5'-O-Alkyl-5-fluorouridines: Synthesis and biological activity

Methyl 2,3-O-isopropylidene-D-ribofuranoside ( IV ) was alkylated with alkyl halides in the presence of sodium hydride and the products were transformed by acid hydrolysis and glycosylation into methyl 5-O-alkyl-D-ribofuranosides VII . Benzoylation of VII followed by acetolysis afforded 1-O-acetyl-2,3-di-O-benzoyl-5-O-alkyl-D-ribofuranoses IX which on reaction with 2,4-bis(trimethylsilyloxy)pyrimidine in the presence of tin tetrachloride in acetonitrile and subsequent hydrolysis gave 5'-O-alkyl-2',3'-di-O-benzoyluridines XIa-XIe . Methanolysis of compounds XI furnished 5'-O-alkyluridines III . The 5-O-allyl derivative XII was hydroxylated in the presence OsO 4 and transformed further to 5'-O-( RS )-(2,3-dihydroxypropyl)uridine ( IIIg ) and its tetrabenzoate XVI . Compounds XI and XVI on reaction with elemental fluorine in acetic acid afforded benzoyl derivatives of 5'-O-alkyl-5-fluorouridines XVIIa-XVIIe and XIX which were methanolyzed to give 5'-O-alkyl-5-fluorouridines II . This procedure afforded 5'-O-methyl ( IIa ), ethyl ( IIb ), n-butyl ( IIc ), n-hexyl ( IId ), n-octyl ( IIe ), and ( RS )-(2,3-dihydroxypropyl) ( IIf ) derivatives of 5-fluorouridine. None of the compounds II exhibited antibacterial effect on Escherichia coli B or antiviral activity against HSV-1, HSV-2, vaccinia virus or vesicular stomatitis viruses. Compounds IIc,d,e suppressed the growth of L 1210 mice leukemic cells at concentrations of 10 -5 to 10 -6 mol l -1 ; the 5'-O-n-butyl derivative IIc has the highest activity (ID 50 2·8 μmol l -1 ) but does not prolong the life span of L 1210 leukemia bearing mice following repeated daily doses of 80 mg/kg.