[(2S,5S)-8-iodo-1-methyl-3-oxo-2-propan-2-yl-2,4,5,6-tetrahydro-1,4-benzodiazocin-5-yl]methyl acetate | 188935-05-9

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吲哚及其衍生物
• 英文名称: [(2S,5S)-8-iodo-1-methyl-3-oxo-2-propan-2-yl-2,4,5,6-tetrahydro-1,4-benzodiazocin-5-yl]methyl acetate
• CAS: 188935-05-9
• 化学式: C₁₇H₂₃IN₂O₃
• 分子量: 430.286
• InChiKey: YXJQQVHVBLJRCR-HOCLYGCPSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.4
• 重原子数：
  23
• 可旋转键数：
  4
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.53
• 拓扑面积：
  58.6
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  [(2S,5S)-8-iodo-1-methyl-3-oxo-2-propan-2-yl-2,4,5,6-tetrahydro-1,4-benzodiazocin-5-yl]methyl acetate 在 palladium on activated charcoal bis-triphenylphosphine-palladium(II) chloride 、 sodium hydroxide 、 copper(l) iodide 、 氢气 、 二乙胺 作用下， 以 甲醇 、 乙酸乙酯 为溶剂， 25.0 ℃ 、1.01 MPa 条件下， 反应 26.5h， 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：

  (2S)-2-[2-[(2S)-3-hydroxy-2-[(2-methylpropan-2-yl)oxycarbonylamino]propyl]anilino]-3-methylbutanoic acid 在 吡啶 、 碘 、 sodium cyanoborohydride 、 碳酸氢钠 、 1-羟基苯并三唑 、 溶剂黄146 、 三乙胺 、 N,N'-二环己基碳二亚胺 、 三氟乙酸 作用下， 以 1,4-二氧六环 、 二氯甲烷 、 水 、 乙酸乙酯 、 乙腈 为溶剂， 反应 124.0h， 生成 [(2S,5S)-8-iodo-1-methyl-3-oxo-2-propan-2-yl-2,4,5,6-tetrahydro-1,4-benzodiazocin-5-yl]methyl acetate
  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