4-[4-(2,4-diamino-6-oxo-1,6-dihydropyrimidin-5-yl)-1-(2,2,2-trifluoroacetyl)butyl]benzoic acid | 553681-16-6

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪类
• 英文名称: 4-[4-(2,4-diamino-6-oxo-1,6-dihydropyrimidin-5-yl)-1-(2,2,2-trifluoroacetyl)butyl]benzoic acid
• 英文别名: 4-[4-(2,4-diamino-6-oxo-1,6-dihydropyrimidin-5-yl)-1-(2,2,2-trifluoro-1-oxo-ethyl)butyl]benzoic acid；4-[4-(2,4-Diamino-6-oxo-1,6-dihydropyrimidin-5-yl)-1-(2,2,2-trifluoro-acetyl)butyl]benzoic acid；4-[6-(2,4-diamino-6-oxo-1H-pyrimidin-5-yl)-1,1,1-trifluoro-2-oxohexan-3-yl]benzoic acid
• CAS: 553681-16-6
• 化学式: C₁₇H₁₇F₃N₄O₄
• 分子量: 398.342
• InChiKey: OMVRZFGZTVFDPD-UHFFFAOYSA-N

物化性质

• 沸点：
  592.9±60.0 °C(Predicted)
• 密度：
  1.56±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.4
• 重原子数：
  28
• 可旋转键数：
  7
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.29
• 拓扑面积：
  148
• 氢给体数：
  4
• 氢受体数：
  9

反应信息

• 作为反应物：
  描述：

  4-[4-(2,4-diamino-6-oxo-1,6-dihydropyrimidin-5-yl)-1-(2,2,2-trifluoroacetyl)butyl]benzoic acid 在 碳酸氢钠 、 1-(3-二甲基氨基丙基)-3-乙基碳二亚胺 、 三氟乙酸 作用下， 以 氯仿 、 N,N-二甲基甲酰胺 为溶剂， 反应 30.0h， 生成 2-(4-(6-(2,4-Diamino-6-oxo-1,6-dihydropyrimidin-5-yl)-1,1,1-trifluoro-2-oxohexan-3-yl)benzamido)acetic acid
  参考文献：
  名称：

  Discovery of a Potent, Nonpolyglutamatable Inhibitor of Glycinamide Ribonucleotide Transformylase

  摘要：

  Glycinamide ribonucleotide transformylase (GAR Tfase) catalyzes the first of two formyl transfer steps in the de novo purine biosynthetic pathway that require folate cofactors. Herein we report the discovery of a potent, nonpolyglutamatable, and selective inhibitor of GAR Tfase. Compound 12, which possesses a tetrazole in place of the gamma-carboxylic acid in the L-glutamate subunit of the potent GAR Tfase inhibitor 1, was active in cellular-based functional assays exhibiting purine-sensitive cytotoxic activity (IC50 = 40 nM, CCRF-CEM) and was selective for inhibition of rhGAR Tfase (K-i = 130 nM). Notably, 12 was only 2.5-fold less potent than 1 in cellular assays and 4-fold less potent against rhGAR Tfase. Like 1, this functional activity of 12 in the cell-based assay benefits from and requires transport into the cell by the reduced folate carrier but, unlike 1, is independent of folyl polyglutamate synthase (FPGS) expression levels and polyglutamation.

  DOI：

  10.1021/jm0601147
• 作为产物：
  描述：

  methyl 4-{4-(2,4-diamino-6-oxo-1,6-dihydropyrimidin-5-yl)-1-[1-(dimethylhydrazono)-2,2,2-trifluoroethyl]butyl}benzoate 在 lithium hydroxide 作用下， 以 甲醇 、 水 为溶剂， 反应 24.0h， 以100%的产率得到4-[4-(2,4-diamino-6-oxo-1,6-dihydropyrimidin-5-yl)-1-(2,2,2-trifluoroacetyl)butyl]benzoic acid
  参考文献：
  名称：

  Synthesis and biological evaluation of α- and γ-carboxamide derivatives of 10-CF3CO-DDACTHF

  摘要：

  Structurally-related, but non-polyglutamylatable, derivatives of 10-CF3CO-DDACTHF (1), which incorporate L-glutamine (2) and L-isoglutamine (3) in place Of L-glutamate, were prepared and evaluated as inhibitors of recombinant human (rh) GAR Tfase. While the L-glutamate alpha-carboxamide derivative 3 was much less effective as a rhGAR Tfase inhibitor (K-i = 4.8 mu M) and inactive in cellular functional assays, the gamma-carboxamide derivative 2 was found to be a potent and selective rhGAR Tfase inhibitor (K-i = 0.056 mu M) being only 4-fold less potent than 1 (K-i = 0.0 15 mu M). Moreover, 2 was effective in cellular functional assays exhibiting purine sensitive cytotoxic activity (IC50 = 300 nM, CCRF-CEM) only 20-fold less potent than 1 (IC50 = 16 nM), consistent with inhibition of de novo purine biosynthesis via selective inhibition of GAR Tfase. Like 1, 2 is transported into the cell by the reduced folate carrier. Unlike 1, the functional activity of 2 is not dependent upon FPGS polyglutamylation. (c) 2005 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2004.11.050

文献信息

• [EN] INHIBITORS OF GLYCINAMIDE RIBONUCLEOTIDE TRANSFORMYLASE<br/>[FR] INHIBITEURS DE LA TRANSFORMYLASE DE LA GLYCINAMIDE RIBONUCLEOTIDE
  申请人：SCRIPPS RESEARCH INST

  公开号：WO2003087065A1

  公开（公告）日：2003-10-23

  Potent human inhibitors of human glycinamide ribonucleotide transformylase and of aminoimidazole carboxamide ribonucleotide transformylase are designed, synthesized, and characterized.

  设计、合成和表征了对人类甘氨酰核糖核苷转甲基酶和氨基咪唑甲酰核糖核苷转甲基酶具有强效抑制作用的人类抑制剂。
• Design, synthesis and biological evaluation of 10-CF3CO-DDACTHF analogues and derivatives as inhibitors of GAR Tfase and the de novo purine biosynthetic pathway
  作者：Joel Desharnais、Inkyu Hwang、Yan Zhang、Ali Tavassoli、Justin Baboval、Stephen J Benkovic、Ian A Wilson、Dale L Boger

  DOI：10.1016/s0968-0896(03)00458-9

  日期：2003.10

  The synthesis and evaluation of analogues and key derivatives of 10-CF3CO-DDACTHF as inhibitors of glycinamide ribonucleotide transformylase (GAR Tfase) and aminoimidazole carboxamide transformylase (AICAR Tfase) are reported. Polyglutamate analogues of 1 were evaluated as inhibitors of Escherichia coli and recombinant human (rh) GAR Tfase, and AICAR Tfase. Although the pentaglutamate 6 was found to

  报道了10-CF3CO-DDACTHF作为甘氨酰胺核糖核苷酸转化酶（GAR Tfase）和氨基咪唑羧酰胺转化酶（AICAR Tfase）抑制剂的类似物和关键衍生物的合成和评价。1的聚谷氨酸类似物被评估为大肠杆菌和重组人（rh）GAR Tfase和AICAR Tfase的抑制剂。尽管发现五谷氨酸盐6是测试针对rhGAR Tfase的系列中活性最高的抑制剂（Ki = 0.004 microM），但未观察到单五谷氨酸衍生物之间的区别（Ki = 0.02-0.004 microM），表明其主要作用所需的1的多聚谷氨酸化是细胞内保留。相反，当针对rhAICAR Tfase（Ki = 65-0.120 microM）进行测试时，1及其定义的聚谷氨酸3-6的无活性要低得多，并且选择性很高（> 相对于大肠杆菌GAR Tfase，rh等于或等于100倍）。还检查了其他1的关键类似物（7和8），发现它们的活性
• Inhibitors of glycinamide ribonucleotide transformylase
  申请人：Boger L Dale

  公开号：US20070167377A1

  公开（公告）日：2007-07-19

  Potent human inhibitors of human glycinamide ribonucleotide transformylase and of aminoimidazole carboxamide ribonucleotide transformylase are designed, synthesized, and characterized.

  设计、合成并表征了强效的人类甘氨酰核苷酸转移酶和氨基咪唑甲酸核苷酸转移酶的人类抑制剂。
• EP1495006A4
  申请人：——

  公开号：EP1495006A4

  公开（公告）日：2006-05-10
• INHIBITORS OF GLYCINAMIDE RIBONUCLEOTIDE TRANSFORMYLASE
  申请人：The Scripps Research Institute

  公开号：EP1495006A1

  公开（公告）日：2005-01-12