5-氟-4'-硫代尿苷及一些相关核苷的合成与生物活性

Synthesis and biological activity of 5-fluoro-4'-thiouridine and some related nucleosides.

作者信息

Bobek M, Bloch A, Parthasarathy R, Whistler R L

出版信息

J Med Chem. 1975 Aug;18(8):784-7. doi: 10.1021/jm00242a004.

Abstract

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.

摘要

通过相应嘧啶碱的2,4-双-O-三甲基硅烷基衍生物与受保护的4-硫代-D-核糖呋喃糖基氯缩合，已合成了一系列4'-硫代-5-卤代嘧啶核苷，包括5-氟、氯、溴和碘衍生物。其中，4'-硫代-5-氟尿苷的α和β异头物分别在4×10⁻⁷和2×10⁻⁷M的浓度下抑制白血病L1210细胞的生长，在4×10⁻⁹和6×10⁻¹⁰M的浓度下抑制屎肠球菌的生长。这些化合物对耐10⁻³M 5-氟尿嘧啶或5-氟尿苷的屎肠球菌菌株仍具有显著活性。在屎肠球菌培养物中测定发现，4'-硫代-5-氟尿苷降低细胞总蛋白含量的程度比降低其RNA或DNA含量的程度更显著。X射线晶体学表明，碳水化合物环中硫取代氧会显著改变该部分的构象。