(2R,3S)-N-[(1S,2S)-2-[(2S)-2-[[(2S)-2-aminopropanoyl]amino]but-3-enyl]cyclopropyl]-3-[(2S)-butan-2-yl]-4-oxooxetane-2-carboxamide | 1431768-47-6

• 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: (2R,3S)-N-[(1S,2S)-2-[(2S)-2-[[(2S)-2-aminopropanoyl]amino]but-3-enyl]cyclopropyl]-3-[(2S)-butan-2-yl]-4-oxooxetane-2-carboxamide
• CAS: 1431768-47-6
• 化学式: C₁₈H₂₉N₃O₄
• 分子量: 351.446
• InChiKey: NAWFUEDKJWIYJJ-PUNCIGQSSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.4
• 重原子数：
  25
• 可旋转键数：
  9
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.72
• 拓扑面积：
  111
• 氢给体数：
  3
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  (2R,3S)-N-[(1S,2S)-2-[(2S)-2-[[(2S)-2-aminopropanoyl]amino]but-3-enyl]cyclopropyl]-3-[(2S)-butan-2-yl]-4-oxooxetane-2-carboxamide 、 2-萘甲酰氯 在 三乙胺 作用下， 以 二氯甲烷 为溶剂， 以95%的产率得到(2R,3S)-3-[(2S)-butan-2-yl]-N-[(1S,2S)-2-[(2S)-2-[[(2S)-2-(naphthalene-2-carbonylamino)propanoyl]amino]but-3-enyl]cyclopropyl]-4-oxooxetane-2-carboxamide
  参考文献：
  名称：

  Potent Proteasome Inhibitors Derived from the Unnatural cis-Cyclopropane Isomer of Belactosin A: Synthesis, Biological Activity, and Mode of Action

  摘要：

  The natural product belactosin A (1) with a trans-cyclopropane structure is a useful prototype compound for developing potent proteasome (core particle, CP) inhibitors. To date, 1 and its analogues are the only CP ligands that bind to both the nonprimed S1 pocket as well as the primed substrate binding channel; however, these molecules harbor a high IC50 value of more than 1 mu M. We have performed structure activity relationship studies, thereby elucidating unnatural cis-cyclopropane derivatives of 1 that exhibit high potency to primarily block the chymotrypsin-like active site of the human constitutive (cCP) and immunoproteasome (iCP). The most active compound 3e reversibly inhibits cCP and iCP similarly with an IC50 of 5.7 nM. X-ray crystallographic analysis of the yeast proteasome in complex with 3e revealed that the ligand is accommodated predominantly into the primed substrate binding channel and covalently binds to the active site threonine residue via its beta-lactone ring-opening.

  DOI：

  10.1021/jm4002296
• 作为产物：
  描述：

  tert-butyl N-[(2S)-1-[(1S,2S)-2-formylcyclopropyl]but-3-en-2-yl]carbamate 在 sodium chlorite 、 2-甲基-2-丁烯 、 sodium dihydrogen phosphate dihydrate 、 叠氮磷酸二苯酯 、 三甲基乙酰氯 、 三乙胺 、 三氟乙酸 作用下， 以 二氯甲烷 、 水 、 甲苯 、 叔丁醇 为溶剂， 反应 37.25h， 生成 (2R,3S)-N-[(1S,2S)-2-[(2S)-2-[[(2S)-2-aminopropanoyl]amino]but-3-enyl]cyclopropyl]-3-[(2S)-butan-2-yl]-4-oxooxetane-2-carboxamide
  参考文献：
  名称：

  Potent Proteasome Inhibitors Derived from the Unnatural cis-Cyclopropane Isomer of Belactosin A: Synthesis, Biological Activity, and Mode of Action

  摘要：

  The natural product belactosin A (1) with a trans-cyclopropane structure is a useful prototype compound for developing potent proteasome (core particle, CP) inhibitors. To date, 1 and its analogues are the only CP ligands that bind to both the nonprimed S1 pocket as well as the primed substrate binding channel; however, these molecules harbor a high IC50 value of more than 1 mu M. We have performed structure activity relationship studies, thereby elucidating unnatural cis-cyclopropane derivatives of 1 that exhibit high potency to primarily block the chymotrypsin-like active site of the human constitutive (cCP) and immunoproteasome (iCP). The most active compound 3e reversibly inhibits cCP and iCP similarly with an IC50 of 5.7 nM. X-ray crystallographic analysis of the yeast proteasome in complex with 3e revealed that the ligand is accommodated predominantly into the primed substrate binding channel and covalently binds to the active site threonine residue via its beta-lactone ring-opening.

  DOI：

  10.1021/jm4002296

文献信息

• Potent Proteasome Inhibitors Derived from the Unnatural <i>cis</i>-Cyclopropane Isomer of Belactosin A: Synthesis, Biological Activity, and Mode of Action
  作者：Shuhei Kawamura、Yuka Unno、Anja List、Akirai Mizuno、Motohiro Tanaka、Takuma Sasaki、Mitsuhiro Arisawa、Akira Asai、Michael Groll、Satoshi Shuto

  DOI：10.1021/jm4002296

  日期：2013.5.9

  The natural product belactosin A (1) with a trans-cyclopropane structure is a useful prototype compound for developing potent proteasome (core particle, CP) inhibitors. To date, 1 and its analogues are the only CP ligands that bind to both the nonprimed S1 pocket as well as the primed substrate binding channel; however, these molecules harbor a high IC50 value of more than 1 mu M. We have performed structure activity relationship studies, thereby elucidating unnatural cis-cyclopropane derivatives of 1 that exhibit high potency to primarily block the chymotrypsin-like active site of the human constitutive (cCP) and immunoproteasome (iCP). The most active compound 3e reversibly inhibits cCP and iCP similarly with an IC50 of 5.7 nM. X-ray crystallographic analysis of the yeast proteasome in complex with 3e revealed that the ligand is accommodated predominantly into the primed substrate binding channel and covalently binds to the active site threonine residue via its beta-lactone ring-opening.