(-)-Benzolactam-V8 | 174511-40-1

• 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: (-)-Benzolactam-V8
• 英文别名: (2S,5S)-benzolactam-V8；benzolactam-V8；(2S,5S)-5-(hydroxymethyl)-1-methyl-2-propan-2-yl-2,4,5,6-tetrahydro-1,4-benzodiazocin-3-one
• CAS: 174511-40-1
• 化学式: C₁₅H₂₂N₂O₂
• 分子量: 262.352
• InChiKey: OBEJTRHPRSRHSZ-JSGCOSHPSA-N

物化性质

• 沸点：
  486.6±35.0 °C(Predicted)
• 密度：
  1.066±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.2
• 重原子数：
  19
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.53
• 拓扑面积：
  52.6
• 氢给体数：
  2
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  (-)-Benzolactam-V8 在 palladium on activated charcoal 吡啶 、 bis-triphenylphosphine-palladium(II) chloride 、 sodium hydroxide 、 copper(l) iodide 、 氢气 、 碘 、 二乙胺 、 三乙胺 作用下， 以 1,4-二氧六环 、 甲醇 、 乙酸乙酯 为溶剂， 25.0 ℃ 、1.01 MPa 条件下， 反应 122.5h， 生成 (-)-BL-VA-210
  参考文献：
  名称：

  Modeling, Chemistry, and Biology of the Benzolactam Analogues of Indolactam V (ILV). 2. Identification of the Binding Site of the Benzolactams in the CRD2 Activator-Binding Domain of PKCδ and Discovery of an ILV Analogue of Improved Isozyme Selectivity

  摘要：

  Protein kinase C (PKC) is a complex enzyme system comprised of at least II isozymes that serves to mediate numerous extracellular signals which generate lipid second messengers. The discovery of isozyme-selective activators and inhibitors (modulators) of PKC is crucial to ascertaining the role of the individual isozymes in physiological and pathophysiological processes and to manipulating their function. The discovery of such small molecule modulators of PKC is at present a largely unmet pharmacological need. Herein we detail our modeling studies which reveal how the natural product indolactam V (ILV) and its 8-membered ring analogue, the benzolactam 15, bind to the CRD2 activator domain of PKC. These modeling studies reveal that not all PKC ligands possess a common pharmacophore, and further suggest an important role of specific hydrophobic contacts in the PKC-ligand interaction, The modeling studies find strong experimental support from mutagenesis studies on PKC alpha that reveal the crucial role played by the residues proline 11, leucine 20, leucine 24, and glycine 27. Next, we describe the synthesis of two 8-substituted benzolactams starting from L-phenylalanine and characterize their isozyme selectivity; one of the two benzolactams exhibits improved isozyme selectivity relative to the n-octyl-ILV, Lastly, we report inhibition of cellular proliferation of two different breast carcinoma cell lines by the benzolactam 5 and show that the compound preferentially down-regulates PKC beta in both cell lines.

  DOI：

  10.1021/jm960875h
• 作为产物：
  描述：

  2-碘苄醇 在 palladium on activated charcoal N-甲基吗啉 、 copper(l) iodide 、 锂硼氢 、 草酰氯 、 二苯基磷酸 、 氢气 、 四氯化钛 、 2,4-滴二甲胺盐 、 potassium carbonate 、 二甲基亚砜 、 三乙胺 作用下， 以 四氢呋喃 、 甲醇 、 N,N-二甲基甲酰胺 为溶剂， -65.0~90.0 ℃ 、4.05 MPa 条件下， 反应 160.5h， 生成 (-)-Benzolactam-V8
  参考文献：
  名称：

  α-氨基酸结构在铜催化芳基卤与α-氨基酸偶联反应中的加速作用。苯内酰胺-V8的合成

  摘要：

  光学纯的 α-氨基酸与芳基卤化物的偶联产生对映纯的 N-芳基-α-氨基酸，在 CuI 的催化下保留构型。即使对于富电子的芳基卤化物，该反应也可以在比典型的 Ullmann 缩合低得多的温度下完成，这表明该反应中存在由 α-氨基酸结构诱导的加速效应。具有较大疏水基团的α-氨基酸产生较高的偶联产率，而具有较小疏水基团的α-氨基酸仅产生较低的产率，并且对于具有亲水基团的那些没有检测到偶联产物。在该偶联反应的大多数情况下未观察到外消旋化。经过一些对照实验，提出了一种可能的机制，包括 π 络合物和分子内取代反应。

  DOI：

  10.1021/ja981662f

文献信息

• Synthesis of (−)-benzolactam-V8 by application of asymmetric aziridination
  作者：Itsara Khantikaew、Masato Takahashi、Takuya Kumamoto、Noriyuki Suzuki、Tsutomu Ishikawa

  DOI：10.1016/j.tet.2011.11.033

  日期：2012.1

  (−)-Benzolactam-V8, an artificially-designed cyclic dipeptide with strong tumor-promoter activity, was synthesized from benzyl (S)-N-(2-formylphenyl)-N-methylvalinate by application of guanidinium ylide-participated asymmetric aziridination followed by the reductive ring-opening reaction of 3-arylaziridine-2-carboxylate formed.

  （−）-Benzolactam-V8是由人为设计的环状二肽，具有很强的肿瘤促进活性，是通过苄基（S）-N-（2-甲酰基苯基）-N-甲基缬氨酸盐通过应用胍基内鎓盐参与的不对称叠氮化而合成的由3-芳基氮丙啶-2-羧酸酯的还原性开环反应形成。
• Accelerating Effect Induced by the Structure of α-Amino Acid in the Copper-Catalyzed Coupling Reaction of Aryl Halides with α-Amino Acids. Synthesis of Benzolactam-V8
  作者：Dawei Ma、Yongda Zhang、Jiangchao Yao、Shihui Wu、Fenggang Tao

  DOI：10.1021/ja981662f

  日期：1998.12.1

  hydrophilic groups. No racemization was observed in most cases of this coupling reaction. After some controlled experiments, a possible mechanism including the π-complex and the intramolecular substitution reaction is proposed. Based on this catalyzed reaction, a facile and stereoselective synthesis of benzolactam-V8, a new PKC activator, is achieved.

  光学纯的 α-氨基酸与芳基卤化物的偶联产生对映纯的 N-芳基-α-氨基酸，在 CuI 的催化下保留构型。即使对于富电子的芳基卤化物，该反应也可以在比典型的 Ullmann 缩合低得多的温度下完成，这表明该反应中存在由 α-氨基酸结构诱导的加速效应。具有较大疏水基团的α-氨基酸产生较高的偶联产率，而具有较小疏水基团的α-氨基酸仅产生较低的产率，并且对于具有亲水基团的那些没有检测到偶联产物。在该偶联反应的大多数情况下未观察到外消旋化。经过一些对照实验，提出了一种可能的机制，包括 π 络合物和分子内取代反应。
• Modeling, Chemistry, and Biology of the Benzolactam Analogues of Indolactam V (ILV). 2. Identification of the Binding Site of the Benzolactams in the CRD2 Activator-Binding Domain of PKCδ and Discovery of an ILV Analogue of Improved Isozyme Selectivity
  作者：Alan P. Kozikowski、Shaomeng Wang、Dawei Ma、Jiangchao Yao、Shakeel Ahmad、Robert I. Glazer、Krisztina Bogi、Peter Acs、Shayan Modarres、Nancy E. Lewin、Peter M. Blumberg

  DOI：10.1021/jm960875h

  日期：1997.4.1

  Protein kinase C (PKC) is a complex enzyme system comprised of at least II isozymes that serves to mediate numerous extracellular signals which generate lipid second messengers. The discovery of isozyme-selective activators and inhibitors (modulators) of PKC is crucial to ascertaining the role of the individual isozymes in physiological and pathophysiological processes and to manipulating their function. The discovery of such small molecule modulators of PKC is at present a largely unmet pharmacological need. Herein we detail our modeling studies which reveal how the natural product indolactam V (ILV) and its 8-membered ring analogue, the benzolactam 15, bind to the CRD2 activator domain of PKC. These modeling studies reveal that not all PKC ligands possess a common pharmacophore, and further suggest an important role of specific hydrophobic contacts in the PKC-ligand interaction, The modeling studies find strong experimental support from mutagenesis studies on PKC alpha that reveal the crucial role played by the residues proline 11, leucine 20, leucine 24, and glycine 27. Next, we describe the synthesis of two 8-substituted benzolactams starting from L-phenylalanine and characterize their isozyme selectivity; one of the two benzolactams exhibits improved isozyme selectivity relative to the n-octyl-ILV, Lastly, we report inhibition of cellular proliferation of two different breast carcinoma cell lines by the benzolactam 5 and show that the compound preferentially down-regulates PKC beta in both cell lines.