4-carbamoyl-2-{4-[4-(2,4-diamino-6-oxo-1,6-dihydropyrimidin-5-yl)-1-(2,2,2-trifluoroacetyl)butyl]benzoylamino}butyric acid hydrochloride

• 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: 4-carbamoyl-2-{4-[4-(2,4-diamino-6-oxo-1,6-dihydropyrimidin-5-yl)-1-(2,2,2-trifluoroacetyl)butyl]benzoylamino}butyric acid hydrochloride
• 英文别名: (2S)-5-amino-2-[[4-[6-(2,4-diamino-6-oxo-1H-pyrimidin-5-yl)-1,1,1-trifluoro-2-oxohexan-3-yl]benzoyl]amino]-5-oxopentanoic acid;hydrochloride
• 化学式: C₂₂H₂₅F₃N₆O₆*ClH
• 分子量: 562.933
• InChiKey: NWMNRXBODSGAFC-KQYRMMKASA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.04
• 重原子数：
  38
• 可旋转键数：
  12
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  220
• 氢给体数：
  7
• 氢受体数：
  11

反应信息

• 作为产物：
  描述：

  4-[4-(2,4-diamino-6-oxo-1,6-dihydropyrimidin-5-yl)-1-(2,2,2-trifluoroacetyl)butyl]benzoic acid 在 sodium hydroxide 、 三乙胺 作用下， 以 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 0.75h， 生成 4-carbamoyl-2-{4-[4-(2,4-diamino-6-oxo-1,6-dihydropyrimidin-5-yl)-1-(2,2,2-trifluoroacetyl)butyl]benzoylamino}butyric acid hydrochloride
  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

• Synthesis and biological evaluation of α- and γ-carboxamide derivatives of 10-CF3CO-DDACTHF
  作者：Youhoon Chong、Inkyu Hwang、Ali Tavassoli、Yan Zhang、Ian A. Wilson、Stephen J. Benkovic、Dale L. Boger

  DOI：10.1016/j.bmc.2004.11.050

  日期：2005.5

  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.