Jones T R, Smithers M J, Betteridge R F, Taylor M A, Jackman A L, Calvert A H, Davies L C, Harrap K R
J Med Chem. 1986 Jun;29(6):1114-8. doi: 10.1021/jm00156a033.
Five new analogues (1c-g) of the antifolate N10-propargyl-5,8-dideazafolic acid (1a) are described in which the benzoyl-L-glutamate moiety was replaced by benzoic acid (desglutamyl-N10-propargyl-5,8-dideazafolic acid), benzoyl-L-aspartate, 4-phenylbutyrate, benzoylglycine, and benzoyl-L-alanine. The esters of the appropriate 4-aminophenyl (benzoyl) starting materials were sequentially alkylated upon nitrogen, first with a propargyl halide and then with 2-amino-6-(bromomethyl)-4-hydroxyquinazoline hydrobromide. Saponification of the antifolate esters so produced gave the desired analogues. The new derivatives (1c-g) and also the known diethyl ester of 1a (1b) were tested for their inhibition of purified L1210 thymidylate synthase (TS) and for their inhibition of the growth of L1210 cells in culture. The TS inhibition of the analogues 1b-g was estimated by calculating the inverse relative potency, defined as the ratio IC50(compound)/IC50(1a). The results obtained were as follows: greater than 62, 84, 9, 333, 21, and 5, respectively. All were thus less inhibitory than 1a. None of the compounds improved upon 1a in inhibiting the growth of L1210 cells in culture.
描述了抗叶酸剂N10-炔丙基-5,8-二去氮叶酸（1a）的五种新类似物（1c - g），其中苯甲酰-L-谷氨酸部分被苯甲酸（去谷氨酰-N10-炔丙基-5,8-二去氮叶酸）、苯甲酰-L-天冬氨酸、4-苯基丁酸、苯甲酰甘氨酸和苯甲酰-L-丙氨酸取代。合适的4-氨基苯基（苯甲酰基）起始原料的酯先在氮原子上依次用炔丙基卤进行烷基化，然后用2-氨基-6-(溴甲基)-4-羟基喹唑啉氢溴酸盐进行烷基化。如此制得的抗叶酸酯经皂化得到所需的类似物。对新衍生物（1c - g）以及已知的1a的二乙酯（1b）进行了测试，以检测它们对纯化的L1210胸苷酸合成酶（TS）的抑制作用以及对培养的L1210细胞生长的抑制作用。通过计算反向相对效力来估计类似物1b - g对TS的抑制作用，反向相对效力定义为IC50（化合物）/IC50（1a）的比值。得到的结果如下：分别大于62、84、9、333、21和5。因此，所有这些类似物的抑制作用均小于1a。在抑制培养的L1210细胞生长方面，没有一种化合物比1a表现更好。
