Li S W, Nair M G, Edwards D M, Kisliuk R L, Gaumont Y, Dev I K, Duch D S, Humphreys J, Smith G K, Ferone R
Drug Development Laboratory, University of South Alabama, Mobile 36688.
J Med Chem. 1991 Sep;34(9):2746-54. doi: 10.1021/jm00113a011.
Structural modifications at the pyrimidine ring and at the C9,N10-bridge region of the thymidylate synthase (TS) inhibitors N10-propargyl-5,8-dideazafolate (1; PDDF; CB 3717), 2-desamino-N10-propargyl-5,8-dideazafolate (2, DPDDF), and 2-desamino-2-methyl-N10-propargyl-5,8-dideazafolate (3, DMPDDF) have been carried out. Methods for the synthesis of 2-desamino-N10-propargyl-1,5,8-trideazafolate (4), 2-desamino-2-methyl-N10-propargyl-3,5,8-trideazafolate (5a), and 2-desamino-2-methyl-N10-propargyl-5,8-dideaza-1,2-dihydrofolate (6) have been developed. The bridge-extended analogues isohomo-PDDF (7) and isohomo-DMPDDF (8) contain an additional methylene group interposed between N10 and the phenyl ring of 1 and 3, respectively. All new compounds were evaluated as inhibitors of TS and the growth of tumor cells in culture. Selected analogues were tested as substrates of folylpolyglutamate synthetase (FPGS) and striking differences in substrate activity were observed among these compounds, indicating that structural modifications at the pyrimidine ring of classical antifolates profoundly influence their polyglutamylation. Enzyme inhibition data established that both N1 and N3-H of the pyrimidine ring are essential for efficient binding of quinazoline-type antifolates to human TS.
已对胸苷酸合成酶（TS）抑制剂N10-炔丙基-5,8-二氮杂叶酸（1；PDDF；CB 3717）、2-脱氨基-N10-炔丙基-5,8-二氮杂叶酸（2，DPDDF）和2-脱氨基-2-甲基-N10-炔丙基-5,8-二氮杂叶酸（3，DMPDDF）嘧啶环及C9、N10-桥区域进行了结构修饰。已开发出合成2-脱氨基-N10-炔丙基-1,5,8-三氮杂叶酸（4）、2-脱氨基-2-甲基-N10-炔丙基-3,5,8-三氮杂叶酸（5a）和2-脱氨基-2-甲基-N10-炔丙基-5,8-二氮杂-1,2-二氢叶酸（6）的方法。桥扩展类似物异高同型-PDDF（7）和异高同型-DMPDDF（8）分别在N10与1和3的苯环之间插入了一个额外的亚甲基。所有新化合物均作为TS抑制剂和培养中肿瘤细胞生长的抑制剂进行了评估。所选类似物作为叶酰聚谷氨酸合成酶（FPGS）的底物进行了测试，在这些化合物中观察到底物活性存在显著差异，这表明经典抗叶酸剂嘧啶环的结构修饰深刻影响了它们的多聚谷氨酸化。酶抑制数据表明，嘧啶环的N1和N3-H对于喹唑啉型抗叶酸剂与人TS的有效结合至关重要。
