7-hydroxy-4-oxo-5-(S)-(2,2,2-trifluoroacetylamino)-1,2,4,5,6,7-hexahydroazepino[3,2,1-hi]indole-2-(S)-carboxylic acid methyl ester | 1147126-37-1

• 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: 7-hydroxy-4-oxo-5-(S)-(2,2,2-trifluoroacetylamino)-1,2,4,5,6,7-hexahydroazepino[3,2,1-hi]indole-2-(S)-carboxylic acid methyl ester
• 英文别名: methyl (2S,11S)-9-hydroxy-12-oxo-11-[(2,2,2-trifluoroacetyl)amino]-1-azatricyclo[6.4.1.04,13]trideca-4(13),5,7-triene-2-carboxylate
• CAS: 1147126-37-1
• 化学式: C₁₆H₁₅F₃N₂O₅
• 分子量: 372.301
• InChiKey: JBUXQFCPMCFDHC-QRHSGQBVSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1
• 重原子数：
  26
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.44
• 拓扑面积：
  95.9
• 氢给体数：
  2
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  7-hydroxy-4-oxo-5-(S)-(2,2,2-trifluoroacetylamino)-1,2,4,5,6,7-hexahydroazepino[3,2,1-hi]indole-2-(S)-carboxylic acid methyl ester 、 9-芴甲基-N-琥珀酰亚胺基碳酸酯 在 三氟乙酸 、 lithium hydroxide 、 sodium carbonate 作用下， 以 四氢呋喃 、 水 、 1,4-二氧六环 为溶剂， 反应 27.0h， 以46%的产率得到Fmoc-(5-[(S)-Amino]-1,2,4,5-tetrahydroazepino[3,2,1-hi]indole-4-one-2-(S)-carboxylate)
  参考文献：
  名称：

  Conformationally Constrained Peptidomimetic Inhibitors of Signal Transducer and Activator of Transcription 3: Evaluation and Molecular Modeling

  摘要：

  Signal transducer and activator of transcription 3 (Stat3) is involved in aberrant growth and survival signals in malignant tumor cells and is a validated target for anticancer drug design. We are targeting its SH2 domain to prevent docking to cytokine and growth factor receptors and subsequent signaling. The amino acids of our lead phosphopeptide, Ac-pTyr-Leu-Pro-Gln-Thr-Val-NH2, were replaced with conformationally constrained mimics. Structure-affinity studies led to the peptidomimetic, pCinn-Haic-Gln-NHBn (21). which had an IC50 of 162 nM (fluorescence polarization), compared to 290 nM for the lead phosphopeptide (pCinn = 4-phosphoryloxycinnamate, Haic = (2S,5S)-5-amino-1,2,4,5,6,7-hexahydro-4-oxo-azepino[3,2,1-hi]indole-2-carboxylic acid). pCinn-Haic-Gln-OH was docked to the SH2 domain (AUTODOCK), and the two highest populated clusters were subjected to molecular dynamics simulations. Both converged to a common peptide conformation. The complex exhibits unique hydrogen bonding between Haic and Gln and Stat3 as well as hydrophobic interactions between the protein and pCinn and Haic.

  DOI：

  10.1021/jm801491w
• 作为产物：
  描述：

  methyl (2S,11S)-9,12-dioxo-11-(2,2,2-trifluoroacetamido)-1-azatricyclo[6.4.1.0Λ[4,13]]trideca-4,6,8(13)-triene-2-carboxylate 在 palladium 10% on activated carbon 、 氢气 、 溶剂黄146 作用下， 以 四氢呋喃 为溶剂， 20.0 ℃ 、337.85 kPa 条件下， 反应 4.0h， 以86%的产率得到7-hydroxy-4-oxo-5-(S)-(2,2,2-trifluoroacetylamino)-1,2,4,5,6,7-hexahydroazepino[3,2,1-hi]indole-2-(S)-carboxylic acid methyl ester
  参考文献：
  名称：

  Conformationally Constrained Peptidomimetic Inhibitors of Signal Transducer and Activator of Transcription 3: Evaluation and Molecular Modeling

  摘要：

  Signal transducer and activator of transcription 3 (Stat3) is involved in aberrant growth and survival signals in malignant tumor cells and is a validated target for anticancer drug design. We are targeting its SH2 domain to prevent docking to cytokine and growth factor receptors and subsequent signaling. The amino acids of our lead phosphopeptide, Ac-pTyr-Leu-Pro-Gln-Thr-Val-NH2, were replaced with conformationally constrained mimics. Structure-affinity studies led to the peptidomimetic, pCinn-Haic-Gln-NHBn (21). which had an IC50 of 162 nM (fluorescence polarization), compared to 290 nM for the lead phosphopeptide (pCinn = 4-phosphoryloxycinnamate, Haic = (2S,5S)-5-amino-1,2,4,5,6,7-hexahydro-4-oxo-azepino[3,2,1-hi]indole-2-carboxylic acid). pCinn-Haic-Gln-OH was docked to the SH2 domain (AUTODOCK), and the two highest populated clusters were subjected to molecular dynamics simulations. Both converged to a common peptide conformation. The complex exhibits unique hydrogen bonding between Haic and Gln and Stat3 as well as hydrophobic interactions between the protein and pCinn and Haic.

  DOI：

  10.1021/jm801491w

文献信息

• Conformationally Constrained Peptidomimetic Inhibitors of Signal Transducer and Activator of Transcription 3: Evaluation and Molecular Modeling
  作者：Pijus K. Mandal、Donald Limbrick、David R. Coleman、Garrett A. Dyer、Zhiyong Ren、J. Sanderson Birtwistle、Chiyi Xiong、Xiaomin Chen、James M. Briggs、John S. McMurray

  DOI：10.1021/jm801491w

  日期：2009.4.23

  Signal transducer and activator of transcription 3 (Stat3) is involved in aberrant growth and survival signals in malignant tumor cells and is a validated target for anticancer drug design. We are targeting its SH2 domain to prevent docking to cytokine and growth factor receptors and subsequent signaling. The amino acids of our lead phosphopeptide, Ac-pTyr-Leu-Pro-Gln-Thr-Val-NH2, were replaced with conformationally constrained mimics. Structure-affinity studies led to the peptidomimetic, pCinn-Haic-Gln-NHBn (21). which had an IC50 of 162 nM (fluorescence polarization), compared to 290 nM for the lead phosphopeptide (pCinn = 4-phosphoryloxycinnamate, Haic = (2S,5S)-5-amino-1,2,4,5,6,7-hexahydro-4-oxo-azepino[3,2,1-hi]indole-2-carboxylic acid). pCinn-Haic-Gln-OH was docked to the SH2 domain (AUTODOCK), and the two highest populated clusters were subjected to molecular dynamics simulations. Both converged to a common peptide conformation. The complex exhibits unique hydrogen bonding between Haic and Gln and Stat3 as well as hydrophobic interactions between the protein and pCinn and Haic.