4-[(3E)-3-[(2-chloro-5-methoxy-6-methyl-1H-indol-3-yl)methylidene]-2-oxo-1H-indol-5-yl]-4-oxobutanoic acid

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: 4-[(3E)-3-[(2-chloro-5-methoxy-6-methyl-1H-indol-3-yl)methylidene]-2-oxo-1H-indol-5-yl]-4-oxobutanoic acid
• 化学式: C₂₀H₂₀Cl₂N₃O₅Pol
• 分子量: 438.9
• InChiKey: VQXSNCCOXDMEGK-CXUHLZMHSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.4
• 重原子数：
  31
• 可旋转键数：
  6
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.17
• 拓扑面积：
  109
• 氢给体数：
  3
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  4-[(3E)-3-[(2-chloro-5-methoxy-6-methyl-1H-indol-3-yl)methylidene]-2-oxo-1H-indol-5-yl]-4-oxobutanoic acid 在 DL-dithiothreitol 、 lithium tert-butoxide 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 生成
  参考文献：
  名称：

  Biological Diversity from a Structurally Diverse Library: Systematically Scanning Conformational Space Using a Pyranose Scaffold

  摘要：

  Success in discovering bioactive peptide mimetics is often limited by the difficulties in correctly transposing known binding elements of the active peptide onto a small and metabolically more stable scaffold while maintaining bioactivity. Here we describe a scanning approach using a library of pyranose-based peptidomimetics that is structurally diverse in a systematic manner, designed to cover all possible conformations of tripeptide motifs containing two aromatic groups and one positive charge. Structural diversity was achieved by efficient selection of various chemoforms, characterized by a choice of pyranose scaffold of defined chirality and substitution pattern. A systematic scanning library of 490 compounds was thus designed, produced, and screened in vitro for activity at the somatostatin (sst(1-5)) and melanin-concentrating hormone (MCH1) receptors. Bioactive compounds were found for each target, with specific chemoform preferences identified in each case, which can be used to guide follow-on drug discovery projects without the need for scaffold hopping.

  DOI：

  10.1021/jm1002777
• 作为产物：
  描述：

  N-[(2S,3R,4R,5S,6R)-2-[(4-chlorophenyl)methoxy]-5-hydroxy-6-(methoxymethyl)-4-(naphthalen-2-ylmethoxy)oxan-3-yl]-4-(diaminomethylideneamino)butanamide 在 溶剂黄146 、 1,8-bis(dimethylamino)naphthalene (hydrogen fluoride) 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 生成 4-[(3E)-3-[(2-chloro-5-methoxy-6-methyl-1H-indol-3-yl)methylidene]-2-oxo-1H-indol-5-yl]-4-oxobutanoic acid
  参考文献：
  名称：

  用糖库对抗肥胖：通过新的计算-VAST方法探索GPCR结合位点，发现新型MCH-1R拮抗剂

  摘要：

  肥胖是一种越来越常见的疾病。虽然已经广泛报道了黑色素浓缩激素-1受体（MCH-1R）的拮抗作用是肥胖治疗的一种有希望的治疗途径，但尚未有MCH-1R拮抗剂进入市场。降低HTS成功率和缺乏有关MCH-1R结合位点的结构信息，阻碍了针对MCH-1R的新化学物质的发现和优化。X射线晶体学和NMR是结构信息的主要实验来源，它们是膜蛋白的非常缓慢的过程，目前不适用于每种GPCR或GPCR-配体复合物。这种情况极大地限制了这些方法“实时”影响GPCR靶标的药物发现过程的能力，因此，迫切需要其他实用且具有成本效益的替代方法。我们在这里提出一种在概念上具有先驱性的方法，该方法将GPCR建模与VAST技术（稳定模板上的多功能组装）的多种糖基化合物的设计，合成和筛选相集成，以提供有关MCH-1R结合位点的结构见解。这种方法为针对GPCR靶标的基于结构的药物发现（SBDD）创建了一种经济高效的新途径。在我们的工

  DOI：

  10.1021/ci4000882

文献信息

• Substituted <i>E</i>-3-(3-Indolylmethylene)-1,3-dihydroindol-2-ones with Antitumor Activity. In Depth Study of the Effect on Growth of Breast Cancer Cells
  作者：Aldo Andreani、Stefania Bellini、Silvia Burnelli、Massimiliano Granaiola、Alberto Leoni、Alessandra Locatelli、Rita Morigi、Mirella Rambaldi、Lucilla Varoli、Natalia Calonghi、Concettina Cappadone、Maddalena Zini、Claudio Stefanelli、Lanfranco Masotti、Robert H. Shoemaker

  DOI：10.1021/jm1007165

  日期：2010.8.12

  The synthesis of new substituted E-3-(3-indolylmethylene)-1,3-dihydroindo1-2-ones is reported. The antitumor activity was evaluated according to protocols available at the National Cancer Institute (NCI), Bethesda, MD. Structure activity relationships are discussed. The action of selected compounds was investigated in MCF-7 breast cancer cells. The ability of these derivatives to inhibit cellular proliferation was accompanied by increased level of p53 and its transcriptional targets p21 and Bax, interference in the cell cycle progression with cell accumulation in the G2/M phase, and activation of apoptosis.
• Fighting Obesity with a Sugar-Based Library: Discovery of Novel MCH-1R Antagonists by a New Computational–VAST Approach for Exploration of GPCR Binding Sites
  作者：Alexander Heifetz、Oliver Barker、Geraldine Verquin、Norbert Wimmer、Wim Meutermans、Sandeep Pal、Richard J. Law、Mark Whittaker

  DOI：10.1021/ci4000882

  日期：2013.5.24

  Obesity is an increasingly common disease. While antagonism of the melanin-concentrating hormone-1 receptor (MCH-1R) has been widely reported as a promising therapeutic avenue for obesity treatment, no MCH-1R antagonists have reached the market. Discovery and optimization of new chemical matter targeting MCH-1R is hindered by reduced HTS success rates and a lack of structural information about the

  肥胖是一种越来越常见的疾病。虽然已经广泛报道了黑色素浓缩激素-1受体（MCH-1R）的拮抗作用是肥胖治疗的一种有希望的治疗途径，但尚未有MCH-1R拮抗剂进入市场。降低HTS成功率和缺乏有关MCH-1R结合位点的结构信息，阻碍了针对MCH-1R的新化学物质的发现和优化。X射线晶体学和NMR是结构信息的主要实验来源，它们是膜蛋白的非常缓慢的过程，目前不适用于每种GPCR或GPCR-配体复合物。这种情况极大地限制了这些方法“实时”影响GPCR靶标的药物发现过程的能力，因此，迫切需要其他实用且具有成本效益的替代方法。我们在这里提出一种在概念上具有先驱性的方法，该方法将GPCR建模与VAST技术（稳定模板上的多功能组装）的多种糖基化合物的设计，合成和筛选相集成，以提供有关MCH-1R结合位点的结构见解。这种方法为针对GPCR靶标的基于结构的药物发现（SBDD）创建了一种经济高效的新途径。在我们的工
• Biological Diversity from a Structurally Diverse Library: Systematically Scanning Conformational Space Using a Pyranose Scaffold
  作者：Giovanni Abbenante、Bernd Becker、Sébastien Blanc、Chris Clark、Glenn Condie、Graeme Fraser、Matthias Grathwohl、Judy Halliday、Senka Henderson、Ann Lam、Ligong Liu、Maretta Mann、Craig Muldoon、Andrew Pearson、Rajaratnam Premraj、Tracie Ramsdale、Tony Rossetti、Karl Schafer、Giang Le Thanh、Gerald Tometzki、Frank Vari、Géraldine Verquin、Jennifer Waanders、Michael West、Norbert Wimmer、Annika Yau、Johannes Zuegg、Wim Meutermans

  DOI：10.1021/jm1002777

  日期：2010.8.12

  Success in discovering bioactive peptide mimetics is often limited by the difficulties in correctly transposing known binding elements of the active peptide onto a small and metabolically more stable scaffold while maintaining bioactivity. Here we describe a scanning approach using a library of pyranose-based peptidomimetics that is structurally diverse in a systematic manner, designed to cover all possible conformations of tripeptide motifs containing two aromatic groups and one positive charge. Structural diversity was achieved by efficient selection of various chemoforms, characterized by a choice of pyranose scaffold of defined chirality and substitution pattern. A systematic scanning library of 490 compounds was thus designed, produced, and screened in vitro for activity at the somatostatin (sst(1-5)) and melanin-concentrating hormone (MCH1) receptors. Bioactive compounds were found for each target, with specific chemoform preferences identified in each case, which can be used to guide follow-on drug discovery projects without the need for scaffold hopping.