3-(4-aminophenylthio)-8-oxo-8H-acenaphtho[1,2-b]pyrrole-9-carbonitrile | 1265829-41-1

• 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-aminophenylthio)-8-oxo-8H-acenaphtho[1,2-b]pyrrole-9-carbonitrile
• 英文别名: 3-(4-aminophenyl)sulfanyl-8-oxoacenaphthyleno[1,2-b]pyrrole-9-carbonitrile
• CAS: 1265829-41-1
• 化学式: C₂₁H₁₁N₃OS
• 分子量: 353.404
• InChiKey: FNSJVQXUTIKAPS-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.8
• 重原子数：
  26
• 可旋转键数：
  2
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.0
• 拓扑面积：
  105
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  3-(4-aminophenylthio)-8-oxo-8H-acenaphtho[1,2-b]pyrrole-9-carbonitrile 、 β-环糊精 以 水 、 丙酮 为溶剂， 反应 72.0h， 生成
  参考文献：
  名称：

  ACENAPHTHO HETEROCYCLE COMPOUNDS, CYCLODEXTRIN INCLUSION COMPOUNDS AND COMPLEXES, AND USES IN THE MANUFACTURES OF BH3 PROTEIN ANALOGUE, BCL-2 FAMILY PROTEIN INHIBITORS THEREOF

  摘要：

  本发明涉及乙酰基环戊异维生素类化合物、环糊精包合物及其复合物，以及它们在制造BH3类似物、Bcl-2家族蛋白抑制剂中的应用。乙酰基环戊异维生素类化合物是通过在8-氧代-8H-乙酰基环戊[1,2-b]吡咯-9-碳腈的3、4和6位引入氧、硫、羰基、酯或酰基，或进一步用羧基、酯或酰胺取代9-氰基而得到的。这些化合物可以模拟BH3-only蛋白，在体外或细胞内与Bcl-2、Bel-XL和Mcl-1蛋白竞争性结合和拮抗，诱导细胞凋亡。环糊精包合物和复合物可以提高效果。因此，它们都可以用于抗癌化合物的制造。

  公开号：

  US20110251188A1
• 作为产物：
  描述：

  1-(二氰基亚甲基)-2-氧代苊 在 potassium carbonate 作用下， 以 乙腈 为溶剂， 反应 48.0h， 生成 3-(4-aminophenylthio)-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。
• Chemical entities that kill senescent cells for use in treating age-related disease
  申请人：Unity Biotechnology, Inc.

  公开号：US10195213B2

  公开（公告）日：2019-02-05

  Disclosed herein are compounds that are effective for treatment of various disease states associated with senescence. The disclosed compounds can be used to eliminate senescent cells for disease treatment. The dosing of the compounds includes both single administration and regimens of cycling dosages.

  本文公开的化合物可有效治疗与衰老有关的各种疾病状态。所公开的化合物可用于消除衰老细胞以治疗疾病。化合物的给药方式包括单次给药和循环给药。
• COMPOUNDS AND THERAPEUTIC USES
  申请人：Unity Biotechnology, Inc.

  公开号：US20170281649A1

  公开（公告）日：2017-10-05

  Disclosed herein are compounds that are effective for treatment of various disease states associated with senescence. The disclosed compounds can be used to eliminate senescent cells for disease treatment. The dosing of the compounds includes both single administration and regimens of cycling dosages.