6-((4-bromophenyl)thio)-1-oxo-1H-phenalene-2,3-dicarbonitrile

• 分子结构分类: 有机化合物 - 苯类化合物 - 非那烯类
• 英文名称: 6-((4-bromophenyl)thio)-1-oxo-1H-phenalene-2,3-dicarbonitrile
• 英文别名: 7-(4-Bromophenyl)sulfanyl-3-oxophenalene-1,2-dicarbonitrile；7-(4-bromophenyl)sulfanyl-3-oxophenalene-1,2-dicarbonitrile
• 化学式: C₂₁H₉BrN₂OS
• 分子量: 417.285
• InChiKey: IFUUTGNBTBDNHL-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.3
• 重原子数：
  26
• 可旋转键数：
  2
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.0
• 拓扑面积：
  90
• 氢给体数：
  0
• 氢受体数：
  4

上下游信息

• 上游原料

  中文名称	英文名称	CAS号	化学式	分子量
  ——	1-oxo-1H-phenalene-2,3-dicarbonitrile	——	C15H6N2O	230.225

• 下游产品

  中文名称	英文名称	CAS号	化学式	分子量
  ——	3-((6-((4-bromophenyl)thio)-2-cyano-1-oxo-1H-phenalen-3-yl)amino)propanoic acid	——	C23H15BrN2O3S	479.354
  ——	methyl 3-((6-((4-bromophenyl)thio)-2-cyano-1-oxo-1H-phenalen-3-yl)amino)propanoate	——	C24H17BrN2O3S	493.381
  ——	3-((6-((4-bromophenyl)thio)-2-cyano-1-oxo-1H-phenalen-3-yl)amino)-N-(2-(2-hydroxyethoxy)ethyl)propanamide	——	C27H24BrN3O4S	566.475

反应信息

• 作为反应物：
  描述：

  6-((4-bromophenyl)thio)-1-oxo-1H-phenalene-2,3-dicarbonitrile 在 水 、 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 、 sodium hydroxide 作用下， 以 四氢呋喃 、 二氯甲烷 、 乙腈 为溶剂， 反应 6.0h， 生成
  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：

  5-溴萘乙基-1,2-二酮 在 potassium carbonate 作用下， 以 乙腈 为溶剂， 反应 10.0h， 生成 6-((4-bromophenyl)thio)-1-oxo-1H-phenalene-2,3-dicarbonitrile
  参考文献：
  名称：

  3-氰基非那烯酮类化合物及其应用

  摘要：

  3‑氰基非那烯酮类化合物及其应用，其属于荧光标记的技术领域。本发明采用多种手段检测了3‑氰基非那烯酮类化合物与PKM2的结合能力，该类化合物可以有效的共价结合PKM2蛋白。并通过凝胶荧光成像、活细胞荧光成像实验检测了它们在体外和活细胞（包括肿瘤细胞和正常组织细胞）内特异性荧光标记PKM2蛋白的能力。表明该类化合物可以有效的在体外和活细胞内与PKM2发生亲核取代反应，并生成具有橙红色荧光的结构，实现对于PKM2的特异性荧光标记。肿瘤细胞和正常细胞的活细胞荧光成像实验进一步表明该类化合物能够特异性的对肿瘤细胞进行荧光染色，而不对正常细胞进行荧光染色，实现对于肿瘤细胞、组织的荧光可视化和肿瘤细胞、组织的分子影像学诊断。

  公开号：

  CN111620841B

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。
• A novel Hsp70 inhibitor specifically targeting the cancer-related Hsp70-Bim protein-protein interaction
  作者：Ziqian Wang、Ting Song、Zongwei Guo、Laura B. Uwituze、Yafei Guo、Hong Zhang、Hang Wang、Xiaodong Zhang、Hao Pan、Tong Ji、Fangkui Yin、Sheng Zhou、Jian Dai、Zhichao Zhang

  DOI：10.1016/j.ejmech.2021.113452

  日期：2021.8

  Targeting cancer-related Hsp70-Bim protein-protein interactions (PPIs) offers a new strategy for the design of Hsp70 inhibitors. Herein, we discovered a novel Hsp70 inhibitor, S1g-6, based on the established BH3 mimetics. S1g-6 exhibited sub-μM binding affinity toward Hsp70 and selectively disrupted Hsp70-Bim PPI. The target specificity of S1g-6 in situ was validated by affinity-based protein profiling

  靶向与癌症相关的 Hsp70-Bim 蛋白相互作用 (PPI) 为 Hsp70 抑制剂的设计提供了一种新策略。在此，我们发现了一种基于已建立的 BH3 模拟物的新型 Hsp70 抑制剂S1g-6。S1g-6对 Hsp70 表现出亚 μM 的结合亲和力，并选择性地破坏 Hsp70-Bim PPI。S1g-6 的原位靶标特异性通过基于亲和力的蛋白质分析、免疫共沉淀和基于细胞的 shRNA 测定进行了验证。S1g-6在招募 Bim 时特异性地拮抗 Hsp70 的 ATPase 活性，并通过抑制 Hsp70 的一些致癌客户，在一些癌细胞系中显示出选择性凋亡诱导，而不是正常细胞系，代表了一类新的抗肿瘤候选物。Hsp70-Bim PPI 作为潜在的抗癌靶标表现出依赖于癌症的作用。
• 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.
• 3-氰基非那烯酮类化合物及其应用
  申请人：大连理工大学

  公开号：CN111620841B

  公开（公告）日：2023-03-28

  3‑氰基非那烯酮类化合物及其应用，其属于荧光标记的技术领域。本发明采用多种手段检测了3‑氰基非那烯酮类化合物与PKM2的结合能力，该类化合物可以有效的共价结合PKM2蛋白。并通过凝胶荧光成像、活细胞荧光成像实验检测了它们在体外和活细胞（包括肿瘤细胞和正常组织细胞）内特异性荧光标记PKM2蛋白的能力。表明该类化合物可以有效的在体外和活细胞内与PKM2发生亲核取代反应，并生成具有橙红色荧光的结构，实现对于PKM2的特异性荧光标记。肿瘤细胞和正常细胞的活细胞荧光成像实验进一步表明该类化合物能够特异性的对肿瘤细胞进行荧光染色，而不对正常细胞进行荧光染色，实现对于肿瘤细胞、组织的荧光可视化和肿瘤细胞、组织的分子影像学诊断。
• 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.