Influence of 4′-Substitution on the Activity of Gemcitabine and Its ProTide Against VZV and SARS-CoV-2

[Image: see text] In addition to its therapeutic value as a chemotherapy drug, gemcitabine is of ongoing interest to the scientific community for its broad-spectrum antiviral activity. Herein the synthesis of 4′-methoxy- and 4′-fluoro-substituted gemcitabine analogues along with their phosphoramidat...

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Autores principales: Zheng, Zihua, Groaz, Elisabetta, Snoeck, Robert, De Jonghe, Steven, Herdewijn, Piet, Andrei, Graciela
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2020
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7737538/
https://www.ncbi.nlm.nih.gov/pubmed/33479570
http://dx.doi.org/10.1021/acsmedchemlett.0c00485
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author Zheng, Zihua
Groaz, Elisabetta
Snoeck, Robert
De Jonghe, Steven
Herdewijn, Piet
Andrei, Graciela
author_facet Zheng, Zihua
Groaz, Elisabetta
Snoeck, Robert
De Jonghe, Steven
Herdewijn, Piet
Andrei, Graciela
author_sort Zheng, Zihua
collection PubMed
description [Image: see text] In addition to its therapeutic value as a chemotherapy drug, gemcitabine is of ongoing interest to the scientific community for its broad-spectrum antiviral activity. Herein the synthesis of 4′-methoxy- and 4′-fluoro-substituted gemcitabine analogues along with their phosphoramidate prodrugs is described. Among these derivatives, 4′-fluorogemcitabine proved to be active against varicella zoster virus (VZV, TK+ strain) with an EC(50) of 0.042 μM and produced significant cytotoxicity (CC(50) = 0.11 μM). Upon derivatization of this trifluoro nucleoside as its prodrug, decreased anti-VZV activity was observed, but with a concomitantly improved selectivity index (SI = 36). When this prodrug was tested against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), its antiviral activity (EC(50) = 0.73 μM) was comparable to or slightly lower than its cytotoxic concentration in measurements of cell growth and cell morphology, respectively.
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spelling pubmed-77375382020-12-15 Influence of 4′-Substitution on the Activity of Gemcitabine and Its ProTide Against VZV and SARS-CoV-2 Zheng, Zihua Groaz, Elisabetta Snoeck, Robert De Jonghe, Steven Herdewijn, Piet Andrei, Graciela ACS Med Chem Lett [Image: see text] In addition to its therapeutic value as a chemotherapy drug, gemcitabine is of ongoing interest to the scientific community for its broad-spectrum antiviral activity. Herein the synthesis of 4′-methoxy- and 4′-fluoro-substituted gemcitabine analogues along with their phosphoramidate prodrugs is described. Among these derivatives, 4′-fluorogemcitabine proved to be active against varicella zoster virus (VZV, TK+ strain) with an EC(50) of 0.042 μM and produced significant cytotoxicity (CC(50) = 0.11 μM). Upon derivatization of this trifluoro nucleoside as its prodrug, decreased anti-VZV activity was observed, but with a concomitantly improved selectivity index (SI = 36). When this prodrug was tested against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), its antiviral activity (EC(50) = 0.73 μM) was comparable to or slightly lower than its cytotoxic concentration in measurements of cell growth and cell morphology, respectively. American Chemical Society 2020-12-09 /pmc/articles/PMC7737538/ /pubmed/33479570 http://dx.doi.org/10.1021/acsmedchemlett.0c00485 Text en © 2020 American Chemical Society This article is made available via the ACS COVID-19 subset (https://pubs.acs.org/page/vi/chemistry_coronavirus_research) for unrestricted RESEARCH re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.
spellingShingle Zheng, Zihua
Groaz, Elisabetta
Snoeck, Robert
De Jonghe, Steven
Herdewijn, Piet
Andrei, Graciela
Influence of 4′-Substitution on the Activity of Gemcitabine and Its ProTide Against VZV and SARS-CoV-2
title Influence of 4′-Substitution on the Activity of Gemcitabine and Its ProTide Against VZV and SARS-CoV-2
title_full Influence of 4′-Substitution on the Activity of Gemcitabine and Its ProTide Against VZV and SARS-CoV-2
title_fullStr Influence of 4′-Substitution on the Activity of Gemcitabine and Its ProTide Against VZV and SARS-CoV-2
title_full_unstemmed Influence of 4′-Substitution on the Activity of Gemcitabine and Its ProTide Against VZV and SARS-CoV-2
title_short Influence of 4′-Substitution on the Activity of Gemcitabine and Its ProTide Against VZV and SARS-CoV-2
title_sort influence of 4′-substitution on the activity of gemcitabine and its protide against vzv and sars-cov-2
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7737538/
https://www.ncbi.nlm.nih.gov/pubmed/33479570
http://dx.doi.org/10.1021/acsmedchemlett.0c00485
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