N-[(2S)-1-oxo-3-phenyl-1-{4-[2-(pyridin-2-yl)quinazolin-4-yl]piperazin-1-yl}propan-2-yl]acetamide | 1431939-98-8

• 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: N-[(2S)-1-oxo-3-phenyl-1-{4-[2-(pyridin-2-yl)quinazolin-4-yl]piperazin-1-yl}propan-2-yl]acetamide
• 英文别名: N-[(2S)-1-oxo-3-phenyl-1-[4-(2-pyridin-2-ylquinazolin-4-yl)piperazin-1-yl]propan-2-yl]acetamide
• CAS: 1431939-98-8
• 化学式: C₂₈H₂₈N₆O₂
• 分子量: 480.569
• InChiKey: NHHPRDYQOKYIBK-VWLOTQADSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.2
• 重原子数：
  36
• 可旋转键数：
  6
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.25
• 拓扑面积：
  91.3
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  2-吡啶-2-基-1H-喹唑啉-4-酮 在 O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate 、 N,N-二异丙基乙胺 、 N,N-二乙基苯胺 、 三氯氧磷 作用下， 以 1,4-二氧六环 、 乙腈 、 苯 为溶剂， 反应 4.0h， 生成 N-[(2S)-1-oxo-3-phenyl-1-{4-[2-(pyridin-2-yl)quinazolin-4-yl]piperazin-1-yl}propan-2-yl]acetamide
  参考文献：
  名称：

  Pyridinylquinazolines Selectively Inhibit Human Methionine Aminopeptidase-1 in Cells

  摘要：

  Methionine aminopeptidases (MetAPs), which remove the initiator methionine from nascent peptides, are essential in all organisms. While MetAP2 has been demonstrated to be a therapeutic target for inhibiting angiogenesis in mammals, MetAP1 seems to be vital for cell proliferation. Our earlier efforts identified two structural classes of human MetAP1 (HsMetAP1)-selective inhibitors (14), but all of them failed to inhibit cellular HsMetAP1. Using Mn(II) or Zn(II) to activate HsMetAP1, we found that 14 could only effectively inhibit purified HsMetAP1 in the presence of physiologically unachievable concentrations of Co(II). In an effort to seek Co(II)-independent inhibitors, a novel structural class containing a 2-(pyridin-2-yl)quinazoline core has been discovered. Many compounds in this class potently and selectively inhibited HsMetAP1 without Co(II). Subsequently, we demonstrated that 11j, an auxiliary metal-dependent inhibitor, effectively inhibited HsMetAP1 in primary cells. This is the first report that an HsMetAP1-selective inhibitor is effective against its target in cells.

  DOI：

  10.1021/jm400227z

文献信息

• Pyridinylquinazolines Selectively Inhibit Human Methionine Aminopeptidase-1 in Cells
  作者：Feiran Zhang、Shridhar Bhat、Sandra B. Gabelli、Xiaochun Chen、Michelle S. Miller、Benjamin A. Nacev、Yim Ling Cheng、David J. Meyers、Karen Tenney、Joong Sup Shim、Phillip Crews、L. Mario Amzel、Dawei Ma、Jun O. Liu

  DOI：10.1021/jm400227z

  日期：2013.5.23

  Methionine aminopeptidases (MetAPs), which remove the initiator methionine from nascent peptides, are essential in all organisms. While MetAP2 has been demonstrated to be a therapeutic target for inhibiting angiogenesis in mammals, MetAP1 seems to be vital for cell proliferation. Our earlier efforts identified two structural classes of human MetAP1 (HsMetAP1)-selective inhibitors (14), but all of them failed to inhibit cellular HsMetAP1. Using Mn(II) or Zn(II) to activate HsMetAP1, we found that 14 could only effectively inhibit purified HsMetAP1 in the presence of physiologically unachievable concentrations of Co(II). In an effort to seek Co(II)-independent inhibitors, a novel structural class containing a 2-(pyridin-2-yl)quinazoline core has been discovered. Many compounds in this class potently and selectively inhibited HsMetAP1 without Co(II). Subsequently, we demonstrated that 11j, an auxiliary metal-dependent inhibitor, effectively inhibited HsMetAP1 in primary cells. This is the first report that an HsMetAP1-selective inhibitor is effective against its target in cells.