tetraethyl (((5-phenylpyridin-3-yl)amino)methylene)bis(phosphonate) | 1365538-58-4

• 英文名称: tetraethyl (((5-phenylpyridin-3-yl)amino)methylene)bis(phosphonate)
• CAS: 1365538-58-4
• 化学式: C₂₀H₃₀N₂O₆P₂
• 分子量: 456.416
• InChiKey: BCGAQNUFUXMEEQ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.98
• 重原子数：
  30.0
• 可旋转键数：
  13.0
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.45
• 拓扑面积：
  95.98
• 氢给体数：
  1.0
• 氢受体数：
  8.0

反应信息

• 作为反应物：
  描述：

  tetraethyl (((5-phenylpyridin-3-yl)amino)methylene)bis(phosphonate) 在 甲醇 作用下， 以 二氯甲烷 为溶剂， 生成 [[(5-Phenylpyridin-3-yl)amino]-phosphonomethyl]phosphonic acid
  参考文献：
  名称：

  Design and Synthesis of Active Site Inhibitors of the Human Farnesyl Pyrophosphate Synthase: Apoptosis and Inhibition of ERK Phosphorylation in Multiple Myeloma Cells

  摘要：

  Human farnesyl pyrophosphate synthase (hFPPS) controls intracellular levels of FPP and post-translational prenylation of small GTPase proteins, which are essential for cell signaling and cell proliferation. Clinical investigations provide evidence that N-BP inhibitors of hFPPS are disease modifying agents that improve survival of multiple myeloma (MM) patients via mechanisms unrelated to their skeletal effects. A new series of N-BPs was designed that interact with a larger portion of the GPP subpocket, as compared to the current therapeutic drugs, and rigidify the (KRRK367)-K-364 tail of hFPPS in the closed conformation in the absence of IPP. An analogue of this series was used to demonstrate inhibition of the intended biological target, resulting in apoptosis and down-regulation of ERK phosphorylation in human MM cell lines.

  DOI：

  10.1021/jm201657x

文献信息

• Design of potent bisphosphonate inhibitors of the human farnesyl pyrophosphate synthase via targeted interactions with the active site ‘capping’ phenyls
  作者：Joris W. De Schutter、Joseph Shaw、Yih-Shyan Lin、Youla S. Tsantrizos

  DOI：10.1016/j.bmc.2012.07.019

  日期：2012.9

  Nitrogen-containing bisphosphonates (N-BPs) are potent active site inhibitors of the human farnesyl pyrophosphate synthase (hFPPS) and valuable human therapeutics for the treatment of bone-related malignancies. N-BPs are also useful in combination chemotherapy for patients with breast, prostate and multiple myeloma cancers. A structure-based approach was employed in order to design inhibitors that exhibit higher lipophilicity and better occupancy for the GPP sub-pocket of hFPPS than the current therapeutic drugs. These novel analogs were designed to bind deeper into the GPP sub-pocket by displacing the side chains of the 'capping' residue Phe 113 and engaging in favorable p-interactions with the side chain of Phe112. (C) 2012 Elsevier Ltd. All rights reserved.