ethyl 1-[[(3aR,4R,6R,6aR)-4-(2,4-dioxopyrimidin-1-yl)-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]methyl]piperidine-4-carboxylate | 1119504-16-3

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 哌啶类
• 英文名称: ethyl 1-[[(3aR,4R,6R,6aR)-4-(2,4-dioxopyrimidin-1-yl)-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]methyl]piperidine-4-carboxylate
• CAS: 1119504-16-3
• 化学式: C₂₀H₂₉N₃O₇
• 分子量: 423.466
• InChiKey: XLJISDMFESKXRD-MWQQHZPXSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.1
• 重原子数：
  30
• 可旋转键数：
  6
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.75
• 拓扑面积：
  107
• 氢给体数：
  1
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  ethyl 1-[[(3aR,4R,6R,6aR)-4-(2,4-dioxopyrimidin-1-yl)-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]methyl]piperidine-4-carboxylate 在 水 、 三氟乙酸 、 sodium hydroxide 作用下， 以 四氢呋喃 、 水 为溶剂， 反应 3.0h， 生成 5'-deoxy-5'-N-(4-carboxypiperidinyl)uridine
  参考文献：
  名称：

  5'-修饰的嘧啶核苷作为核糖核酸酶A的抑制剂

  摘要：

  合成并表征了4个5'-脱氧-5'-庚酸取代的嘧啶核苷。通过酶动力学和对接实验研究了它们对核糖核酸酶A（RNase A）的抑制活性。获得的所有抑制常数均在亚毫摩尔范围内。生化分析表明，尿苷衍生物比相应的胸苷衍生物更有效，抑制作用在本质上具有竞争性。对于胸苷衍生物，3'-羟基在结合以及抑制中起重要作用。对接研究也支持实验结果。在对接构象中，发现尿苷衍生物与P 1 P 2结合 亚位点与酸基团在活性位点组氨酸残基的氢键距离内。

  DOI：

  10.1016/j.bmc.2010.08.059
• 作为产物：
  描述：

  哌啶-4-甲酸乙酯 、 2',3'-O-isopropylidene-5'-O-tosyluridine 反应 24.0h， 以63%的产率得到ethyl 1-[[(3aR,4R,6R,6aR)-4-(2,4-dioxopyrimidin-1-yl)-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]methyl]piperidine-4-carboxylate
  参考文献：
  名称：

  Morpholino, Piperidino, and Pyrrolidino Derivatives of Pyrimidine Nucleosides as Inhibitors of Ribonuclease A: Synthesis, Biochemical, and Crystallographic Evaluation^,

  摘要：

  Six 5'-deoxy-5'-morpholine, piperidine, and pyrrolidine of pyrimidine nucleosides have been synthesized and characterized. Their inhibitory action to ribonuclease A has been studied by biochemical analysis and X-ray crystallography. These compounds are moderate inhibitors of RNase A with mid-to-upper micromolar inhibition constants (K(i)). The high resolution X-ray crystal structures of the RNase A-inhibitor complexes have shown that all inhibitors bind at the enzyme catalytic cleft with the pyrimidine nucleobase at the B(1)R(2) subsites while the 5' group binds away from the main subsite P(1), where P-O(5') bond cleavage occurs, toward the solvent close to subsite P(0). Structure-activity relationship analysis has demonstrated that the compounds with the larger group in the 5' position are more potent. Comparative structural analysis of these RNase A complexes with other similar RNase A-ligand complexes provides a structural explanation of their potency and suggests ways to improve their efficiency and selectivity. These inhibitors can be the starting point for the development of compounds that can be used as pharmaceuticals against pathologies associated with RNase A homologues such as human angiogenin, which is implicated in tumor induced neovascularization.

  DOI：

  10.1021/jm800724t

文献信息

• 5′-Modified pyrimidine nucleosides as inhibitors of ribonuclease A
  作者：Anirban Samanta、Swagata Dasgupta、Tanmaya Pathak

  DOI：10.1016/j.bmc.2010.08.059

  日期：2011.4

  derivatives and that the inhibition is competitive in nature. For thymidine derivatives, the 3′-hydroxy group plays an important role in binding as well as in inhibition. Docking studies also support the experimental results. In the docking conformation the uridine derivative was found to bind to the P1P2 subsite with the acid group within hydrogen bonding distance of the active site histidine residues

  合成并表征了4个5'-脱氧-5'-庚酸取代的嘧啶核苷。通过酶动力学和对接实验研究了它们对核糖核酸酶A（RNase A）的抑制活性。获得的所有抑制常数均在亚毫摩尔范围内。生化分析表明，尿苷衍生物比相应的胸苷衍生物更有效，抑制作用在本质上具有竞争性。对于胸苷衍生物，3'-羟基在结合以及抑制中起重要作用。对接研究也支持实验结果。在对接构象中，发现尿苷衍生物与P 1 P 2结合 亚位点与酸基团在活性位点组氨酸残基的氢键距离内。
• Morpholino, Piperidino, and Pyrrolidino Derivatives of Pyrimidine Nucleosides as Inhibitors of Ribonuclease A: Synthesis, Biochemical, and Crystallographic Evaluation^,
  作者：Anirban Samanta、Demetres D. Leonidas、Swagata Dasgupta、Tanmaya Pathak、Spyros E. Zographos、Nikos G. Oikonomakos

  DOI：10.1021/jm800724t

  日期：2009.2.26

  Six 5'-deoxy-5'-morpholine, piperidine, and pyrrolidine of pyrimidine nucleosides have been synthesized and characterized. Their inhibitory action to ribonuclease A has been studied by biochemical analysis and X-ray crystallography. These compounds are moderate inhibitors of RNase A with mid-to-upper micromolar inhibition constants (K(i)). The high resolution X-ray crystal structures of the RNase A-inhibitor complexes have shown that all inhibitors bind at the enzyme catalytic cleft with the pyrimidine nucleobase at the B(1)R(2) subsites while the 5' group binds away from the main subsite P(1), where P-O(5') bond cleavage occurs, toward the solvent close to subsite P(0). Structure-activity relationship analysis has demonstrated that the compounds with the larger group in the 5' position are more potent. Comparative structural analysis of these RNase A complexes with other similar RNase A-ligand complexes provides a structural explanation of their potency and suggests ways to improve their efficiency and selectivity. These inhibitors can be the starting point for the development of compounds that can be used as pharmaceuticals against pathologies associated with RNase A homologues such as human angiogenin, which is implicated in tumor induced neovascularization.