Holshouser M H, Shipp A M, Ferguson P W
J Med Chem. 1985 Feb;28(2):242-5. doi: 10.1021/jm00380a016.
To test the effect of changes in electronegativity within the alicyclic N-1 substituent 5-fluorouracil analogues on cytotoxic activity, a series of derivatives of ftorafur, 1-(2'-tetrahydrofuranyl)-5-fluorouracil, was synthesized and tested for antitumor activity in the P388 lymphocytic leukemia screen and cytotoxic activity in the L1210 cell culture screen. Two compounds of N-1 substituent with high electronegativity, the 2'-tetrahydrothiophene 1'-oxide and the 2'-tetrahydrothiophene 1',1'-dioxide derivatives, demonstrated the highest in vitro L1210 cell inhibition (84.5% and 92.0%, respectively). Furthermore, against P388 lymphocytic leukemia in vivo, the 2'-tetrahydrothiophene 1'-oxide derivative showed significant activity (T/C = 143). Other compounds of similar or lower electronegativity within the N-1 cyclic substituent were inactive against P388 lymphocytic leukemia and less active against L1210 cells.
为了测试脂环族N-1取代基5-氟尿嘧啶类似物中电负性变化对细胞毒性活性的影响，合成了一系列呋氟尿嘧啶（1-(2'-四氢呋喃基)-5-氟尿嘧啶）的衍生物，并在P388淋巴细胞白血病筛选中测试其抗肿瘤活性，在L1210细胞培养筛选中测试其细胞毒性活性。两种具有高电负性的N-1取代基化合物，即2'-四氢噻吩1'-氧化物和2'-四氢噻吩1',1'-二氧化物衍生物，表现出最高的体外L1210细胞抑制率（分别为84.5%和92.0%）。此外，在体内对P388淋巴细胞白血病，2'-四氢噻吩1'-氧化物衍生物显示出显著活性（T/C = 143）。N-1环状取代基中电负性相似或较低的其他化合物对P388淋巴细胞白血病无活性，对L1210细胞的活性较低。
