title: Acyclic nucleoside thiophosphonates as potent inhibitors of HIV and HBV replication.
abstract: 9-[2-(Thiophosphonomethoxy)ethyl]adenine 3 and (R)-9-[2-(Thiophosphonomethoxy)propyl]adenine 4 were synthesized as the first thiophosphonate nucleosides bearing a sulfur atom at the α-position of the acyclic nucleoside phosphonates PMEA and PMPA. Thiophosphonates S-PMEA 3 and S-PMPA 4 were evaluated for in vitro activity against HIV-1 (subtypes A to G), HIV-2 and HBV-infected cells, and found to exhibit potent antiretroviral activity. We showed that their diphosphate forms S-PMEApp 5 and S-PMPApp 6 are readily incorporated by wild-type (WT) HIV-1 RT into DNA and act as DNA chain terminators. Compounds 3 and 4 were evaluated for in vitro activity against a broad panel of DNA and RNA viruses and displayed beside HIV a moderate activity against herpes simplex virus and vaccinia viruses. In order to measure enzymatic stabilities of the target derivatives 3 and 4, kinetic data and decomposition pathways were studied at 37 °C in several media.
authors.affiliation: Laboratoire d'Architecture et Fonction des Macromolécules Biologiques, UMR CNRS 6098, Equipe Réplicases Virales: Structure, Mécanisme, et Drug-design, Universités Aix-Marseille I et II, Parc scientifique de Luminy, 163 av de Luminy, 13288 Marseille Cedex 9, France.
authors.forename: Karine
authors.initials: K
authors.lastname: Barral
authors.forename: Clément
authors.initials: C
authors.lastname: Weck
authors.forename: Nadine
authors.initials: N
authors.lastname: Payrot
authors.forename: Loic
authors.initials: L
authors.lastname: Roux
authors.forename: Céline
authors.initials: C
authors.lastname: Durafour
authors.forename: Fabien
authors.initials: F
authors.lastname: Zoulim
authors.forename: Johan
authors.initials: J
authors.lastname: Neyts
authors.forename: Jan
authors.initials: J
authors.lastname: Balzarini
authors.forename: Bruno
authors.initials: B
authors.lastname: Canard
authors.forename: Stéphane
authors.initials: S
authors.lastname: Priet
authors.forename: Karine
authors.initials: K
authors.lastname: Alvarez
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology*; D002460:Cell Line; D002851:Chromatography, High Pressure Liquid; D004355:Drug Stability; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D006515:Hepatitis B virus / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D063065:Organophosphonates / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D016339:Spectrometry, Mass, Fast Atom Bombardment; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D000998:Antiviral Agents; D063065:Organophosphonates