DeGraw J I, Colwell W T, Brown V H, Sato M, Kisliuk R L, Gaumont Y, Thorndike J, Sirotnak F M
Bio-Organic Chemistry Laboratory, SRI International, Menlo Park, California 94025.
J Med Chem. 1988 Jan;31(1):150-3. doi: 10.1021/jm00396a022.
The syntheses of 8-deazahomofolic acid and its tetrahydro derivative, potential inhibitors of thymidylate synthase (TS) and other folate related enzymes, are described. Wittig condensation of 2-acetamido-6-formyl-4-pyrimidinol with the triphenylphosphine ylide 3 derived from N-acetyl-4-(p-carbethoxyanilino)-1-chloro-2-butanone, hydrogenation of the enone intermediate 5, introduction of a 5-amino group via diazonium coupling, and reductive ring closure yielded ethyl N11-acetyl-8-deazahomopteroate (8). Alkaline hydrolysis gave 8-deazahomopteroic acid, which was blocked as the 11-trifluoroacetyl derivative, coupled with diethyl L-glutamate, and the blocking groups saponified to afford 8-deazahomofolic acid (12). Hydrogenation of the glutamate diester intermediate and subsequent saponification yielded the tetrahydro-8-deazahomofolate (14). Growth inhibition of Streptococcus faecium, Lactobacillus casei, and L1210 cells in culture by the target compounds was modest. They were also weak inhibitors of thymidylate synthase, dihydrofolate reductase, glycinamide-ribonucleotide transformylase, and aminoimidazolecarboxamide ribonucleotide transformylase. In contrast, 8-deazafolate showed moderate inhibition of aminoimidazolecarboxamide ribonucleotide transformylase, suggesting that inhibition of this enzyme may be related to its cytotoxic action. Tetrahydro-8-deazahomofolate showed low substrate activity with thymidylate synthase.
本文描述了8-脱氮高叶酸及其四氢衍生物的合成，它们是胸苷酸合酶（TS）及其他叶酸相关酶的潜在抑制剂。2-乙酰氨基-6-甲酰基-4-嘧啶醇与由N-乙酰基-4-（对-乙氧羰基苯胺基）-1-氯-2-丁酮衍生的三苯基膦叶立德3进行维蒂希缩合反应，烯酮中间体5进行氢化反应，通过重氮偶合引入5-氨基，然后进行还原闭环反应，得到N11-乙酰基-8-脱氮高蝶呤酸乙酯（8）。碱性水解得到8-脱氮高蝶呤酸，将其作为11-三氟乙酰基衍生物进行保护，与L-谷氨酸二乙酯偶联，然后将保护基团皂化，得到8-脱氮高叶酸（12）。谷氨酸二酯中间体进行氢化反应，随后进行皂化反应，得到四氢-8-脱氮高叶酸（14）。目标化合物对粪肠球菌、干酪乳杆菌和L1210细胞培养物的生长抑制作用较弱。它们也是胸苷酸合酶、二氢叶酸还原酶、甘氨酰胺-核糖核苷酸转甲酰基酶和氨基咪唑甲酰胺核糖核苷酸转甲酰基酶的弱抑制剂。相比之下，8-脱氮叶酸对氨基咪唑甲酰胺核糖核苷酸转甲酰基酶有中度抑制作用，这表明对该酶的抑制作用可能与其细胞毒性作用有关。四氢-8-脱氮高叶酸对胸苷酸合酶的底物活性较低。
