title: Ester prodrugs of acyclic nucleoside thiophosphonates compared to phosphonates: synthesis, antiviral activity and decomposition study.
abstract: 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.
authors.affiliation: Laboratoire d'Architecture et Fonction des Macromolécules Biologiques, UMR CNRS 7257, Equipe Chimie Médicinale et Virologie Structurale, Université Aix-Marseille, Parc scientifique de Luminy, 163 av. de Luminy, 13288 Marseille Cedex 9, France.
authors.forename: Loïc
authors.initials: L
authors.lastname: Roux
authors.forename: Stéphane
authors.initials: S
authors.lastname: Priet
authors.forename: Nadine
authors.initials: N
authors.lastname: Payrot
authors.forename: Clément
authors.initials: C
authors.lastname: Weck
authors.forename: Maëlenn
authors.initials: M
authors.lastname: Fournier
authors.forename: Fabien
authors.initials: F
authors.lastname: Zoulim
authors.forename: Jan
authors.initials: J
authors.lastname: Balzarini
authors.forename: Bruno
authors.initials: B
authors.lastname: Canard
authors.forename: Karine
authors.initials: K
authors.lastname: Alvarez
mesh_terms: D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004267:DNA Viruses / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004952:Esters / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects; D015498:HIV-2 / Q000187:drug effects; D006515:Hepatitis B virus / Q000187:drug effects; D006801:Humans; D008956:Models, Chemical; D015394:Molecular Structure; D009705:Nucleosides / Q000737:chemistry; D063065:Organophosphonates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D063085:Organothiophosphonates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011355:Prodrugs / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000998:Antiviral Agents; D004952:Esters; D009705:Nucleosides; D063065:Organophosphonates; D063085:Organothiophosphonates; D011355:Prodrugs