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

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 su...

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Autores principales: Vágvölgyi, Máté, Girst, Gábor, Kúsz, Norbert, Ötvös, Sándor B., Fülöp, Ferenc, Hohmann, Judit, Servais, Jean-Yves, Seguin-Devaux, Carole, Chang, Fang-Rong, Chen, Michael S., Chang, Li-Kwan, Hunyadi, Attila
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6940897/
https://www.ncbi.nlm.nih.gov/pubmed/31842358
http://dx.doi.org/10.3390/ijms20246269
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author Vágvölgyi, Máté
Girst, Gábor
Kúsz, Norbert
Ötvös, Sándor B.
Fülöp, Ferenc
Hohmann, Judit
Servais, Jean-Yves
Seguin-Devaux, Carole
Chang, Fang-Rong
Chen, Michael S.
Chang, Li-Kwan
Hunyadi, Attila
author_facet Vágvölgyi, Máté
Girst, Gábor
Kúsz, Norbert
Ötvös, Sándor B.
Fülöp, Ferenc
Hohmann, Judit
Servais, Jean-Yves
Seguin-Devaux, Carole
Chang, Fang-Rong
Chen, Michael S.
Chang, Li-Kwan
Hunyadi, Attila
author_sort Vágvölgyi, Máté
collection PubMed
description 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.
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spelling pubmed-69408972020-01-09 Less Cytotoxic Protoflavones as Antiviral Agents: Protoapigenone 1′-O-isopropyl ether Shows Improved Selectivity Against the Epstein–Barr Virus Lytic Cycle Vágvölgyi, Máté Girst, Gábor Kúsz, Norbert Ötvös, Sándor B. Fülöp, Ferenc Hohmann, Judit Servais, Jean-Yves Seguin-Devaux, Carole Chang, Fang-Rong Chen, Michael S. Chang, Li-Kwan Hunyadi, Attila Int J Mol Sci Article 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. MDPI 2019-12-12 /pmc/articles/PMC6940897/ /pubmed/31842358 http://dx.doi.org/10.3390/ijms20246269 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Vágvölgyi, Máté
Girst, Gábor
Kúsz, Norbert
Ötvös, Sándor B.
Fülöp, Ferenc
Hohmann, Judit
Servais, Jean-Yves
Seguin-Devaux, Carole
Chang, Fang-Rong
Chen, Michael S.
Chang, Li-Kwan
Hunyadi, Attila
Less Cytotoxic Protoflavones as Antiviral Agents: Protoapigenone 1′-O-isopropyl ether Shows Improved Selectivity Against the Epstein–Barr Virus Lytic Cycle
title Less Cytotoxic Protoflavones as Antiviral Agents: Protoapigenone 1′-O-isopropyl ether Shows Improved Selectivity Against the Epstein–Barr Virus Lytic Cycle
title_full Less Cytotoxic Protoflavones as Antiviral Agents: Protoapigenone 1′-O-isopropyl ether Shows Improved Selectivity Against the Epstein–Barr Virus Lytic Cycle
title_fullStr Less Cytotoxic Protoflavones as Antiviral Agents: Protoapigenone 1′-O-isopropyl ether Shows Improved Selectivity Against the Epstein–Barr Virus Lytic Cycle
title_full_unstemmed Less Cytotoxic Protoflavones as Antiviral Agents: Protoapigenone 1′-O-isopropyl ether Shows Improved Selectivity Against the Epstein–Barr Virus Lytic Cycle
title_short Less Cytotoxic Protoflavones as Antiviral Agents: Protoapigenone 1′-O-isopropyl ether Shows Improved Selectivity Against the Epstein–Barr Virus Lytic Cycle
title_sort less cytotoxic protoflavones as antiviral agents: protoapigenone 1′-o-isopropyl ether shows improved selectivity against the epstein–barr virus lytic cycle
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6940897/
https://www.ncbi.nlm.nih.gov/pubmed/31842358
http://dx.doi.org/10.3390/ijms20246269
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