Synthesis and antiviral activity of IVFRU, a potential probe for the non-invasive diagnosis of herpes simplex encephalitis.
Synthesis of (E)-5-(2-iodovinyl)-1-(2-deoxy-2-fluoro-beta-D-ribofuranosyl)uracil (IVFRU; 4a), and its [125I] and [131I] derivatives (4b and 4c) are described. Compared with IVDU, IVFRU had comparable antiviral activity (MIC50 = 0.01-0.1 microgram/ml), and a greater ethanol/water partition coefficient; its affinity for the murine erythrocyte nucleoside transporter system was greater than that of 2'-deoxyuridine. The [125I] derivative (4b) was selectively trapped within rabbit kidney cells (27.9 and 41.2% at 4 and 24 hr, respectively) infected in vitro by thymidine kinase-positive (TK+) herpes simplex virus (HSV-1), but not within either HSV (TK-) or mock-infected cells where uptake was less than 1%. It was resistant to glycosidic bond cleavage by pyrimidine nucleoside phosphorylases, but underwent catabolism to an unidentified metabolite and iodide during in vivo plasma and urinary excretion studies in mice. We conclude that the [123I] derivative of IVFRU warrants further evaluation as a non-invasive radiopharmaceutical agent for the diagnosis of herpes simplex encephalitis (HSE), and that IVFRU warrants further evaluation as an antiviral agent.
Iwashina
T
T
Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Canada.
Tovell
D R
DR
Xu
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Tyrrell
D L
DL
Knaus
E E
EE
Wiebe
L I
LI
D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D002478:Cells, Cultured; D055598:Chemical Phenomena; D002621:Chemistry; D004285:Dogs; D004660:Encephalitis / Q000175:diagnosis*; D004912:Erythrocytes / Q000378:metabolism; D005467:Floxuridine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D006561:Herpes Simplex / Q000175:diagnosis*; D066298:In Vitro Techniques; D007457:Iodine Radioisotopes; D051379:Mice; D008815:Mice, Inbred Strains; D011817:Rabbits; D018139:Simplexvirus / Q000502:physiology; D014779:Virus Replication / Q000187:drug effects
D000998:Antiviral Agents; D007457:Iodine Radioisotopes; D005467:Floxuridine; C060868:5-(2-iodovinyl)-1-(2'-fluoro-2'-deoxyuridine)