(6R,6S)-5,8,10-Trideaza-5,6,7,8-tetrahydrofolic Acid

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: (6R,6S)-5,8,10-Trideaza-5,6,7,8-tetrahydrofolic Acid
• 英文别名: (2S)-2-[[4-[2-(2-amino-4-oxo-5,6,7,8-tetrahydro-3H-quinazolin-6-yl)ethyl]benzoyl]amino]pentanedioic acid
• 化学式: C₂₂H₂₆N₄O₆
• 分子量: 442.472
• InChiKey: TXHRVJYDANXEGJ-RUINGEJQSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.9
• 重原子数：
  32
• 可旋转键数：
  9
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.41
• 拓扑面积：
  171
• 氢给体数：
  5
• 氢受体数：
  7

反应信息

• 作为产物：
  描述：

  4-[2-(3-Methoxycarbonyl-4-oxo-cyclohexyl)-ethyl]-benzoic acid tert-butyl ester 在 三乙胺 、 三氟乙酸 作用下， 以 甲醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 18.5h， 生成 (6R,6S)-5,8,10-Trideaza-5,6,7,8-tetrahydrofolic Acid
  参考文献：
  名称：

  (6R,6S)-5,8,10-Trideaza-5,6,7,8-tetrahydrofolate and (6R,6S)-5,8,10-trideaza-5,6,7,8-tetrahydropteroyl-L-ornithine as potential antifolates and antitumor agents. 35

  摘要：

  (6R,6S)-5,8,10-三去氮-5,6,7,8-四氢蝶酰酸通过多步反应由4,4-(环氧乙烷氧基)-环己酮和[4-(叔丁基氧基羰基)苄基]三苯基𬭸溴化物合成，并进一步转化为(6R,6S)-5,8,10-三去氮-5,6,7,8-四氢蝶酰-L-谷氨酸和(6R,6S)-5,8,10-三去氮-5,6,7,8-四氢蝶酰-L-精氨酸。化合物1被发现是部分纯化的鼠肝叶酸多谷氨酸合成酶（FPGS）的良好底物，其米氏常数（Km = 15 μM）与报道的还原型叶酸底物（6S）-5,6,7,8-四氢蝶酰-L-谷氨酸以及(6R,6S)-5,10-二去氮-5,6,7,8-四氢蝶酰-L-谷氨酸（DDATHF）的值相当。然而，与具有强细胞毒性的DDATHF形成鲜明对比的是，化合物1在高达100 μM的浓度下未能抑制肿瘤细胞的生长。这些结果表明，DDATHF中位于8号位的NH对于细胞毒性活性至关重要，但并非多谷氨酸化的必要条件。与1作为FPGS的良好底物类似，精氨酸类似物2证明是迄今为止发现的对该酶的较强竞争性抑制剂之一，其Ki值为10 μM。尽管2与5,6,7,8-四氢蝶酰-L-精氨酸（H4PteOrn）相比结合亲和力较低，但在N5、N8和N10位被碳取代的情况下，仍观察到显著的FPGS抑制作用。这表明，FPGS对环B和桥区的生物等价替代表现出一定的耐受性。化合物1和2在高达100 μM的浓度下均未显示出抑制细胞生长的活性。作为潜在前药的化合物2的Nδ半邻苯二甲酰衍生物也未表现出活性。

  DOI：

  10.1021/jm00123a037

文献信息

• (6R,6S)-5,8,10-Trideaza-5,6,7,8-tetrahydrofolate and (6R,6S)-5,8,10-trideaza-5,6,7,8-tetrahydropteroyl-L-ornithine as potential antifolates and antitumor agents. 35
  作者：Andre Rosowsky、Ronald A. Forsch、Richard G. Moran

  DOI：10.1021/jm00123a037

  日期：1989.3

  (6R,6S)-5,8,10-Trideaza-5,6,7,8-tetrahydropteroic acid was synthesized in several steps from 4,4-(ethylenedioxy)-cyclohexanone and [4-(tert-butyloxycarbonyl)benzyl]triphenylphosphonium bromide and was elaborated to (6R,6S)-5,8,10-trideaza-5,6,7,8-tetrahydropteroyl-L-glutamic acid and (6R,6S)-5,8,10-trideaza-5,6,7,8-tetrahydropteroyl-L-ornithin e. Compound 1 was found to be a good substrate for partially purified mouse liver folypolyglutamate synthetase (FPGS), with a Michaelis constant (Km = 15 microM) comparable to that reported for the reduced folate substrate (6S)-5,6,7,8-tetrahydropteroyl-L-glutamic acid and for (6R,6S)-5,10-dideaza-5,6,7,8-tetrahydropteroyl-L-glutamic acid (DDATHF). However, in striking contrast to DDATHF, which is potently cytotoxic, 1 failed to inhibit tumor cell growth in culture at concentrations of up to 100 microM. These results suggested that the NH at position 8 of DDATHF is important for cytotoxic activity but not for polyglutamylation. Just as 1 was a good substrate for FPGS, the ornithine analogue 2 proved to be among the more potent competitive inhibitors of this enzyme discovered to date, with a Ki,s of 10 microM. While the binding affinity of 2 was lower than that reported for 5,6,7,8-tetrahydropteroyl-L-ornithine (H4PteOrn), very substantial FPGS inhibition was observed even though N5,N8, and N10 in H4PteOrn were replaced by carbon. Binding to FPGS thus appears to be tolerant of bioisosteric replacements made simultaneously in ring B and the bridge region. Neither 1 nor 2 was active in preventing cell growth in culture at concentrations of up 100 microM. The N delta-hemiphthaloyl derivative of 2, synthesized as a potential prodrug, was also inactive.

  (6R,6S)-5,8,10-三去氮-5,6,7,8-四氢蝶酰酸通过多步反应由4,4-(环氧乙烷氧基)-环己酮和[4-(叔丁基氧基羰基)苄基]三苯基𬭸溴化物合成，并进一步转化为(6R,6S)-5,8,10-三去氮-5,6,7,8-四氢蝶酰-L-谷氨酸和(6R,6S)-5,8,10-三去氮-5,6,7,8-四氢蝶酰-L-精氨酸。化合物1被发现是部分纯化的鼠肝叶酸多谷氨酸合成酶（FPGS）的良好底物，其米氏常数（Km = 15 μM）与报道的还原型叶酸底物（6S）-5,6,7,8-四氢蝶酰-L-谷氨酸以及(6R,6S)-5,10-二去氮-5,6,7,8-四氢蝶酰-L-谷氨酸（DDATHF）的值相当。然而，与具有强细胞毒性的DDATHF形成鲜明对比的是，化合物1在高达100 μM的浓度下未能抑制肿瘤细胞的生长。这些结果表明，DDATHF中位于8号位的NH对于细胞毒性活性至关重要，但并非多谷氨酸化的必要条件。与1作为FPGS的良好底物类似，精氨酸类似物2证明是迄今为止发现的对该酶的较强竞争性抑制剂之一，其Ki值为10 μM。尽管2与5,6,7,8-四氢蝶酰-L-精氨酸（H4PteOrn）相比结合亲和力较低，但在N5、N8和N10位被碳取代的情况下，仍观察到显著的FPGS抑制作用。这表明，FPGS对环B和桥区的生物等价替代表现出一定的耐受性。化合物1和2在高达100 μM的浓度下均未显示出抑制细胞生长的活性。作为潜在前药的化合物2的Nδ半邻苯二甲酰衍生物也未表现出活性。