Nucleosides. 136. Synthesis and antiviral effects of several 1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)-5-alkyluracils. Some structure-activity relationships.
In order to study structure-activity relationships between antiherpetic activity and the size of the C-5 alkyl substituents of 2'-fluoro-ara-U derivatives, six new nucleosides (1c-h) were synthesized. The 5-allyl analogue 1c was prepared by a Pd(II)-catalyzed reaction of 5-(chloromercuri)-1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)uracil with allyl chloride. Partial hydrogenation of 1c afforded the 5-n-propyl derivative 1d (FPAU). Nucleosides 1e-h were obtained by condensation of 3-O-acetyl-5-O-benzoyl-2-deoxy-2-fluoro-D-arabinosyl bromide with the corresponding 5-substituted uracils. Preliminary in vitro data show that, as the alkyl side chain is increased by one carbon unit, the antiherpetic potency is decreased by approximately 1 log order. The cytotoxicity also diminishes as the size of the 5-substituent is increased. FPAU exerts good activity against HSV-1 and HSV-2. FiPAU still shows good therapeutic indices, whereas the higher alkyl analogues are essentially inactive.
D001087:Arabinonucleosides / Q000138:chemical synthesis / Q000494:pharmacology*; D055598:Chemical Phenomena; D002621:Chemistry; D009682:Magnetic Resonance Spectroscopy; D008968:Molecular Conformation; D018139:Simplexvirus / Q000187:drug effects*; D013056:Spectrophotometry, Ultraviolet; D013329:Structure-Activity Relationship; D014498:Uracil / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology
D001087:Arabinonucleosides; D014498:Uracil