(2S,5S)-O-acetylbenzolactam V | 174363-74-7

• 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: (2S,5S)-O-acetylbenzolactam V
• 英文别名: (2S,5S)-O-acetylobenzolactam；[(2S,5S)-1-methyl-3-oxo-2-propan-2-yl-2,4,5,6-tetrahydro-1,4-benzodiazocin-5-yl]methyl acetate
• CAS: 174363-74-7
• 化学式: C₁₇H₂₄N₂O₃
• 分子量: 304.389
• InChiKey: XFGLNSKJGWKJKA-HOCLYGCPSA-N

物化性质

• 沸点：
  484.6±35.0 °C(Predicted)
• 密度：
  1.068±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.7
• 重原子数：
  22
• 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)-O-acetylbenzolactam V 在 吡啶 、 碘 作用下， 以 1,4-二氧六环 为溶剂， 反应 72.0h， 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
• 作为产物：
  描述：

  (2S)-2-[2-[(2S)-2-amino-3-hydroxypropyl]anilino]-3-methylbutanoic acid 在 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 二氯甲烷 、 水 、 乙酸乙酯 、 乙腈 为溶剂， 反应 76.0h， 生成 (2S,5S)-O-acetylbenzolactam V
  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

文献信息

• New Amide-Bearing Benzolactam-Based Protein Kinase C Modulators Induce Enhanced Secretion of the Amyloid Precursor Protein Metabolite sAPPα
  作者：Alan P. Kozikowski、Ireneusz Nowak、Pavel A. Petukhov、Rene Etcheberrigaray、Ali Mohamed、Mathew Tan、Nancy Lewin、Henry Hennings、Larry L. Pearce、Peter M. Blumberg

  DOI：10.1021/jm020350r

  日期：2003.1.1

  Protein kinase C (PKC) is known to participate in the processing of the amyloid precursor protein (APP). Abnormal processing of APP through the action of the beta- and gamma-secretases leads to the production of the 39-43 amino acid Abeta fragment, which is neurotoxic and which is believed to play an important role in the etiology of Alzheimer's disease. PKC activation enhances alpha-secretase activity

  已知蛋白激酶C（PKC）参与淀粉样前体蛋白（APP）的加工。通过β-和γ-分泌酶的作用，APP的异常加工导致产生39-43个氨基酸的Abeta片段，该片段具有神经毒性，据信在阿尔茨海默氏病的病因中起重要作用。PKC激活增强了α分泌酶的活性，从而导致β分泌酶的淀粉样蛋白生成产物减少。在本文中，我们描述了10种基于苯并内酰胺V8的新型PKC活化剂的合成，该活化剂具有不同的饱和度和亲脂性的侧链通过酰胺基与芳环相连。所测量的抑制佛波酯与PKCalpha结合的K（i）值在纳摩尔范围内，并显示出与它们的亲脂性相关。在合成的10个苯并内酰胺中，化合物5g和5h显示出最佳的结合亲和力。通过使用源自AD患者的细胞系，大多数研究的化合物在1 microM的浓度下获得了sAPPalpha分泌的显着增强，而化合物5e和5f在0.1 microM的情况下获得了sAPPalpha分泌的显着增强。在1 microM时，
• [EN] PROTEIN KINASE C MODULATORS, AND METHODS OF USE THEREOF<br/>[FR] MODULATEURS DE PROTEINE KINASE C ET PROCEDES PERMETTANT DE LES UTILISER
  申请人：UNIV GEORGETOWN

  公开号：WO2004007445A3

  公开（公告）日：2004-09-10