2,5-di-O-allyl-L-mannaro-1,4:3,6-di-γ-lactone | 654072-02-3

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 内酯类
• 英文名称: 2,5-di-O-allyl-L-mannaro-1,4:3,6-di-γ-lactone
• CAS: 654072-02-3
• 化学式: C₁₂H₁₄O₆
• 分子量: 254.24
• InChiKey: XWCUBYPEEQEZHY-ZYUZMQFOSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -0.02
• 重原子数：
  18.0
• 可旋转键数：
  6.0
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  71.06
• 氢给体数：
  0.0
• 氢受体数：
  6.0

反应信息

• 作为反应物：
  描述：

  2,5-di-O-allyl-L-mannaro-1,4:3,6-di-γ-lactone 在 2-羟基吡啶 作用下， 以 二氯甲烷 为溶剂， 反应 17.0h， 生成 (2R,3R,4R,5R)-2,5-Bis-allyloxy-3,4-dihydroxy-6-oxo-6-[N'-(3-phenyl-propionyl)-hydrazino]-hexanoic acid ((1S,2R)-2-hydroxy-indan-1-yl)-amide
  参考文献：
  名称：

  Synthesis of Malarial Plasmepsin Inhibitors and Prediction of Binding Modes by Molecular Dynamics Simulations

  摘要：

  A series of inhibitors of the malarial aspartic proteases Plm I and II have been synthesized with L-mannitol as precursor. These inhibitors are characterized by either a diacylhydrazine or a five-membered oxadiazole ring replacing backbone amide functionalities. Molecular dynamics simulations were applied in the design process. The computationally predicted Plm II K-i values were generally in excellent agreement with the biological results. The diacylhydrazine was found to be superior over the oxadiazole as an amide bond replacement in the Plm I and II inhibitors studied. An extensive flexibility of the S2 ' pocket was captured by the simulations predicting the binding mode of the unsymmetrical inhibitors. Plm I and II inhibitors with single digit nanomolar K-i values devoid of inhibitory activity toward human Cat D were identified. One compound, lacking amide bonds, was found to be Plm IV selective and very potent, with a K-i value of 35 nM.

  DOI：

  10.1021/jm050463l
• 作为产物：
  描述：

  2,2,2-三氯乙酰胺烯丙酯 、 L-mannaro-1,4:3,6-di-γ-lactone 在 三氟化硼乙醚 作用下， 以 1,4-二氧六环 为溶剂， 反应 3.0h， 以76%的产率得到2,5-di-O-allyl-L-mannaro-1,4:3,6-di-γ-lactone
  参考文献：
  名称：

  C2-Symmetric inhibitors of Plasmodium falciparum plasmepsin II: synthesis and theoretical predictions

  摘要：

  A series of C-2-symmetric compounds with a mannitol-based scaffold has been investigated, both theoretically and experimentally, as Plm II inhibitors. Four different stereoisomers with either benzyloxy or allyloxy P1/P1' side chains were studied. Computational ranking of the binding affinities of the eight compounds was carried out using the linear interaction energy (LIE) method relying on a complex previously determined by crystallography. Within both series of isomers the theoretical binding energies were in agreement with the enzymatic measurements, illustrating the power of the LIE method for the prediction of ligand affinities prior to synthesis. The structural models of the enzyme-inhibitor complexes obtained from the MD simulations provided a basis for interpretation of further structure-activity relationships. Hence, the affinity of a structurally similar ligand, but with a different P2/P2' substituent was examined using the same procedure. The predicted improvement in binding constant agreed well with experimental results. (C) 2003 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/s0968-0896(03)00339-0

文献信息

• Macrocyclic inhibitors of the malarial aspartic proteases plasmepsin I, II, and IV
  作者：Karolina Ersmark、Martin Nervall、Hugo Gutiérrez-de-Terán、Elizabeth Hamelink、Linda K. Janka、Jose C. Clemente、Ben M. Dunn、Adolf Gogoll、Bertil Samuelsson、Johan Åqvist、Anders Hallberg

  DOI：10.1016/j.bmc.2005.11.003

  日期：2006.4

  The first macrocyclic inhibitor of the Plasmodium falciparum aspartic proteases plasmepsin I, II, and IV with considerable selectivity over the human aspartic protease cathepsin D has been identified. A series of macrocyclic compounds were designed and synthesized. Cyclizations were accomplished using ring-closing metathesis with the second generation Grubbs catalyst. These compounds contain either

  已经鉴定出恶性疟原虫天冬氨酸蛋白酶纤溶酶I，II和IV的第一种大环抑制剂，其对人天冬氨酸蛋白酶组织蛋白酶D具有相当大的选择性。设计并合成了一系列大环化合物。环化是使用第二代Grubbs催化剂通过闭环复分解完成的。这些化合物包含13元或16元大环，并结合有1，2-二羟基乙烯作为过渡态模拟单元。通过自动对接和分子动力学模拟预测了这类新化合物的结合模式，并通过线性相互作用能（LIE）方法估算了结合亲和力。