Synthesis and biological activities of 4-O-(difluoromethyl)-5-substituted-uracil nucleoside analogues.
Various 4-O-difluoromethyl analogues of 5-substituted uridine (Urd), 2'-deoxyuridine (dUrd), and arabinofuranosyluracil (araU) nucleosides were prepared via a CF2-insertion reaction into 4-O-silylated nucleosides and evaluated for activity against herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) and cytotoxicity in human embryonic lung fibroblast (HELF) cell cultures. The introduction of the 4-substituent led to a strong reduction of antiviral activity for dUrd but not for araU analogues. Three of the 4,5-disubstituted uracil nucleoside derivatives, 4-O-(difluoromethyl)-5-bromo-araU (5c),-5-methyl-araU (5e), and -(E)-5-(2-bromovinyl)-araU (5g), displayed a high and selective inhibitory effect against HSV-1, but only 5e was effective against both HSV-1 and HSV-2 comparably with the antiherpes potential of the reference compounds 9-[(2-hydroxyethoxy)methyl]guanine (acyclovir) and 1-beta-D-arabino-furanosylthymine (araT).
Reefschläger
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J
Medical Department (Charité), Humboldt University of Berlin, GDR.
Pein
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Cech
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D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D001086:Arabinofuranosyluracil / Q000031:analogs & derivatives* / Q000494:pharmacology; D003857:Deoxyuridine / Q000031:analogs & derivatives / Q000494:pharmacology; D006801:Humans; D018139:Simplexvirus / Q000187:drug effects; D013329:Structure-Activity Relationship; D014529:Uridine / Q000031:analogs & derivatives* / Q000494:pharmacology
D000998:Antiviral Agents; D001086:Arabinofuranosyluracil; D003857:Deoxyuridine; D014529:Uridine