3-((6-((4-bromophenyl)thio)-2-cyano-1-oxo-1H-phenalen-3-yl)amino)-N-(2-(2-hydroxyethoxy)ethyl)propanamide

• 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)-N-(2-(2-hydroxyethoxy)ethyl)propanamide
• 英文别名: 3-[[7-(4-bromophenyl)sulfanyl-2-cyano-3-oxophenalen-1-yl]amino]-N-[2-(2-hydroxyethoxy)ethyl]propanamide
• 化学式: C₂₇H₂₄BrN₃O₄S
• 分子量: 566.475
• InChiKey: GMTUTGVUNKARAZ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.5
• 重原子数：
  36
• 可旋转键数：
  11
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.22
• 拓扑面积：
  137
• 氢给体数：
  3
• 氢受体数：
  7

反应信息

• 作为产物：
  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 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