5-(2-fluorophenyl)-2-(1-((2-methoxyphenyl)amino)ethylidene)cyclohexane-1,3-dione | 1609374-94-8

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯酚醚
• 英文名称: 5-(2-fluorophenyl)-2-(1-((2-methoxyphenyl)amino)ethylidene)cyclohexane-1,3-dione
• CAS: 1609374-94-8
• 化学式: C₂₁H₂₀FNO₃
• 分子量: 353.393
• InChiKey: HNZVEDQEDVPNCS-BKUYFWCQSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.24
• 重原子数：
  26.0
• 可旋转键数：
  4.0
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.24
• 拓扑面积：
  55.4
• 氢给体数：
  1.0
• 氢受体数：
  4.0

反应信息

• 作为产物：
  描述：

  5-(2-氟苯基)-环己烷-1,3-二酮 在 1H-1,2,4-三唑 、 四丁基溴化铵 、 potassium carbonate 作用下， 以 甲苯 、 乙腈 为溶剂， 反应 2.0h， 生成 5-(2-fluorophenyl)-2-(1-((2-methoxyphenyl)amino)ethylidene)cyclohexane-1,3-dione
  参考文献：
  名称：

  Novel Colchicine-Site Binders with a Cyclohexanedione Scaffold Identified through a Ligand-Based Virtual Screening Approach

  摘要：

  Vascular disrupting agents (VDAs) constitute an innovative anticancer therapy that targets the tumor endothelium, leading to tumor necrosis. Our approach for the identification of new VDAs has relied on a ligand 3-D shape similarity virtual screening (VS) approach using the ROCS program as the VS tool and as query colchicine and TN-16, which both bind the alpha,beta-tubulin dimer. One of the hits identified, using TN-16 as query, has been explored by the synthesis of its structural analogues, leading to 2-(1-((2-methoxyphenyl)amino)ethylidene)-5-phenylcyclohexane-1,3-dione (compound 16c) with an IC50 = 0.09 +/- 0.01 mu M in HMEC-1 and BAEC, being 100-fold more potent than the initial hit. Compound 16c caused cell cycle arrest in the G2/M phase and interacted with the colchicine-binding site in tubulin, as confirmed by a competition assay with N,N'-ethylenebis(iodoacetamide) and by fluorescence spectroscopy. Moreover, 16c destroyed an established endothelial tubular network at 1 mu M and inhibited the migration and invasion of human breast carcinoma cells at 0.4 mu M. In conclusion, our approach has led to a new chemotype of promising antiproliferative compounds with antimitotic and potential VDA properties.

  DOI：

  10.1021/jm401939g

文献信息

• Novel Colchicine-Site Binders with a Cyclohexanedione Scaffold Identified through a Ligand-Based Virtual Screening Approach
  作者：María-Dolores Canela、María-Jesús Pérez-Pérez、Sam Noppen、Gonzalo Sáez-Calvo、J. Fernando Díaz、María-José Camarasa、Sandra Liekens、Eva-María Priego

  DOI：10.1021/jm401939g

  日期：2014.5.22

  Vascular disrupting agents (VDAs) constitute an innovative anticancer therapy that targets the tumor endothelium, leading to tumor necrosis. Our approach for the identification of new VDAs has relied on a ligand 3-D shape similarity virtual screening (VS) approach using the ROCS program as the VS tool and as query colchicine and TN-16, which both bind the alpha,beta-tubulin dimer. One of the hits identified, using TN-16 as query, has been explored by the synthesis of its structural analogues, leading to 2-(1-((2-methoxyphenyl)amino)ethylidene)-5-phenylcyclohexane-1,3-dione (compound 16c) with an IC50 = 0.09 +/- 0.01 mu M in HMEC-1 and BAEC, being 100-fold more potent than the initial hit. Compound 16c caused cell cycle arrest in the G2/M phase and interacted with the colchicine-binding site in tubulin, as confirmed by a competition assay with N,N'-ethylenebis(iodoacetamide) and by fluorescence spectroscopy. Moreover, 16c destroyed an established endothelial tubular network at 1 mu M and inhibited the migration and invasion of human breast carcinoma cells at 0.4 mu M. In conclusion, our approach has led to a new chemotype of promising antiproliferative compounds with antimitotic and potential VDA properties.