5-(4-isopropylphenoxy)acenaphthenequinone | 1265828-86-1

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: 5-(4-isopropylphenoxy)acenaphthenequinone
• 英文别名: 5-(4-isopropylphenoxy)acenaphthylene-1,2-dione；5-(4-Propan-2-ylphenoxy)acenaphthylene-1,2-dione；5-(4-propan-2-ylphenoxy)acenaphthylene-1,2-dione
• CAS: 1265828-86-1
• 化学式: C₂₁H₁₆O₃
• 分子量: 316.356
• InChiKey: FUHCTURXKFJJKS-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.9
• 重原子数：
  24
• 可旋转键数：
  3
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.14
• 拓扑面积：
  43.4
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  5-(4-isopropylphenoxy)acenaphthenequinone 在 potassium carbonate 作用下， 以 乙腈 为溶剂， 反应 3.0h， 生成 3-(4-isopropylphenoxy)-8-oxo-8H-acenaphtho[1,2-b]pyrrole-9-carbonitrile
  参考文献：
  名称：

  3-Thiomorpholin-8-oxo-8 H -ac [1,2 - b ]吡咯-9-甲腈（S1）分子为强势，B细胞淋巴瘤2（Bcl-2）和骨髓细胞白血病序列的双重抑制剂。 1（Mcl-1）：基于结构的设计和结构活动关系研究

  摘要：

  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。

  DOI：

  10.1021/jm101181u
• 作为产物：
  描述：

  苊醌 在 溴 、 potassium carbonate 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 4.0h， 生成 5-(4-isopropylphenoxy)acenaphthenequinone
  参考文献：
  名称：

  3-Thiomorpholin-8-oxo-8 H -ac [1,2 - b ]吡咯-9-甲腈（S1）分子为强势，B细胞淋巴瘤2（Bcl-2）和骨髓细胞白血病序列的双重抑制剂。 1（Mcl-1）：基于结构的设计和结构活动关系研究

  摘要：

  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。

  DOI：

  10.1021/jm101181u

文献信息

• ACENAPHTHO HETEROCYCLIC COMPOUND AND APPLICATION THEREOF
  申请人：Zhang Zhichao

  公开号：US20130123492A1

  公开（公告）日：2013-05-16

  The present invention relates to acenaphtho heterocyclic compounds and their uses in manufacturing the BH3 mimetics as Bcl-2-like protein inhibitors. Structures are shown in the following: Statistical analysis of their bio-activities showed these compounds exhibit better BH3 mimicking property than the reported compounds. These compounds can simulate BH3-only protein, competitively bind and antagonizing Bcl-2 and Mcl-1 proteins in vitro and in cells, and then induce apoptosis. Therefore, they all can be used in the manufactures of anticancer compounds.

  本发明涉及蒽醌杂环化合物及其在制造类似Bcl-2蛋白抑制剂的BH3模拟物中的用途。结构如下所示：对它们的生物活性进行的统计分析表明，这些化合物表现出比已报告的化合物更好的BH3模拟性能。这些化合物可以模拟BH3-只蛋白，在体外和细胞中与Bcl-2和Mcl-1蛋白竞争性结合和拮抗，然后诱导细胞凋亡。因此，它们都可以用于抗癌化合物的制造。
• 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。
• Novel soluble myeloid cell leukemia sequence 1 (Mcl-1) inhibitor (E,E)-2-(benzylaminocarbonyl)-3-styrylacrylonitrile (4g) developed using a fragment-based approach
  作者：Zhichao Zhang、Ting Song、Xiangqian Li、Zhiyong Wu、Yingang Feng、Feibo Xie、Chengwu Liu、Jianquan Qin、Hongbo Chen

  DOI：10.1016/j.ejmech.2012.10.050

  日期：2013.1

  Based on a known nanomolar Bcl-2 homology domain 3 (BH3) mimetic 3-thiomorpholin-8-oxo-8H-acenaphtho[1,2-b] pyrrole-9-carbonitrile (SI, MW: 331), we applied a fragment-based approach to obtain BH3 mimetics with improved affinity and improved solubility in a water ethanol (9:1) cosolvent. After the deconstruction of 1 (S1), we obtained fragment cyanoacetamide (4), which was determined to be a ligand efficiency (LE) hot part. After a rational optimization through fragment evolution beginning with fragment 4, a smaller Mcl-1 inhibitor (E,E)-2-(benzylaminocarbonyl)-3-styrylacrylonitrile (4g, MW: 288) with a 6-fold increase in affinity compared to I was obtained, as predicted by our optimization curve and identified by Mcl-1 protein nuclear magnetic resonance (NMR). (C) 2012 Elsevier Masson SAS. All rights reserved.
• US8614333B2
  申请人：——

  公开号：US8614333B2

  公开（公告）日：2013-12-24
• 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
  作者：Ting Song、Xiangqian Li、Xilong Chang、Xiaomeng Liang、Yan Zhao、Guiye Wu、Shenghui Xie、Pengchen Su、Zhiyong Wu、Yingang Feng、Zhichao Zhang

  DOI：10.1016/j.bmc.2012.11.008

  日期：2013.1

  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.