title: Synthesis and cellular uptake of 2'-substituted analogues of (E)-5-(2-[125I]iodovinyl)-2'-deoxyuridine in tumor cells transduced with the herpes simplex type-1 thymidine kinase gene. Evaluation as probes for monitoring gene therapy.
abstract: A useful synthetic methodology was developed to synthesize and radiolabel a series of (E)-5-(2-[125I]iodovinyl)uracil nucleoside substrates for herpes simplex virus type-1 thymidine kinase (HSV-1 TK). (E)-5-(2-[125I]Iodovinyl)-2'-deoxyuridine ([125I]IVDU, 10), (E)-5-(2-[125I]iodovinyl)-2'-fluoro-2'-deoxyuridine ([125I]IVFRU, 11), (E)-5-(2-[125I]iodovinyl)-2'-fluoro-2'-deoxyarabinouridine ([125I]IVFAU, 12), and (E)-5-(2-[125I]iodovinyl)arabinouridine ([125I]IVAU, 13) were synthesized in 63-83% radiochemical yield by reaction of the unprotected (E)-5-(2-(trimethylsilyl)vinyl) precursors (6-9) with [125I]ICl. Cellular uptake of these labeled compounds (10-13) was evaluated in vitro. All compounds showed minimal uptake in the KBALB cell line. However, increased uptake was observed for all compounds in KBALB-STK cells which are transduced with a replication incompetent Moloney murine leukemia virus vector encoding the HSV-1 TK gene. The results indicate that uptake of these compounds in KBALB-STK cells is variable and highly dependent on the nature of the sugar 2'-substituent. When a fluoro (12) or a hydroxy (13) substituent is present in the arabinofuranosyl (up) configuration at the 2'-position, there is diminished cellular uptake in KBALB-STK cells relative to hydrogen (10) or fluorine (11) in the ribofuranosyl (down) configuration at the 2'-position. Our results indicate that radiolabeled IVFRU (11) is most promising for further in vivo studies.
authors.affiliation: Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Canada.
authors.forename: K W
authors.initials: KW
authors.lastname: Morin
authors.forename: E D
authors.initials: ED
authors.lastname: Atrazheva
authors.forename: E E
authors.initials: EE
authors.lastname: Knaus
authors.forename: L I
authors.initials: LI
authors.lastname: Wiebe
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000493:pharmacokinetics* / Q000494:pharmacology; D001692:Biological Transport; D002460:Cell Line; D005814:Genes, Viral; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors; D018259:Herpesvirus 1, Human / Q000201:enzymology* / Q000235:genetics; D007065:Idoxuridine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000493:pharmacokinetics* / Q000494:pharmacology; D007202:Indicators and Reagents; D007457:Iodine Radioisotopes; D007553:Isotope Labeling / Q000379:methods; D007700:Kinetics; D051379:Mice; D015394:Molecular Structure; D008979:Moloney murine leukemia virus; D008991:Monitoring, Physiologic / Q000379:methods; D011994:Recombinant Proteins / Q000096:biosynthesis; D013329:Structure-Activity Relationship; D013937:Thymidine Kinase / Q000096:biosynthesis / Q000235:genetics*; D014162:Transfection
chemical_list: D000998:Antiviral Agents; D007202:Indicators and Reagents; D007457:Iodine Radioisotopes; D011994:Recombinant Proteins; C030360:5-(2-iodovinyl)-2'-deoxyuridine; D013937:Thymidine Kinase; D007065:Idoxuridine