Synthesis and biological activity of 5-fluoro-4'-thiouridine and some related nucleosides.
The synthesis of a series of 4'-thio-5-halogenopyrimidine nucleosides, including the 5-fluoro, chloro, bromo and iodo derivatives, has been carried out by condensation of the 2,4-bis-O-trimethylsilyl derivatives of the corresponding pyrimidine bases with the protected 4-thio-D-ribofuranosyl chloride. Among these, the alpha and beta anomers of 4'-thio-5-fluorouridine inhibited the growth of leukemia L1210 cells at concentrations of 4 x 10(-7) and 2 x 10(-7) M, respectively, and that of S. faecium at 4 x 10(-9) and 6 x 10(-10) M, respectively. These compounds retained marked activity against strains of S. faecium resistant to 10(-3) M 5-fluorouracil or 5-fluorouridine. As determined in S. faecium cultures, 4'-thio-5-fluorouridine decreased the total protein content of the cells more markedly than it did their RNA or DNA content. X-Ray crystallography showed that substitution of sulfur for the oxygen in the carbohydrate ring markedly changes the conformation of that moiety.
D000818:Animals; D001426:Bacterial Proteins / Q000378:metabolism; D002478:Cells, Cultured; D003461:Crystallography; D013293:Enterococcus faecalis / Q000187:drug effects; D004926:Escherichia coli / Q000187:drug effects; D007939:Leukemia L1210 / Q000378:metabolism; D008325:Mammary Neoplasms, Experimental / Q000378:metabolism; D051379:Mice; D008958:Models, Molecular; D009690:Nucleic Acid Conformation; D013056:Spectrophotometry, Ultraviolet; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013891:Thiouridine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology
D001426:Bacterial Proteins; D013891:Thiouridine