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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...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2019
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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. |
format | Online Article Text |
id | pubmed-6940897 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
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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