Ester prodrugs of acyclic nucleoside thiophosphonates compared to phosphonates: Synthesis, antiviral activity and decomposition study
| Autor: | Bruno Canard, Loic Roux, Karine Alvarez, Clément Weck, Fabien Zoulim, Nadine Payrot, Jan Balzarini, Maëlenn Fournier, Stéphane Priet |
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| Rok vydání: | 2013 |
| Předmět: |
Hepatitis B virus
Cell Survival Stereochemistry Organophosphonates Antiviral Agents chemistry.chemical_compound Decomposition pathway Cell Line Tumor Infected cell Drug Discovery Humans Prodrugs Pharmacology Dose-Response Relationship Drug Molecular Structure Chemistry Acyclic nucleoside Organic Chemistry DNA Viruses Esters Nucleosides General Medicine Metabolism Prodrug Decomposition In vitro Models Chemical Organothiophosphonates HIV-2 HIV-1 DNA |
| Zdroj: | European Journal of Medicinal Chemistry. 63:869-881 |
| ISSN: | 0223-5234 |
| DOI: | 10.1016/j.ejmech.2013.02.039 |
| Popis: | 9-[2-(Thiophosphonomethoxy)ethyl]adenine [S-PMEA, 8] and (R)-9-[2-(Thiophosphonomethoxy)propyl]adenine [S-PMPA, 9] are acyclic nucleoside thiophosphonates we described recently that display the same antiviral spectrum (DNA viruses) as approved and potent phosphonates PMEA and (R)-PMPA. Here, we describe the synthesis, antiviral activities in infected cell cultures and decomposition study of bis(pivaloyloxymethoxy)-S-PMEA [Bis-POM-S-PMEA, 13] and bis(isopropyloxymethylcarbonyl)-S-PMPA [Bis-POC-S-PMPA, 14] as orally bioavailable prodrugs of the S-PMEA 8 and S-PMPA 9, in comparison to the equivalent "non-thio" derivatives [Bis-POM-PMEA, 11] and [Bis-POC-PMPA, 12]. Compounds 11, 12, 13 and 14 were evaluated for their in vitro antiviral activity against HIV-1-, HIV-2-, HBV- and a broad panel of DNA viruses, and found to exhibit moderate to potent antiviral activity. In order to determine the decomposition pathway of the prodrugs 11, 12, 13 and 14 into parent compounds PMEA, PMPA, 8 and 9, kinetic data and decomposition pathways in several media are presented. As expected, bis-POM-S-PMEA 13 and bis-POC-S-PMPA 14 behaved as prodrugs of S-PMEA 8 and S-PMPA 9. However, thiophosphonates 8 and 9 were released very smoothly in cell extracts, in contrast to the release of PMEA and PMPA from "non-thio" prodrugs 11 and 12. |
| Databáze: | OpenAIRE |
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