Ac-pTyr-(3S,6R,9R)-ABN-Gln-Thr-NH2 | 1147126-11-1

• 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: Ac-pTyr-(3S,6R,9R)-ABN-Gln-Thr-NH2
• 英文别名: 4-((S)-2-acetamido-3-((3R,6S,8aR)-3-((S)-5-amino-1-((2S,3R)-1-amino-3-hydroxy-1-oxobutan-2-ylamino)-1,5-dioxopentan-2-ylcarbamoyl)-5-oxooctahydroindolizin-6-ylamino)-3-oxopropyl)phenyl dihydrogen phosphate；[4-[(2S)-3-[[(3R,6S,8aR)-3-[[(2S)-5-amino-1-[[(2S,3R)-1-amino-3-hydroxy-1-oxobutan-2-yl]amino]-1,5-dioxopentan-2-yl]carbamoyl]-5-oxo-2,3,6,7,8,8a-hexahydro-1H-indolizin-6-yl]amino]-2-acetamido-3-oxopropyl]phenyl] dihydrogen phosphate
• CAS: 1147126-11-1
• 化学式: C₂₉H₄₂N₇O₁₂P
• 分子量: 711.666
• InChiKey: MYQWIYLNQXTZLF-MXXZCERBSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -3.5
• 重原子数：
  49
• 可旋转键数：
  16
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.55
• 拓扑面积：
  310
• 氢给体数：
  9
• 氢受体数：
  12

反应信息

• 作为产物：
  描述：

  Fmoc-L-谷氨酰胺 、 Fmoc-L-酪氨酸 、 2-[(2S,5R,8S,11S)-5-benzyl-11-[3-(diaminomethylideneamino)propyl]-8-[4-[[4-(3-methoxy-3-oxopropyl)sulfanyl-4-oxobutanoyl]amino]butyl]-3,6,9,12,15-pentaoxo-1,4,7,10,13-pentazacyclopentadec-2-yl]acetic acid 、 (2S,6R,9R)-2-oxo-3-(9-fluorenyloxycarbonylamino)-1-azabicyclo[4.2.0]nonane-9-carboxylic acid 在 哌啶 、 1-羟基苯并三唑 、 N,N'-二异丙基碳二亚胺 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 生成 Ac-pTyr-(3S,6R,9R)-ABN-Gln-Thr-NH2
  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.