benzyl N-[(2S)-1-[[(2R)-1-[(1S,2S)-2-[[(2R,3S)-3-[(2S)-butan-2-yl]-4-oxooxetane-2-carbonyl]amino]cyclopropyl]-4-phenylbutan-2-yl]amino]-1-oxopropan-2-yl]carbamate | 1431768-60-3

• 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: benzyl N-[(2S)-1-[[(2R)-1-[(1S,2S)-2-[[(2R,3S)-3-[(2S)-butan-2-yl]-4-oxooxetane-2-carbonyl]amino]cyclopropyl]-4-phenylbutan-2-yl]amino]-1-oxopropan-2-yl]carbamate
• CAS: 1431768-60-3
• 化学式: C₃₂H₄₁N₃O₆
• 分子量: 563.694
• InChiKey: YUZQDEBWPUFQAF-XZSSXHOESA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.3
• 重原子数：
  41
• 可旋转键数：
  15
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  123
• 氢给体数：
  3
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  benzyl N-[(2S)-1-[[(2R)-1-[(1S,2S)-2-[[(2R,3S)-3-[(2S)-butan-2-yl]-4-oxooxetane-2-carbonyl]amino]cyclopropyl]-4-phenylbutan-2-yl]amino]-1-oxopropan-2-yl]carbamate 在 palladium on activated charcoal 、 氢气 、 三氟乙酸 作用下， 以 二氯甲烷 为溶剂， 反应 2.0h， 以100%的产率得到(2R,3S)-N-((1S,2S)-2-((R)-2-((S)-2-aminopropanamido)-4-phenylbutyl)cyclopropyl)-3-((S)-sec-butyl)-4-oxooxetane-2-carboxamide 2,2,2-trifluoroacetate
  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：

  (3S,4R)-3-((S)-sec-butyl)-4-oxooxetane-2-carboxylic acid 在 三乙胺 作用下， 以 二氯甲烷 为溶剂， 反应 20.5h， 生成 benzyl N-[(2S)-1-[[(2R)-1-[(1S,2S)-2-[[(2R,3S)-3-[(2S)-butan-2-yl]-4-oxooxetane-2-carbonyl]amino]cyclopropyl]-4-phenylbutan-2-yl]amino]-1-oxopropan-2-yl]carbamate
  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

• Investigation of the Noncovalent Binding Mode of Covalent Proteasome Inhibitors around the Transition State by Combined Use of Cyclopropylic Strain-Based Conformational Restriction and Computational Modeling
  作者：Shuhei Kawamura、Yuka Unno、Motohiro Tanaka、Takuma Sasaki、Akihito Yamano、Takatsugu Hirokawa、Tomoshi Kameda、Akira Asai、Mitsuhiro Arisawa、Satoshi Shuto

  DOI：10.1021/jm400542h

  日期：2013.7.25

  To develop potent covalent inhibitors, the noncovalent interactions around the transition state to form covalent bonding should be optimized because the potency of the inhibitor can be depending on the energy of the transition state. Here, we report an efficient analysis of the noncovalent binding mode of a potent covalent proteasome inhibitor 3a around the transition state by a combined use of the

  为了开发有效的共价抑制剂，应当优化过渡态周围形成共价键的非共价相互作用，因为抑制剂的效能可能取决于过渡态的能量。在这里，我们报告了通过结合使用化学方法（即基于环丙基菌株的构象限制和计算对接方法）对有效的共价蛋白酶体抑制剂3a在过渡态附近的非共价结合模式的有效分析。此外，我们利用本研究构建的蛋白酶体模拟模型，计算了过渡态周围预测的非共价复合物中一系列盐基孢酰胺衍生物的结合能，这与它们的pIC 50密切相关。因此，提出的预测共价抑制剂过渡态附近非共价结合模式的对接方法将有助于共价抑制剂的开发。
• 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.