(E)-3-(4-((diethoxyphosphoryl)-difluoromethyl)phenyl)but-2-enoic acid | 1247847-54-6

• 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: (E)-3-(4-((diethoxyphosphoryl)-difluoromethyl)phenyl)but-2-enoic acid
• 英文别名: (E)-3-[4-[diethoxyphosphoryl(difluoro)methyl]phenyl]but-2-enoic acid
• CAS: 1247847-54-6
• 化学式: C₁₅H₁₉F₂O₅P
• 分子量: 348.283
• InChiKey: WOJXMBKZINQVNV-ZHACJKMWSA-N

物化性质

• 沸点：
  440.7±45.0 °C(Predicted)
• 密度：
  1.262±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3
• 重原子数：
  23
• 可旋转键数：
  8
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.4
• 拓扑面积：
  72.8
• 氢给体数：
  1
• 氢受体数：
  7

反应信息

• 作为反应物：
  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 、 2,2,2-三氟-N,N-二(三甲硅基)乙酰胺 、 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 pentachlorophenyl (2E)-3-[4-[[bis[(2,2-dimethyl-1-oxopropoxy)methoxy]phosphinyl]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
• 作为产物：
  描述：

  tert-butyl (E)-3-(4-iodophenyl)but-2-enoate 在 三氟乙酸 、 镉 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 33.0h， 生成 (E)-3-(4-((diethoxyphosphoryl)-difluoromethyl)phenyl)but-2-enoic acid
  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

• Structure-Based Discovery of SD-36 as a Potent, Selective, and Efficacious PROTAC Degrader of STAT3 Protein
  作者：Haibin Zhou、Longchuan Bai、Renqi Xu、Yujun Zhao、Jianyong Chen、Donna McEachern、Krishnapriya Chinnaswamy、Bo Wen、Lipeng Dai、Praveen Kumar、Chao-Yie Yang、Zhaomin Liu、Mi Wang、Liu Liu、Jennifer L. Meagher、Han Yi、Duxin Sun、Jeanne A. Stuckey、Shaomeng Wang

  DOI：10.1021/acs.jmedchem.9b01530

  日期：2019.12.26

  structure-based discovery of potent small-molecule STAT3 degraders based upon the proteolysis targeting chimera (PROTAC) concept. We first designed SI-109 as a potent, small-molecule inhibitor of the STAT3 SH2 domain. Employing ligands for cereblon/cullin 4A E3 ligase and SI-109, we obtained a series of potent PROTAC STAT3 degraders, exemplified by SD-36. SD-36 induces rapid STAT3 degradation at low nanomolar

  信号转导和转录激活因子 3 (STAT3) 是一种转录因子，是癌症和其他人类疾病的有吸引力的治疗靶点。尽管进行了 20 年的持续研究努力，但针对 STAT3 的目标一直非常具有挑战性。我们在此报告了基于蛋白水解靶向嵌合体 (PROTAC) 概念的有效小分子 STAT3 降解剂的基于结构的发现。我们首先将 SI-109 设计为 STAT3 SH2 结构域的有效小分子抑制剂。使用 cereblon/cullin 4A E3 连接酶和 SI-109 的配体，我们获得了一系列有效的 PROTAC STAT3 降解剂，以 SD-36 为例。SD-36 在细胞中以低纳摩尔浓度诱导 STAT3 快速降解，并且不能降解其他 STAT 蛋白。SD-36 在具有高水平磷酸化 STAT3 的白血病和淋巴瘤细胞系中实现纳摩尔细胞生长抑制活性。单剂量的 SD-36 会导致异种移植肿瘤组织和正常小鼠组织中的 STAT3
• [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
• US8841257B2
  申请人：——

  公开号：US8841257B2

  公开（公告）日：2014-09-23