1,8-dichloro-10-(2-hydroxy-3-methoxybenzylidene)-10H-anthracen-9-one | 1237513-80-2

• 分子结构分类: 有机化合物 - 苯类化合物 - 蒽
• 英文名称: 1,8-dichloro-10-(2-hydroxy-3-methoxybenzylidene)-10H-anthracen-9-one
• 英文别名: 1,8-Dichloro-10-[(2-hydroxy-3-methoxyphenyl)methylidene]anthracen-9-one
• CAS: 1237513-80-2
• 化学式: C₂₂H₁₄Cl₂O₃
• 分子量: 397.257
• InChiKey: LCIZKKFUFJLBFS-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.8
• 重原子数：
  27
• 可旋转键数：
  2
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.05
• 拓扑面积：
  46.5
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为产物：
  描述：

  1,8-二氯蒽醌 在 盐酸 、 氯化亚锡 、 溶剂黄146 作用下， 生成 1,8-dichloro-10-(2-hydroxy-3-methoxybenzylidene)-10H-anthracen-9-one
  参考文献：
  名称：

  Small molecule-induced degradation of the full length and V7 truncated variant forms of human androgen receptor

  摘要：

  The androgen receptor (AR) is a hormone-activated transcription factor that regulates the development and progression of prostate cancer (PCa) and represents one of the most well-established drug targets. Currently clinically approved small molecule inhibitors of AR, such as enzalutamide, are built upon a common chemical scaffold that interacts with the AR by the same mechanism of action. These inhibitors eventually fail due to the emergence of drug-resistance in the form of AR mutations and expression of truncated AR splice variants (e.g. AR-V7) that are constitutively active, signalling the progression of the castration-resistant state of the disease. The urgent need therefore continues for novel classes of AR inhibitors that can overcome drug resistance, especially since AR signalling remains important even in late-stage advanced PCa.Previously, we identified a collection of 10-benzylidene-10H-anthracen-9-ones that effectively inhibit AR transcriptional activity, induce AR degradation and display some ability to block recruitment of hormones to the receptor. In the current work, we extended the analysis of the lead compounds, and used methods of both ligand- and structure-based drug design to develop a panel of novel 10-benzylidene-10H-anthracen-9-one derivatives capable of suppressing transcriptional activity and protein expression levels of both full length- and AR-V7 truncated forms of human androgen receptor. Importantly, the developed compounds efficiently inhibited the growth of AR-V7 dependent prostate cancer cell-lines which are completely resistant to all current anti-androgens. (C) 2018 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2018.08.059

文献信息

• Synthesis, antiproliferative activity and inhibition of tubulin polymerization by 1,5- and 1,8-disubstituted 10H-anthracen-9-ones bearing a 10-benzylidene or 10-(2-oxo-2-phenylethylidene) moiety
  作者：Holger C. Nickel、Peter Schmidt、Konrad J. Böhm、Silke Baasner、Klaus Müller、Matthias Gerlach、Eberhard Unger、Eckhard G. Günther、Helge Prinz

  DOI：10.1016/j.ejmech.2010.04.032

  日期：2010.8

  A novel series of 1,5- and 1,8-disubstituted 10-benzylidene-10H-anthracen-9-ones and 10-(2-oxo-2-phenylethylidene)-10H-anthracen-9-ones was synthesized to assess the substituent effects on biological activity. The 3-hydroxy-2,4-dimethoxy-benzylidene analogue 16h displayed strong antiproliferative activity against several tumor cell lines, including multi-drug resistant phenotypes. Flow cytometric studies showed that KB/HeLa cells treated by elected compounds were arrested in the G2/M phases of the cell cycle. Among the compounds tested for inhibition of tubulin polymerization, 14 compounds proved to be exceptionally active with IC50 values < 1 mu M. In the 1,5-dichloro-derived series of benzylideneanthracenones, E/Z isomers were separated and biological effects were monitored. We found that the olefinic geometry had no significant effect on biological activity. Furthermore, the E isomeric 1,5-dichloro-substituted phenacylidenes entirely proved to be more potent inhibitors of tubulin polymerization than the recently described 10-(2-oxo-2-phenylethylidene)-10H-anthracen-9-ones. In conclusion, the present study improves understanding of the action of anthracenone-based tubulin polymerization inhibitors and contributes to the design of further potent anti-tubulin drugs. (C) 2010 Elsevier Masson SAS. All rights reserved.
• Small molecule-induced degradation of the full length and V7 truncated variant forms of human androgen receptor
  作者：Kush Dalal、Helene Morin、Fuqiang Ban、Ashley Shepherd、Michael Fernandez、Kevin J. Tam、Huifang Li、Eric LeBlanc、Nathan Lack、Helge Prinz、Paul S. Rennie、Artem Cherkasov

  DOI：10.1016/j.ejmech.2018.08.059

  日期：2018.9

  The androgen receptor (AR) is a hormone-activated transcription factor that regulates the development and progression of prostate cancer (PCa) and represents one of the most well-established drug targets. Currently clinically approved small molecule inhibitors of AR, such as enzalutamide, are built upon a common chemical scaffold that interacts with the AR by the same mechanism of action. These inhibitors eventually fail due to the emergence of drug-resistance in the form of AR mutations and expression of truncated AR splice variants (e.g. AR-V7) that are constitutively active, signalling the progression of the castration-resistant state of the disease. The urgent need therefore continues for novel classes of AR inhibitors that can overcome drug resistance, especially since AR signalling remains important even in late-stage advanced PCa.Previously, we identified a collection of 10-benzylidene-10H-anthracen-9-ones that effectively inhibit AR transcriptional activity, induce AR degradation and display some ability to block recruitment of hormones to the receptor. In the current work, we extended the analysis of the lead compounds, and used methods of both ligand- and structure-based drug design to develop a panel of novel 10-benzylidene-10H-anthracen-9-one derivatives capable of suppressing transcriptional activity and protein expression levels of both full length- and AR-V7 truncated forms of human androgen receptor. Importantly, the developed compounds efficiently inhibited the growth of AR-V7 dependent prostate cancer cell-lines which are completely resistant to all current anti-androgens. (C) 2018 Elsevier Masson SAS. All rights reserved.