title: Synthesis and an antiviral activity evaluation of nucleoside 5´-O-(N-acyl) phosphoramidates.
abstract: BACKGROUND
  pyrimidine nucleoside analogues represent an established class of clinically useful antiviral agents. Once inside the cell, they are activated by a series of intracellular phosphorylation steps to produce 5´-triphosphate derivatives. In many cases, nucleoside analogues are poor substrates for the cellular kinases needed for their activation. It is clear that intracellular introduction of nucleoside analogues as phosphorylated metabolites (so called pronucleotides) could circumvent difficulties associated with the use of non-phosphorylated nucleoside analogues.
  
  
  METHODS
  among the current diverse pronucleotide approaches, nucleoside phosphoramidate derivatives appear to be an interesting class of potential antiviral agents because of the known relatively low stability of the P-N bond in cellular media. On the basis of oxathiaphospholane chemistry, a series of novel conjugates of 5´-O-phosphorylated zidovudine (AZT) and stavudine (d4T) with amino acids carboxamidates were obtained. The synthesis was performed using N-(2-thiono-1,3,2-oxathiaphospholane) derivatives of amino acids carboxamides as precursors.
  
  
  RESULTS
  all synthesized compounds were studied against DNA and RNA viruses. Specific antiviral activities were only detected against HIV type-1 and HIV type-2 in MT-4 cell cultures at compound concentrations that were equally active or slightly inferior to the activity of their parent drugs (2- to 20-fold for the AZT prodrugs and 6- to 40-fold for the d4T prodrugs). The compounds were also evaluated for their anti-HIV activity in CEM and in CEM thymidine-kinase-deficient (CEM/TK(-)) cell cultures.
  
  
  CONCLUSIONS
  loss of compound antiviral potency in the CEM/TK(-) cells suggested an eventual conversion of the test compounds to the free nucleosides prior to further phosphorylation to the active 5´-triphosphate metabolite.
authors.affiliation: Department of Bioorganic Chemistry, Center of Molecular and Macromolecular Studies, Polish Academy of Sciences, Lódź, Poland.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Kulik
authors.forename: Ewa
authors.initials: E
authors.lastname: Radzikowska
authors.forename: Renata
authors.initials: R
authors.lastname: Kaczmarek
authors.forename: Janina
authors.initials: J
authors.lastname: Baraniak
authors.forename: Wojciech J
authors.initials: WJ
authors.lastname: Stec
authors.forename: Erik
authors.initials: E
authors.lastname: De Clercq
authors.forename: Jan
authors.initials: J
authors.lastname: Balzarini
authors.forename: Christophe
authors.initials: C
authors.lastname: Pannecouque
mesh_terms: D000577:Amides / Q000138:chemical synthesis* / Q000494:pharmacology*; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D018929:Cell Culture Techniques; D006367:HeLa Cells; D006801:Humans; D009705:Nucleosides / Q000138:chemical synthesis* / Q000494:pharmacology*; D010756:Phosphoric Acids / Q000138:chemical synthesis* / Q000494:pharmacology*
chemical_list: D000577:Amides; D000998:Antiviral Agents; D009705:Nucleosides; D010756:Phosphoric Acids; C011067:phosphoramidic acid