Less Cytotoxic Protoflavones as Antiviral Agents: Protoapigenone 1′-O-isopropyl ether Shows Improved Selectivity Against the Epstein–Barr Virus Lytic Cycle
Journal
International Journal of Molecular Sciences
Journal Volume
20
Journal Issue
24
Pages
Article number 6269
Date Issued
2019
Author(s)
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.
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. ? 2019 by the authors. Licensee MDPI, Basel, Switzerland.
Subjects
Antitumor; Antiviral; Barr virus; Continuous-flow chemistry; Drug discovery; Epstein; Lytic cycle; Natural product; Oxime; Protoflavonoid
SDGs
Other Subjects
alpha tubulin; antivirus agent; apigenin; dimethyl sulfoxide; ether derivative; flavonoid; oxime derivative; protoapigenone 1' o isopropyl ether; protoapigenone derivative; proto?avone; proto?avone 4' oxime; tetrahydroprotoapigenone derivative; tetrahydroproto?avone 4' oxime; unclassified drug; antineoplastic agent; cyclohexanone derivative; diisopropyl ether; ether derivative; flavone derivative; protoapigenone; 4' oxime formation; animal cell; animal experiment; animal model; antiretroviral therapy; antiviral activity; Article; biological activity; carbon nuclear magnetic resonance; cell lysate; cell viability; chemical structure; chromatography; controlled study; cytotoxicity; deuteration; drug selectivity; drug synthesis; enantiomer; Epstein Barr virus; high performance liquid chromatography; human; human cell; hydrogenation; IC50; immunoblotting; isotope labeling; mass spectrometry; MTT assay; nonhuman; nuclear magnetic resonance; pathology; pharmacophore; proton nuclear magnetic resonance; racemic mixture; rat; reversed phase high performance liquid chromatography; structure activity relation; virus replication; chemistry; drug effect; Epstein Barr virus; nuclear magnetic resonance spectroscopy; physiology; viral phenomena and functions; Antineoplastic Agents; Cyclohexanones; Ethers; Flavones; Herpesvirus 4, Human; Humans; Magnetic Resonance Spectroscopy; Molecular Structure; Structure-Activity Relationship; Virus Physiological Phenomena; Virus Replication
Publisher
MDPI AG
Type
journal article