title: 5',6'-nucleoside phosphonate analogues architecture: synthesis and comparative evaluation towards metabolic enzymes.
abstract: Nucleoside phosphonates have been designed as stable 5'-mononucleotide mimics and are nowadays considered a potent class of antiviral agents. Within cells, they must be metabolised to the corresponding diphosphate to exert their biological activity. In this process, the first phosphorylation step, catalysed by nucleoside monophosphate kinases (NMP kinases), has been proposed as a bottleneck. Herein, we report the synthesis of a series of ribonucleoside phosphonate derivatives isosteric to 5'-mononucleotides, with different degrees of flexibility within the 5',6'-C-C bond, as well as different polarities, through the introduction of hydroxy groups. The influence of these modifications on the capacity of the compounds to act as substrates for appropriate human NMP kinases, involved in nucleic acids metabolism, has been investigated. Low flexibility, as well as an absence of hydroxy groups within the ribose-phosphorus architecture, is critical for efficient phosphotransfer. Among the series of pyrimidine analogues, one derivative was shown to be phosphorylated by human UMP-CMP kinase, with rates similar to those of dUMP and even better than dCMP.
authors.affiliation: Institut des Biomolécules Max Mousseron (IBMM), UMR 5247 CNRS-UM1&2, Université Montpellier 2, cc1705, Place E. Bataillon, 34095 Montpellier Cedex 5, France.
authors.forename: Franck
authors.initials: F
authors.lastname: Gallier
authors.forename: Julie A C
authors.initials: JA
authors.lastname: Alexandre
authors.forename: Chahrazade
authors.initials: C
authors.lastname: El Amri
authors.forename: Dominique
authors.initials: D
authors.lastname: Deville-Bonne
authors.forename: Suzanne
authors.initials: S
authors.lastname: Peyrottes
authors.forename: Christian
authors.initials: C
authors.lastname: Périgaud
mesh_terms: D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D006801:Humans; D008958:Models, Molecular; D009703:Nucleoside-Phosphate Kinase / Q000378:metabolism*; D063065:Organophosphonates / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D011485:Protein Binding; D012263:Ribonucleosides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013379:Substrate Specificity
chemical_list: D000998:Antiviral Agents; D063065:Organophosphonates; D012263:Ribonucleosides; D009703:Nucleoside-Phosphate Kinase