4-nitrophenyl (2E)-3-[4-[(bis[[(2,2-dimethylpropanoyl)oxy]methoxy]phosphoryl)difluoromethyl]phenyl]but-2-enoate | 1247847-59-1

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 肉桂酸及其衍生物
• 英文名称: 4-nitrophenyl (2E)-3-[4-[(bis[[(2,2-dimethylpropanoyl)oxy]methoxy]phosphoryl)difluoromethyl]phenyl]but-2-enoate
• 英文别名: p-nitrophenyl (2E)-3-[4-[[bis[(2,2-dimethyl-1-oxopropoxy)methoxy]phosphinyl]difluoromethyl]phenyl]but-2-enoate；[[difluoro-[4-[(E)-4-(4-nitrophenoxy)-4-oxobut-2-en-2-yl]phenyl]methyl]-(2,2-dimethylpropanoyloxymethoxy)phosphoryl]oxymethyl 2,2-dimethylpropanoate
• CAS: 1247847-59-1
• 化学式: C₂₉H₃₄F₂NO₁₁P
• 分子量: 641.56
• InChiKey: HPTICQSUSUXGBY-KNTRCKAVSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.8
• 重原子数：
  44
• 可旋转键数：
  16
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.41
• 拓扑面积：
  160
• 氢给体数：
  0
• 氢受体数：
  13

反应信息

• 作为反应物：
  描述：

  4-nitrophenyl (2E)-3-[4-[(bis[[(2,2-dimethylpropanoyl)oxy]methoxy]phosphoryl)difluoromethyl]phenyl]but-2-enoate 、 (4S,5R)-4-[[(2S,11S)-11-amino-12-oxo-1-azatricyclo[6.4.1.0^[4,13]]trideca-4(13),5,7-trien-2-yl]formamido]-5-([4-[3-(2-[3-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-1,3-benzodiazol-5-yl]propoxy]ethoxy)propyl]phenyl]methoxy)hexanamide acetate 在 N-甲基吗啉 、 4-二甲氨基吡啶 作用下， 以 N-甲基吡咯烷酮 、 乙腈 为溶剂， 反应 2.0h， 以19%的产率得到[([4-[(1E)-1-[[(2S,11S)-2-[[(3S,4R)-1-carbamoyl-4-([4-[3-(2-[3-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-1,3-benzodiazol-5-yl]propoxy]ethoxy)propyl]phenyl]methoxy)pentan-3-yl]carbamoyl]-12-oxo-1-azatricyclo[6.4.1.0^[4,13]]trideca-4(13),5,7-trien-11-yl]carbamoyl]prop-1-en-2-yl]phenyl]difluoromethyl([(2,2-dimethylpropanoyl)oxy]methoxy)phosphoryl)oxy]methyl 2,2-dimethylpropanoate
  参考文献：
  名称：

  [EN] STAT DEGRADERS AND USES THEREOF
  [FR] AGENTS DE DÉGRADATION DE STAT ET LEURS UTILISATIONS

  摘要：

  本发明提供了化合物、其组合物以及使用方法。

  公开号：

  WO2020206424A1
• 作为产物：
  描述：

  (E)-3-(4-((diethoxyphosphoryl)difluoromethyl)phenyl)but-2-enoic acid 在 4-二甲氨基吡啶 、 碘代三甲硅烷 、 silver nitrate 、 N,N'-二环己基碳二亚胺 、 sodium hydroxide 作用下， 以 二氯甲烷 、 水 、 乙酸乙酯 为溶剂， 反应 76.0h， 生成 4-nitrophenyl (2E)-3-[4-[(bis[[(2,2-dimethylpropanoyl)oxy]methoxy]phosphoryl)difluoromethyl]phenyl]but-2-enoate
  参考文献：
  名称：

  Potent and Selective Phosphopeptide Mimetic Prodrugs Targeted to the Src Homology 2 (SH2) Domain of Signal Transducer and Activator of Transcription 3

  摘要：

  Signal transducer and activator of transcription 3 (Stat3), a target for anticancer drug design, is activated by recruitment to phosphotyrosine residues on growth factor and cytokine receptors via its SH2 domain. We report here structure activity relationship studies on phosphopeptide mimics targeted to the SH2 domain of Stat3. Inclusion of a methyl group on the beta-position of the pTyr mimic 4-phosphocinnamide enhanced affinity 2- to 3-fold. Bis-pivaloyloxymethyl prodrugs containing beta-methylcinnamide, dipeptide scaffolds Haic and Nle-cis-3,4-methanoproline, and glutamine surrogates were highly potent, completely inhibiting phosphorylation of Stat3 Tyr705 at 0.5-1,mu M in a variety of cancer cell lines. The inhibitors were selective for Stat3 over Stat1, Stat5, Src, and p85 of PI3K, indicating ability to discriminate individual SH2 domains in intact cells. At concentrations that completely inhibited Stat3 phosphorylation, the prodrugs were not cytotoxic to a panel of tumor cells, thereby showing clear distinction between cytotoxicity and effects downstream of activated Stat3.

  DOI：

  10.1021/jm2000882

文献信息

• [EN] INHIBITORS OF STAT3 AND USES THEREOF<br/>[FR] INHIBITEURS DU STAT3 ET LEURS UTILISATIONS
  申请人：UNIV TEXAS

  公开号：WO2010118309A3

  公开（公告）日：2011-01-13
• [EN] STAT DEGRADERS AND USES THEREOF<br/>[FR] AGENTS DE DÉGRADATION DE STAT ET LEURS UTILISATIONS
  申请人：KYMERA THERAPEUTICS INC

  公开号：WO2020206424A1

  公开（公告）日：2020-10-08

  The present invention provides compounds, compositions thereof, and methods of using the same.

  本发明提供了化合物、其组合物以及使用方法。
• Potent and Selective Phosphopeptide Mimetic Prodrugs Targeted to the Src Homology 2 (SH2) Domain of Signal Transducer and Activator of Transcription 3
  作者：Pijus K. Mandal、Fengqin Gao、Zhen Lu、Zhiyong Ren、Rajagopal Ramesh、J. Sanderson Birtwistle、Kumaralal K. Kaluarachchi、Xiaomin Chen、Robert C. Bast、Warren S. Liao、John S. McMurray

  DOI：10.1021/jm2000882

  日期：2011.5.26

  Signal transducer and activator of transcription 3 (Stat3), a target for anticancer drug design, is activated by recruitment to phosphotyrosine residues on growth factor and cytokine receptors via its SH2 domain. We report here structure activity relationship studies on phosphopeptide mimics targeted to the SH2 domain of Stat3. Inclusion of a methyl group on the beta-position of the pTyr mimic 4-phosphocinnamide enhanced affinity 2- to 3-fold. Bis-pivaloyloxymethyl prodrugs containing beta-methylcinnamide, dipeptide scaffolds Haic and Nle-cis-3,4-methanoproline, and glutamine surrogates were highly potent, completely inhibiting phosphorylation of Stat3 Tyr705 at 0.5-1,mu M in a variety of cancer cell lines. The inhibitors were selective for Stat3 over Stat1, Stat5, Src, and p85 of PI3K, indicating ability to discriminate individual SH2 domains in intact cells. At concentrations that completely inhibited Stat3 phosphorylation, the prodrugs were not cytotoxic to a panel of tumor cells, thereby showing clear distinction between cytotoxicity and effects downstream of activated Stat3.