3-bromo-5-[4-(morpholin-4-yl)pyrido[3',2':4,5]furo[3,2-d]pyrimidin-2-yl]phenol | 1509919-71-4

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 呋喃吡啶类
• 英文名称: 3-bromo-5-[4-(morpholin-4-yl)pyrido[3',2':4,5]furo[3,2-d]pyrimidin-2-yl]phenol
• 英文别名: 3-Bromo-5-(6-morpholin-4-yl-8-oxa-3,5,10-triazatricyclo[7.4.0.02,7]trideca-1(9),2(7),3,5,10,12-hexaen-4-yl)phenol；3-bromo-5-(6-morpholin-4-yl-8-oxa-3,5,10-triazatricyclo[7.4.0.02,7]trideca-1(9),2(7),3,5,10,12-hexaen-4-yl)phenol
• CAS: 1509919-71-4
• 化学式: C₁₉H₁₅BrN₄O₃
• 分子量: 427.257
• InChiKey: BXLSARMEZYQRDW-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.4
• 重原子数：
  27
• 可旋转键数：
  2
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.21
• 拓扑面积：
  84.5
• 氢给体数：
  1
• 氢受体数：
  7

反应信息

• 作为产物：
  描述：

  3-氨基-呋喃并[2,3-B]嘧啶-2-甲酸乙酯 在 吡啶 、 ammonium hydroxide 、 水 、 氢溴酸 、 sodium hydroxide 、 三氯氧磷 作用下， 以 四氢呋喃 、 甲醇 、 溶剂黄146 、 异丙醇 、 甲苯 为溶剂， 反应 66.0h， 生成 3-bromo-5-[4-(morpholin-4-yl)pyrido[3',2':4,5]furo[3,2-d]pyrimidin-2-yl]phenol
  参考文献：
  名称：

  Crystal Structures of PI3Kα Complexed with PI103 and Its Derivatives: New Directions for Inhibitors Design

  摘要：

  The phosphatidylinositol 3-kinase (PI3K) signaling pathway plays important roles in cell proliferation, growth, and survival. Hyperactivated PI3K is frequently found in a wide variety of human cancers, validating it as a promising target for cancer therapy. We determined the crystal structure of the human PI3K alpha-PI103 complex to unravel molecular interactions. Based on the structure, substitution at the R-1 position of the phenol portion of PI103 was demonstrated to improve binding affinity via forming a new H-bond with Lys802 at the bottom of the ATP catalytic site. Interestingly, the crystal structure of the PI3K alpha-9d complex revealed that the flexibility of Lys802 can also induce additional space at the catalytic site for further modification. Thus, these crystal structures provide a molecular basis for the strong and specific interactions and demonstrate the important role of Lys802 in the design of novel PI3K alpha inhibitors.

  DOI：

  10.1021/ml400378e

文献信息

• Crystal Structures of PI3Kα Complexed with PI103 and Its Derivatives: New Directions for Inhibitors Design
  作者：Yanlong Zhao、Xi Zhang、Yingyi Chen、Shaoyong Lu、Yuefeng Peng、Xiang Wang、Chengliang Guo、Aiwu Zhou、Jingmiao Zhang、Yu Luo、QianCheng Shen、Jian Ding、Linghua Meng、Jian Zhang

  DOI：10.1021/ml400378e

  日期：2014.2.13

  The phosphatidylinositol 3-kinase (PI3K) signaling pathway plays important roles in cell proliferation, growth, and survival. Hyperactivated PI3K is frequently found in a wide variety of human cancers, validating it as a promising target for cancer therapy. We determined the crystal structure of the human PI3K alpha-PI103 complex to unravel molecular interactions. Based on the structure, substitution at the R-1 position of the phenol portion of PI103 was demonstrated to improve binding affinity via forming a new H-bond with Lys802 at the bottom of the ATP catalytic site. Interestingly, the crystal structure of the PI3K alpha-9d complex revealed that the flexibility of Lys802 can also induce additional space at the catalytic site for further modification. Thus, these crystal structures provide a molecular basis for the strong and specific interactions and demonstrate the important role of Lys802 in the design of novel PI3K alpha inhibitors.