title: Design and synthesis of α-carboxy nucleoside phosphonate analogues and evaluation as HIV-1 reverse transcriptase-targeting agents.
abstract: The synthesis of the first series of a new class of nucleoside phosphonate analogues is described. Addition of a carboxyl group at the α position of carbocyclic nucleoside phosphonate analogues leads to a novel class of potent HIV reverse transcriptase (RT) inhibitors, α-carboxy nucleoside phosphonates (α-CNPs). Key steps in the synthesis of the compounds are Rh-catalyzed O-H insertion and Pd-catalyzed allylation reactions. In cell-free assays, the final products are markedly inhibitory against HIV RT and do not require phosphorylation to exhibit anti-RT activity, which indicates that the α-carboxyphosphonate function is efficiently recognized by HIV RT as a triphosphate entity, an unprecedented property of nucleoside monophosph(on)ates.
authors.affiliation: Department of Chemistry, Analytical and Biological Chemistry Research Facility, Synthesis and Solid State Pharmaceutical Centre, University College , Cork, Ireland.
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Keane
authors.forename: Alan
authors.initials: A
authors.lastname: Ford
authors.forename: Nicholas D
authors.initials: ND
authors.lastname: Mullins
authors.forename: Nuala M
authors.initials: NM
authors.lastname: Maguire
authors.forename: Thibaut
authors.initials: T
authors.lastname: Legigan
authors.forename: Jan
authors.initials: J
authors.lastname: Balzarini
authors.forename: Anita R
authors.initials: AR
authors.lastname: Maguire
mesh_terms: D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D002384:Catalysis; D015195:Drug Design; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D008958:Models, Molecular; D009705:Nucleosides / Q000138:chemical synthesis* / Q000494:pharmacology; D063065:Organophosphonates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D010165:Palladium / Q000737:chemistry*; D010766:Phosphorylation; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D019380:Anti-HIV Agents; D000998:Antiviral Agents; D009705:Nucleosides; D063065:Organophosphonates; D018894:Reverse Transcriptase Inhibitors; D010165:Palladium