Nucleosides. 114. 5'-O-Glucuronides of 5-fluorouridine and 5-fluorocytidine. Masked precursors of anticancer nucleosides.
5'-O-Glucuronides of anticancer nucleosides, 5-fluorouridine and 5-fluorocytidine, were synthesized by three different methods. The best preparative procedure was the one starting from benzyl 5-O-(methyl 2', 3', 4'-tri-O-acetyl-beta-D-glucopyranosyluronate)-2,3-O-isopropylidene-beta-D-ribof uranoside (15) that was obtained almost quantitatively by condensation of benzyl 2,3-O-isopropylidene-beta-D-ribofuranoside (8) with methyl (2,3,4-tri-O-acetyl-alpha-D-glucopyranosyl bromide)uronate (2). After de-O-isopropylidenation of 15, the crystalline product, benzyl 5-O-(methyl 2', 3', 4'-tri-O-acetyl-beta-D-glucopyranosyluronate)-beta-D-ribofuranoside (16), was de-O-benzylated catalytically to 5-O-(methyl 2', 3', 4'-tri-O-acetyl-beta-glucopyranosyluronate)-D-ribofuranose (17). Compound 17 was acetylated to crystalline 5-O-(methyl 2',3',4'-tri-O-acteyl-beta-D-glucopyranosyluronate)-1,2,3-tri-O-acetyl-beta-D-ribofuranose (18) and condensed with trimethylsilylated 5-fluorouracil of 5-fluorocytosine in the presence of SnCl4 to afford the corresponding protected nucleosides 5 and 19 in good yields. Saponification of these compounds gave 5'-O-beta-D-glucuronides of 5-fluorouridine and 5-fluorocytidine (20 and 21) isolated as their crystalline N salts. These glucuronides were substrates of both bacterial and bovine beta-glucuronidase. They were, as expected, much less toxic against several leukemia cell lines in tissue culture.
D000970:Antineoplastic Agents / Q000138:chemical synthesis*; D002478:Cells, Cultured; D003562:Cytidine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D005965:Glucuronates / Q000138:chemical synthesis; D009374:Neoplasms, Experimental / Q000188:drug therapy; D014529:Uridine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology
D000970:Antineoplastic Agents; D005965:Glucuronates; C001943:5-fluorouridine; D003562:Cytidine; C007745:5-fluorocytidine; D014529:Uridine