8-oxo-3-(thiomorpholin-4-yl)-8H-acenaphthyleno[1,2-b]pyrrole-9-carbonitrile

• 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: 8-oxo-3-(thiomorpholin-4-yl)-8H-acenaphthyleno[1,2-b]pyrrole-9-carbonitrile
• 英文别名: 3-thiomorpholin-4-yl-8-oxo-8H-acenaphtho[1,2-b]pyrrole-9-carbonitrile；8-oxo-3-thiomorpholin-4-yl-8H-acenaphtho[1,2-b]pyrrole-9-carbonitrile；8-oxo-3-thiomorpholino-8H-acenaphtho[1,2-b]pyrrole-9-carbonitrile；8-oxo-3-thiomorpholin-4-ylacenaphthyleno[1,2-b]pyrrole-9-carbonitrile
• 化学式: C₁₉H₁₃N₃OS
• 分子量: 331.398
• InChiKey: BRPRPURMGRJSHP-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3
• 重原子数：
  24
• 可旋转键数：
  1
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.21
• 拓扑面积：
  81.8
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  8-oxo-3-(thiomorpholin-4-yl)-8H-acenaphthyleno[1,2-b]pyrrole-9-carbonitrile 、 1-氨基戊烷 以 乙腈 为溶剂， 反应 1.0h， 以31%的产率得到9-pentylimino-3-thiomorpholin-4-yl-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：

  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 2.0h， 生成 8-oxo-3-(thiomorpholin-4-yl)-8H-acenaphthyleno[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

• 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。
• 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。
• Versatile acenaphtho[1,2-b]pyrrol-carbonitriles as a new family of heterocycles: diverse SNArH reactions, cytotoxicity and spectral behavior
  作者：Fengyu Liu、Yi Xiao、Xuhong Qian、Zhichao Zhang、Jingnan Cui、Dawei Cui、Rong Zhang

  DOI：10.1016/j.tet.2005.08.106

  日期：2005.11

  The diverse reactivity of highly electron-deficient 8-oxo-8H-acenaphtho[1,2-b]pyrrol-9-carbonitrile I is attractive for the preparation of derivatives bearing different substituents via SNArH reaction with N, O, S nucleophiles. These derivatives were versatile, possessing potential antitumor activities and displaying tunable fluorescence spectral behavior. (c) 2005 Published by Elsevier Ltd.
• 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.
• US8614333B2
  申请人：——

  公开号：US8614333B2

  公开（公告）日：2013-12-24