2,2-dimethylpropanoyl (2R,3S)-3-[(2S)-butan-2-yl]-4-oxooxetane-2-carboxylate | 1013331-17-3

• 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: 2,2-dimethylpropanoyl (2R,3S)-3-[(2S)-butan-2-yl]-4-oxooxetane-2-carboxylate
• CAS: 1013331-17-3
• 化学式: C₁₃H₂₀O₅
• 分子量: 256.299
• InChiKey: KTVDJFGNPISJHN-XHNCKOQMSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.9
• 重原子数：
  18
• 可旋转键数：
  6
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.77
• 拓扑面积：
  69.7
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  2,2-dimethylpropanoyl (2R,3S)-3-[(2S)-butan-2-yl]-4-oxooxetane-2-carboxylate 在 palladium on activated charcoal 、 氢气 、 三乙胺 、 三氟乙酸 作用下， 以 四氢呋喃 、 二氯甲烷 为溶剂， 反应 22.17h， 生成 (2R,3S)-3-[(2S)-butan-2-yl]-N-[(1S,2S)-2-[(2R)-2-[[(2S)-2-(naphthalene-2-carbonylamino)propanoyl]amino]-4-phenylbutyl]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：

  三甲基乙酰氯 、 (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 1.0h， 生成 2,2-dimethylpropanoyl (2R,3S)-3-[(2S)-butan-2-yl]-4-oxooxetane-2-carboxylate
  参考文献：
  名称：

  结合使用基于环丙基菌株的构象限制和计算模型对过渡态周围共价蛋白酶体抑制剂的非共价结合模式的研究

  摘要：

  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。

  DOI：

  10.1021/jm400542h

文献信息

• Three-dimensional structure-activity relationship study of belactosin A and its stereo- and regioisomers: development of potent proteasome inhibitors by a stereochemical diversity-oriented strategy
  作者：Keisuke Yoshida、Kazuya Yamaguchi、Akira Mizuno、Yuka Unno、Akira Asai、Takayuki Sone、Hideyoshi Yokosawa、Akira Matsuda、Mitsuhiro Arisawa、Satoshi Shuto

  DOI：10.1039/b900384c

  日期：——

  The development of potent proteasome inhibitors based on the stereochemical diversity-oriented strategy using a conformationally rigid cyclopropane structure was investigated. Thus, a series of stereo- and regioisomeric analogs of belactosin A (2), a cyclopropane amino acid (methanoamino acid)-containing tripeptidic proteasome inhibitor, were designed, in which the central cyclopropane amino acid part

  研究了基于构象刚性环丙烷结构的基于立体化学多样性导向策略的有效蛋白酶体抑制剂的开发。因此，设计了一系列的Belactosin A（2）立体异构体和区域异构体，这是一种含有环丙烷氨基酸（甲氨基氨基酸）的三肽蛋白酶体抑制剂，其中中央的环丙烷氨基酸部分被相应的立体异构体或区域异构体。使用一系列立体异构体的环丙烷氨基酸等效物，具有顺/反，D / L和syn / anti我们先前开发的立体化学多样性作为关键单元，已成功合成了目标化合物。生物学评价表明，如所预期，化合物活性改取决于中心环丙烷氨基酸部分的立体化学：在反式/ L-顺式异构体7和所述顺式/ L-抗-异构体9分别超过两倍强效天然Belactosin A（反式/ L-反异构体）。此外，三肽化合物13，非天然的顺式/ L-抗异构体9的合成前体被鉴定为高效蛋白酶体抑制剂。该化合物的效力是贝洛斯托因A的20倍，甚至比众所周知的抑制剂乳腺抑肽（4）更有
• 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。
• Synthesis of 2,3- and 3,4-Methanoamino Acid Equivalents with Stereochemical Diversity and Their Conversion into the Tripeptide Proteasome Inhibitor Belactosin A and Its Highly Potent <i>Cis</i>-Cyclopropane Stereoisomer
  作者：Keisuke Yoshida、Kazuya Yamaguchi、Takayuki Sone、Yuka Unno、Akira Asai、Hideyoshi Yokosawa、Akira Matsuda、Mitsuhiro Arisawa、Satoshi Shuto

  DOI：10.1021/ol8013304

  日期：2008.8.21

  A series of chiral 2,3- and 3,4-methanoamino acid equivalents of stereochernical diversity were designed and synthesized from our chiral cyclopropane units, using a diastereoselective Grignard addition with (R)- or (S)-t-butanesulfinyl imines as the key step. These equivalents were converted into the proteasome inhibitor belactosin A and its cis-cyclopropane stereoisomer. The unnatural cis-isomer was shown to be more than twice as potent as belactosin A as a proteasome inhibitor.
• 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.
• Rational hopping of a peptidic scaffold into non-peptidic scaffolds: structurally novel potent proteasome inhibitors derived from a natural product, belactosin A
  作者：Shuhei Kawamura、Yuka Unno、Takatsugu Hirokawa、Akira Asai、Mitsuhiro Arisawa、Satoshi Shuto

  DOI：10.1039/c3cc48818g

  日期：——

  Rational scaffold hopping of a natural product belactosin A derivative based on the pharmacophore model constructed resulted in the identification of the significantly simplified highly potent non-peptide derivatives.

  基于构建的药效团模型，对天然产物belactosin A衍生物进行合理的支架跳跃，最终导致识别出明显简化的高效非肽衍生物。