3-((6-((4-bromophenyl)thio)-2-cyano-1-oxo-1H-phenalen-3-yl)amino)propanoic acid

• 分子结构分类: 有机化合物 - 苯类化合物 - 非那烯类
• 英文名称: 3-((6-((4-bromophenyl)thio)-2-cyano-1-oxo-1H-phenalen-3-yl)amino)propanoic acid
• 英文别名: 3-[[7-(4-Bromophenyl)sulfanyl-2-cyano-3-oxophenalen-1-yl]amino]propanoic acid；3-[[7-(4-bromophenyl)sulfanyl-2-cyano-3-oxophenalen-1-yl]amino]propanoic acid
• 化学式: C₂₃H₁₅BrN₂O₃S
• 分子量: 479.354
• InChiKey: FWJMOAWZSBQTJU-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.6
• 重原子数：
  30
• 可旋转键数：
  6
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.09
• 拓扑面积：
  116
• 氢给体数：
  2
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  3-((6-((4-bromophenyl)thio)-2-cyano-1-oxo-1H-phenalen-3-yl)amino)propanoic acid 、 二甘醇胺 在 N,N-二异丙基乙胺 、 N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate 作用下， 以 二氯甲烷 为溶剂， 反应 6.0h， 生成 3-((6-((4-bromophenyl)thio)-2-cyano-1-oxo-1H-phenalen-3-yl)amino)-N-(2-(2-hydroxyethoxy)ethyl)propanamide
  参考文献：
  名称：

  Targeting the Allosteric Pathway That Interconnects the Core-Functional Scaffold and the Distal Phosphorylation Sites for Specific Dephosphorylation of Bcl-2

  摘要：

  Protein phosphorylation is the most significant post-translational modification for regulating cellular activities, but site-specific modulation of phosphorylation is still challenging. Using three-dimensional NMR spectra, molecular dynamics simulations, and alanine mutations, we identified that the interaction network between pT69/pS70 and R106/R109 residues prevents the phosphorylation sites from exposure to phosphatase and subsequent dephosphorylation. A Bcl-2-dephosphorylation probe, S1-6e, was designed by installing a carboxylic acid group to a Bcl-2 inhibitor. The carboxyl group competitively disrupts the interaction network between R106/R109 and pT69/pS70 and subsequently facilitates Bcl-2 dephosphorylation in living cells. As a result, S1-6e manifests a more effective apoptosis induction in pBcl-2-dependent cancer cells than other inhibitors exhibiting a similar binding affinity for Bcl-2. We believe that targeting the allosteric pathways interconnecting the core-functional domain and the phosphorylation site can be a general strategy for a rational design of site-specific dephosphorylating probes, since the allosteric pathway has been discovered in a variety of proteins.

  DOI：

  10.1021/acs.jmedchem.0c01290
• 作为产物：
  描述：

  4-溴苯硫酚 在 水 、 sodium hydroxide 作用下， 以 四氢呋喃 、 乙腈 为溶剂， 生成 3-((6-((4-bromophenyl)thio)-2-cyano-1-oxo-1H-phenalen-3-yl)amino)propanoic acid
  参考文献：
  名称：

  Targeting the Allosteric Pathway That Interconnects the Core-Functional Scaffold and the Distal Phosphorylation Sites for Specific Dephosphorylation of Bcl-2

  摘要：

  Protein phosphorylation is the most significant post-translational modification for regulating cellular activities, but site-specific modulation of phosphorylation is still challenging. Using three-dimensional NMR spectra, molecular dynamics simulations, and alanine mutations, we identified that the interaction network between pT69/pS70 and R106/R109 residues prevents the phosphorylation sites from exposure to phosphatase and subsequent dephosphorylation. A Bcl-2-dephosphorylation probe, S1-6e, was designed by installing a carboxylic acid group to a Bcl-2 inhibitor. The carboxyl group competitively disrupts the interaction network between R106/R109 and pT69/pS70 and subsequently facilitates Bcl-2 dephosphorylation in living cells. As a result, S1-6e manifests a more effective apoptosis induction in pBcl-2-dependent cancer cells than other inhibitors exhibiting a similar binding affinity for Bcl-2. We believe that targeting the allosteric pathways interconnecting the core-functional domain and the phosphorylation site can be a general strategy for a rational design of site-specific dephosphorylating probes, since the allosteric pathway has been discovered in a variety of proteins.

  DOI：

  10.1021/acs.jmedchem.0c01290

文献信息

• Deactivation of Mcl-1 by Dual-Function Small-Molecule Inhibitors Targeting the Bcl-2 Homology 3 Domain and Facilitating Mcl-1 Ubiquitination
  作者：Ting Song、Ziqian Wang、Fangling Ji、Yingang Feng、Yudan Fan、Gaobo Chai、Xiangqian Li、Zhiqiang Li、Zhichao Zhang

  DOI：10.1002/anie.201606543

  日期：2016.11.7

  leading to the inhibition of ubiquitination. A dual function Mcl‐1 inhibitor, which locates at the BH3 domain of Mcl‐1 and forms hydrogen bond with His224 to drive a helical QRN conformation, so that it not only interferes with the pro‐apoptotic partners, but also facilitates Mcl‐1 ubiquitination in living cells, is described. As a result, this inhibitor manifests a more effective apoptosis induction

  通过有限的蛋白水解测定，三维NMR，X射线晶体学和丙氨酸突变，已确定Mcl-1的Bcl-2同源3（BH3）域中Q221R222N223基序的动态区域是构象转换，控制Mcl-1泛素化。Noxa BH3结合使QRN基序偏向螺旋构象，从而导致Mcl-1的体外泛素化增强。相比之下，Bim BH3结合使QRN基序偏向非螺旋构象，从而导致泛素化的抑制。Mcl-1双重功能抑制剂，位于Mcl-1的BH3结构域并与His224形成氢键以驱动螺旋QRN构象，因此它不仅干扰促凋亡伴侣，而且促进Mcl-1描述了活细胞中的泛素化。结果，这种抑制剂在Mcl-1依赖性癌细胞中表现出比其他具有相似结合亲和力的抑制剂更有效的凋亡诱导作用。
• Proteolysis Targeting Chimeras for the Selective Degradation of Mcl-1/Bcl-2 Derived from Nonselective Target Binding Ligands
  作者：Ziqian Wang、Nianzhe He、Zongwei Guo、Cuili Niu、Ting Song、Yafei Guo、Keke Cao、Anhui Wang、Junjie Zhu、Xiaodong Zhang、Zhichao Zhang

  DOI：10.1021/acs.jmedchem.9b00919

  日期：2019.9.12

  Proteolysis targeting chimera (PROTAC) recruits an E3 ligase to a target protein to induce its ubiquitination and subsequent degradation. We reported success in the development of two PROTACs (C3 and C5) that potently and selectively induce the degradation of Mcl-1 and Bcl-2 (DC50 = 0.7 and 3.0 mu M), respectively, by introducing the E3 ligase cereblon-binding ligand pomalidomide to Mcl-1/Bcl-2 dual inhibitors S1-6 and Nap-1 with micromolar-range affinity. C3-induced Mcl-1 ubiquitination translated into much more lethality in Mcl-1-dependent H23 cells than the most potent Mcl-1 occupancy-based inhibitor A-1210477 with nanomolar-range affinity. Moreover, structure-activity relationship analysis and molecular dynamic simulations discovered the structural basis for turning nonselective or promiscuous Bcl-2 family ligands into selective PROTACs. C3 and C5 exhibited reversible depletion in living cells, which provides a new potent toolkit for gain-of-function studies to probe the dynamic roles of Bcl-2 and Mcl-1 in apoptosis networks.
• Targeting the Allosteric Pathway That Interconnects the Core-Functional Scaffold and the Distal Phosphorylation Sites for Specific Dephosphorylation of Bcl-2
  作者：Ziqian Wang、Ting Song、Zongwei Guo、Keke Cao、Chao Chen、Yingang Feng、Hang Wang、Fangkui Yin、Sheng Zhou、Jian Dai、Zhichao Zhang

  DOI：10.1021/acs.jmedchem.0c01290

  日期：2020.11.25

  Protein phosphorylation is the most significant post-translational modification for regulating cellular activities, but site-specific modulation of phosphorylation is still challenging. Using three-dimensional NMR spectra, molecular dynamics simulations, and alanine mutations, we identified that the interaction network between pT69/pS70 and R106/R109 residues prevents the phosphorylation sites from exposure to phosphatase and subsequent dephosphorylation. A Bcl-2-dephosphorylation probe, S1-6e, was designed by installing a carboxylic acid group to a Bcl-2 inhibitor. The carboxyl group competitively disrupts the interaction network between R106/R109 and pT69/pS70 and subsequently facilitates Bcl-2 dephosphorylation in living cells. As a result, S1-6e manifests a more effective apoptosis induction in pBcl-2-dependent cancer cells than other inhibitors exhibiting a similar binding affinity for Bcl-2. We believe that targeting the allosteric pathways interconnecting the core-functional domain and the phosphorylation site can be a general strategy for a rational design of site-specific dephosphorylating probes, since the allosteric pathway has been discovered in a variety of proteins.