsiung 807, Taiwan
7
Department of Biochemical Science and Technology, College of Life Science, National Taiwan University, Taipei City 10617, Taiwan
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2019, 20(24), 6269; https://doi.org/10.3390/ijms20246269
Received: 17 October 2019 / Revised: 6 December 2019 / Accepted: 9 December 2019 / Published: 12 December 2019
(This article belongs to the Special Issue Natural Products against Viral Infections II)
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. View Full-Text
Keywords: natural product; drug discovery; protoflavonoid; continuous-flow chemistry; oxime; antitumor; antiviral; Epstein–Barr virus; lytic cycle natural product; drug discovery; protoflavonoid; continuous-flow chemistry; oxime; antitumor; antiviral; Epstein–Barr virus; lytic cycle
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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.

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