Schroeder A C, Hughes R G, Bloch A
J Med Chem. 1981 Sep;24(9):1078-83. doi: 10.1021/jm00141a012.
A series of nucleoside analogues has been prepared, wherein the cyclic carbohydrate moiety is replaced by aliphatic side chains attached to cytosine, thymine, uracil, and 5-fluorouracil. The 1-[(2-hydroxyethoxy)methyl] derivatives of these heterocycles were synthesized by reacting the silylated bases with 2-(chloromethoxy)ethyl benzoate, followed by removal of the protecting groups with methanolic ammonia. The hydroxy groups of a number of these derivatives was subsequently replaced by an azido, amino, or carbamoyloxy moiety. The 1-(2-oxo-3-butyl) and 1-(2-oxo-3-nonyl) derivatives of cytosine were also prepared, their synthesis being accomplished by condensation of the silylated heterocycle with the appropriate alpha-halo ketone. At 10(-4) M concentrations, the newly prepared compounds were inactive against leukemia L-1210 cells in culture. However, a number of the agents inhibited the in vitro growth of Escherichia coli K-12, the most potent among these, 1-[(2-hydroxyethoxy)methyl]-5-fluorouracil being active at an IC50 of 1.2 micro M. This compound was equally active in preventing the growth of a 5-fluorouracil resistant strain of E. coli. Some of the analogues were also found to selectively interfere with herpes simplex virus replication in vitro. None of the cytosine derivatives tested served as either substrates or inhibitors of human liver cytosine nucleoside deaminase.
已经制备了一系列核苷类似物，其中环状碳水化合物部分被连接到胞嘧啶、胸腺嘧啶、尿嘧啶和5-氟尿嘧啶上的脂肪族侧链所取代。这些杂环的1-[(2-羟基乙氧基)甲基]衍生物是通过使甲硅烷基化的碱基与2-(氯甲氧基)乙基苯甲酸酯反应，然后用甲醇氨除去保护基团而合成的。随后，许多这些衍生物的羟基被叠氮基、氨基或氨甲酰氧基部分所取代。还制备了胞嘧啶的1-(2-氧代-3-丁基)和1-(2-氧代-3-壬基)衍生物，它们的合成是通过甲硅烷基化的杂环与适当的α-卤代酮缩合来完成的。在10(-4)M浓度下，新制备的化合物对培养中的白血病L-1210细胞无活性。然而，一些试剂抑制了大肠杆菌K-12的体外生长，其中最有效的1-[(2-羟基乙氧基)甲基]-5-氟尿嘧啶在IC50为1.2微摩尔时具有活性。该化合物在阻止大肠杆菌的5-氟尿嘧啶抗性菌株生长方面同样具有活性。还发现一些类似物在体外选择性地干扰单纯疱疹病毒的复制。所测试的胞嘧啶衍生物均未作为人肝细胞嘧啶核苷脱氨酶的底物或抑制剂。
