Hronowski L J, Szarek W A
J Med Chem. 1982 May;25(5):522-6. doi: 10.1021/jm00347a008.
Nine pyrimidine nucleoside analogues, in which the group attached at N-1 is a six-membered ring containing two heteroatoms, have been synthesized using the Vorbrüggen and Bennua (Vorbrüggen, H.; Bennua, B. Tetrahedron Lett. 1978, 1339) coupling procedure. These are 1-(1,4-oxathian-3-yl)-5-fluorouracil (8), 1-(4-oxo-1,4-oxathian-3-yl)-5-fluorouracil (two stereoisomers 9 and 10, resolved by silica gel column chromatography, 1-(1,4-oxathian-3-yl)-5-fluorouracil (11), 1-(1,4-oxathian-2-yl)-5-fluorouracil (12), 1-(1,4-dithin-2-yl)-5-flourouracil (15), 1-(1,4-dithian-2-yl)uracil (16), 1-(1,4-dithian-2-yl)thymine (17), and 1-(1,4-dioxan-2-yl)-5-fluorouracil (20). All of the analogous were tested for cell-growth inhibition using mouse and human tumor cell lines. The ID50 values of all of the analogues are greater than 10(-4) M, except in the case of 11 using the L1210 cell line. The most active analogues found are compounds 11 and 17, which were found to be 100 and 200 times less active, respectively, than 5-fluorouracil in the human erythroleukemia cell line, K-562.
利用沃布吕根和本努阿（沃布吕根，H.；本努阿，B.《四面体快报》，1978年，第1339页）偶联方法，合成了九种嘧啶核苷类似物，其中在N-1处连接的基团是含有两个杂原子的六元环。这些类似物分别是1-(1,4-氧硫杂环己烷-3-基)-5-氟尿嘧啶（8）、1-(4-氧代-1,4-氧硫杂环己烷-3-基)-5-氟尿嘧啶（两种立体异构体9和10，通过硅胶柱色谱法拆分）、1-(1,4-氧硫杂环己烷-3-基)-5-氟尿嘧啶（11）、1-(1,4-氧硫杂环己烷-2-基)-5-氟尿嘧啶（12）、1-(1,4-二硫杂环己烷-2-基)-5-氟尿嘧啶（15）、1-(1,4-二硫杂环己烷-2-基)尿嘧啶（16）、1-(1,4-二硫杂环己烷-2-基)胸腺嘧啶（17）以及1-(1,4-二氧六环-2-基)-5-氟尿嘧啶（20）。使用小鼠和人类肿瘤细胞系对所有这些类似物进行了细胞生长抑制测试。除了使用L1210细胞系测试11时，所有类似物的半数抑制浓度（ID50）值均大于10⁻⁴ M。发现的活性最高的类似物是化合物11和17，在人类红白血病细胞系K-562中，它们的活性分别比5-氟尿嘧啶低100倍和200倍。
