3-(4-methoxyphenylthio)-8-oxo-8H-acenaphtho[1,2-b]pyrrole-9-carbonitrile | 1265829-35-3

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: 3-(4-methoxyphenylthio)-8-oxo-8H-acenaphtho[1,2-b]pyrrole-9-carbonitrile
• 英文别名: 3-(4-methoxyphenyl)sulfanyl-8-oxoacenaphthyleno[1,2-b]pyrrole-9-carbonitrile
• CAS: 1265829-35-3
• 化学式: C₂₂H₁₂N₂O₂S
• 分子量: 368.415
• InChiKey: UQVOXUZIGHRSOD-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.5
• 重原子数：
  27
• 可旋转键数：
  3
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.05
• 拓扑面积：
  87.8
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  3-(4-methoxyphenylthio)-8-oxo-8H-acenaphtho[1,2-b]pyrrole-9-carbonitrile 、 3-苯基-1-丙胺 以 乙腈 为溶剂， 反应 1.0h， 以17%的产率得到3-(4-methoxyphenyl)sulfanyl-9-(3-phenylpropylimino)-7H-acenaphthyleno[1,2-b]pyrrol-8-one
  参考文献：
  名称：

  3-Thiomorpholin-8-oxo-8H-acenaphtho [1,2-b] pyrrole-9-carbonitrile (S1) derivatives as pan-Bcl-2-inhibitors of Bcl-2, Bcl-xL and Mcl-1

  摘要：

  Based on the binding mode of our previously discovered dual inhibitor of Bcl-2 and Mcl-1, 3-thiomorpholin-8-oxo-8H-acenaphtho[1,2-b]pyrrole-9-carbonitrile (3, S1), a library of 9-substituted 3 derivatives was synthesized to further probe the p4 pocket of the two targets. By NMR, structure-activity relationship study, and site-directed mutation, compound 6d (3-(4-aminophenylthio)-8-oxo-8H-acenaphtho[1,2-b]pyrrole-9-3-phenyl)propylamine) was identified to span p2-p4 pockets of Mcl-1, Bcl-2 and Bcl-x(L), and then exhibited 9- to 35-fold better affinity to the three targets than 3 (IC50 = 10, 20 and 18 nM, respectively), which led to greater activity in induction of apoptosis in multiple cancer cell lines. Different contribution of p4 pocket to binding Bcl-2 and Mcl-1 was also investigated by plotting the potency and the HAC of the derivatives. (C) 2012 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2012.11.008
• 作为产物：
  描述：

  苊醌 在 potassium carbonate 作用下， 以 乙腈 为溶剂， 反应 48.0h， 生成 3-(4-methoxyphenylthio)-8-oxo-8H-acenaphtho[1,2-b]pyrrole-9-carbonitrile
  参考文献：
  名称：

  3-Thiomorpholin-8-oxo-8H-acenaphtho [1,2-b] pyrrole-9-carbonitrile (S1) derivatives as pan-Bcl-2-inhibitors of Bcl-2, Bcl-xL and Mcl-1

  摘要：

  Based on the binding mode of our previously discovered dual inhibitor of Bcl-2 and Mcl-1, 3-thiomorpholin-8-oxo-8H-acenaphtho[1,2-b]pyrrole-9-carbonitrile (3, S1), a library of 9-substituted 3 derivatives was synthesized to further probe the p4 pocket of the two targets. By NMR, structure-activity relationship study, and site-directed mutation, compound 6d (3-(4-aminophenylthio)-8-oxo-8H-acenaphtho[1,2-b]pyrrole-9-3-phenyl)propylamine) was identified to span p2-p4 pockets of Mcl-1, Bcl-2 and Bcl-x(L), and then exhibited 9- to 35-fold better affinity to the three targets than 3 (IC50 = 10, 20 and 18 nM, respectively), which led to greater activity in induction of apoptosis in multiple cancer cell lines. Different contribution of p4 pocket to binding Bcl-2 and Mcl-1 was also investigated by plotting the potency and the HAC of the derivatives. (C) 2012 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2012.11.008

文献信息

• 3-Thiomorpholin-8-oxo-8<i>H</i>-acenaphtho[1,2-<i>b</i>]pyrrole-9-carbonitrile (S1) Based Molecules as Potent, Dual Inhibitors of B-Cell Lymphoma 2 (Bcl-2) and Myeloid Cell Leukemia Sequence 1 (Mcl-1): Structure-Based Design and Structure−Activity Relationship Studies
  作者：Zhichao Zhang、Guiye Wu、Feibo Xie、Ting Song、Xilong Chang

  DOI：10.1021/jm101181u

  日期：2011.2.24

  discovery of a dual inhibitor of Bcl-2 and Mcl-1, 3-thiomorpholin-8-oxo-8H-acenaphtho[1,2-b]pyrrole-9-carbonitrile (3, S1). Here we report a structure-guided design in combination with structure−activity relationship studies to exploit the difference in the p2 binding pocket of Bcl-2 and Mcl-1, from which a novel dual inhibitor 3-(4-aminophenylthio)-8-oxo-8H-acenaphtho[1,2-b]pyrrole-9-carbonitrile (6h) was

  我们最近描述了Bcl-2和Mcl-1的双重抑制剂3- thiomorpholin -8-oxo-8 H -ac [1,2 - b ]吡咯-9-腈（3，S1）的发现。在这里，我们报告结构指导的设计与结构活性关系研究相结合，以利用Bcl-2和Mcl-1在p2结合口袋中的差异，从而从中获得新型的双重抑制剂3-（4-氨基苯硫基）-8-获得了oxo-8 H -ac [1,2 - b ]吡咯-9-腈（6h），显示出对Mcl-1（5 nM）的IC 50值显着提高，Mcl-1 / Bak破坏潜力更大，并且因此，细胞毒性比3增加了10倍。