title: Nucleosides. 139. Synthesis and anticytomegalovirus and antiherpes simplex virus activity of 5'-modified analogues of 2'-fluoroarabinosylpyrimidine nucleosides.
abstract: In order to determine if modification of the 5'-position reduces or abolishes the antiviral activity of 2'-fluoro-5-iodo-ara-C (FIAC), 2'-fluoro-5-iodo-ara-U (FIAU), or 2'-fluoro-5-methyl-ara-U (FMAU) against human cytomegalovirus (HCMV) and herpes simplex virus (HSV), the 5'-deoxy, 5'-mercapto, and 5'-amino analogues of these nucleosides were prepared. 5'-Deoxy-FIAC and 5'-deoxy-FIAU were prepared by catalytic hydrogenation of 5'-iodo-FIAC and 5'-iodo-FIAU to 5'-deoxy-FAC and 5'-deoxy-FAU, respectively, followed by reiodination at C-5. Reduction of 5'-iodo-FMAU afforded 5'-deoxy-FMAU. These 5'-deoxy nucleosides were found to be inactive against HCMV, indicating that the conversion to 5'-phosphate by the cellular enzyme(s) is a requirement for antiviral activity against this virus. Other 5'-modified (NH2 and SH) analogues were also prepared from 5'-O-tosyl-FIAC and 5'-O-tosyl-FMAU. Treatment of these tosylates with LiN3 in DMF afforded the corresponding 5'-N3 products. Catalytic hydrogenation of 5'-N3-FMAU afforded 5'-NH2-FMAU, whereas 5'-NH2-FIAC was obtained by treatment of 5'-N3-FIAC with Ph3P in pyridine. 5'-Mercapto analogues were prepared by treatment of 5'-O-tosyl-3'-O-acetyl nucleosides with KSAc followed by deacetylation. 5'-NH2-FMAU was the only compound that showed good activity against HSV-1 and HSV-2 in vitro. However, this compound was less potent and had a lower therapeutic index than FMAU.
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis*; D001086:Arabinofuranosyluracil / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D003561:Cytarabine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D003587:Cytomegalovirus / Q000187:drug effects*; D004353:Drug Evaluation, Preclinical; D005461:Fluorine / Q000494:pharmacology; D007202:Indicators and Reagents; D009682:Magnetic Resonance Spectroscopy; D018139:Simplexvirus / Q000187:drug effects*; D013329:Structure-Activity Relationship; D014529:Uridine / Q000031:analogs & derivatives*; D014709:Vero Cells
chemical_list: D000998:Antiviral Agents; D007202:Indicators and Reagents; D003561:Cytarabine; D005461:Fluorine; D001086:Arabinofuranosyluracil; D014529:Uridine