2,4,5,6,7-Pentabromo-1-methylbenzimidazole | 787630-12-0

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并咪唑类
• 英文名称: 2,4,5,6,7-Pentabromo-1-methylbenzimidazole
• CAS: 787630-12-0
• 化学式: C₈H₃Br₅N₂
• 分子量: 526.645
• InChiKey: KNJJVITYQSTQKE-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.2
• 重原子数：
  15
• 可旋转键数：
  0
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.12
• 拓扑面积：
  17.8
• 氢给体数：
  0
• 氢受体数：
  1

反应信息

• 作为反应物：
  描述：

  2,4,5,6,7-Pentabromo-1-methylbenzimidazole 在 氢氧化钾 作用下， 以 乙醇 为溶剂， 反应 2.0h， 以83%的产率得到4,5,6,7-Tetrabromo-1-methyl-1,3-dihydro-benzoimidazol-2-one
  参考文献：
  名称：

  Optimization of Protein Kinase CK2 Inhibitors Derived from 4,5,6,7-Tetrabromobenzimidazole

  摘要：

  Casein kinase 2 (CK2) is a ubiquitous, essential, and highly pleiotropic protein kinase whose abnormally high constitutive activity is suspected to underlie its pathogenic potential in neoplasia and infective diseases. Thus, CK2 inhibitors designed to dissect the signaling pathways affected by this kinase, in perspective, may give rise to pharmacological tools. One of the most successful CK2 inhibitors is TBB (4,5,6,7-tetrabromobenzotriazole). Here we show that its inhibitory properties can be markedly improved by generating adducts in which N-2 is replaced by a carbon atom bound to a variety of polar functions. The most efficient inhibitor is 4,5,6,7-tetrabromo-2-(dimethylamino)benzimidazole (2c) followed by the methylsulfanyl (8), isopropylamino (2e), and amino (2a) congeners. All these compounds display K-i values < 100 nM (40 nM in the case of 2c). 2c induces apoptosis of Jurkat cells more readily than TBB (DC50 value 2.7 vs 17 muM) and, unlike TBB, it does not display any side effect on mitochondria polarization up to 10 muM concentration. Molecular modeling of the CK2-2c complex, based on the crystal structure of the CK2-TBB complex suggests that a number of additional apolar contacts between its two methyl groups and hydrophobic residues nearby could account for its superior inhibitory properties. Consequently, 2c is even more susceptible than TBB to mutations of the unique hydrophobic residues V66 and/or I174 to alanine. We propose to adopt 2c as first choice CK2 inhibitor instead of TBB, especially for in cell studies.

  DOI：

  10.1021/jm049854a
• 作为产物：
  描述：

  硫酸二甲酯 、 2,4,5,6,7-五溴-1H-苯并咪唑 在 氢氧化钾 作用下， 以 乙醇 为溶剂， 以79%的产率得到2,4,5,6,7-Pentabromo-1-methylbenzimidazole
  参考文献：
  名称：

  Optimization of Protein Kinase CK2 Inhibitors Derived from 4,5,6,7-Tetrabromobenzimidazole

  摘要：

  Casein kinase 2 (CK2) is a ubiquitous, essential, and highly pleiotropic protein kinase whose abnormally high constitutive activity is suspected to underlie its pathogenic potential in neoplasia and infective diseases. Thus, CK2 inhibitors designed to dissect the signaling pathways affected by this kinase, in perspective, may give rise to pharmacological tools. One of the most successful CK2 inhibitors is TBB (4,5,6,7-tetrabromobenzotriazole). Here we show that its inhibitory properties can be markedly improved by generating adducts in which N-2 is replaced by a carbon atom bound to a variety of polar functions. The most efficient inhibitor is 4,5,6,7-tetrabromo-2-(dimethylamino)benzimidazole (2c) followed by the methylsulfanyl (8), isopropylamino (2e), and amino (2a) congeners. All these compounds display K-i values < 100 nM (40 nM in the case of 2c). 2c induces apoptosis of Jurkat cells more readily than TBB (DC50 value 2.7 vs 17 muM) and, unlike TBB, it does not display any side effect on mitochondria polarization up to 10 muM concentration. Molecular modeling of the CK2-2c complex, based on the crystal structure of the CK2-TBB complex suggests that a number of additional apolar contacts between its two methyl groups and hydrophobic residues nearby could account for its superior inhibitory properties. Consequently, 2c is even more susceptible than TBB to mutations of the unique hydrophobic residues V66 and/or I174 to alanine. We propose to adopt 2c as first choice CK2 inhibitor instead of TBB, especially for in cell studies.

  DOI：

  10.1021/jm049854a

文献信息

• Modified tetrahalogenated benzimidazoles with CK2 inhibitory activity are active against human prostate cancer cells LNCaP in vitro
  作者：Carolin C. Schneider、Sabine Kartarius、Mathias Montenarh、Andrzej Orzeszko、Zygmunt Kazimierczuk

  DOI：10.1016/j.bmc.2012.05.038

  日期：2012.7

  A series of novel CK2 inhibitors, tetrahalogenated benzimidazoles carrying an aminoalkylamino group at position 2, has been prepared by nucleophilic substitution of the respective 2,4,5,6,7-pentabromobenzimidazoles and 2-bromo-4,5,6,7-tetraiodobenzimidazoles. The new derivatives as well as some previously obtained tetrahalogenobenzimidazoles, including 4,5,6,7-tetrabromobenzimidazole (TBI) and 4,5,6,7-tetraiodobenzimidazole (TIBI), were evaluated for activity against the hormone-sensitive human prostate cancer cell line LNCaP. The activity of 2-aminoalkylamino derivatives was notably higher (LD50 4.75-9.37 mu M) than that of TBI and TIBI (LD50 approximate to 20 mu M). The determination of the LD50 value identified the 2-aminoethylamino-4,5,6,7-tetraiodobenzimidazole with an additional methyl group at position 1 (6) as the most efficient compound (LD50: 4.75 +/- 1.02 mu M). Interestingly, there was no clear correlation between cell viability and apoptosis induction indicating additional cell death mechanisms. (C) 2012 Elsevier Ltd. All rights reserved.
• Optimization of Protein Kinase CK2 Inhibitors Derived from 4,5,6,7-Tetrabromobenzimidazole
  作者：Mario A. Pagano、Mariola Andrzejewska、Maria Ruzzene、Stefania Sarno、Luca Cesaro、Jenny Bain、Matthew Elliott、Flavio Meggio、Zygmunt Kazimierczuk、Lorenzo A. Pinna

  DOI：10.1021/jm049854a

  日期：2004.12.1

  Casein kinase 2 (CK2) is a ubiquitous, essential, and highly pleiotropic protein kinase whose abnormally high constitutive activity is suspected to underlie its pathogenic potential in neoplasia and infective diseases. Thus, CK2 inhibitors designed to dissect the signaling pathways affected by this kinase, in perspective, may give rise to pharmacological tools. One of the most successful CK2 inhibitors is TBB (4,5,6,7-tetrabromobenzotriazole). Here we show that its inhibitory properties can be markedly improved by generating adducts in which N-2 is replaced by a carbon atom bound to a variety of polar functions. The most efficient inhibitor is 4,5,6,7-tetrabromo-2-(dimethylamino)benzimidazole (2c) followed by the methylsulfanyl (8), isopropylamino (2e), and amino (2a) congeners. All these compounds display K-i values < 100 nM (40 nM in the case of 2c). 2c induces apoptosis of Jurkat cells more readily than TBB (DC50 value 2.7 vs 17 muM) and, unlike TBB, it does not display any side effect on mitochondria polarization up to 10 muM concentration. Molecular modeling of the CK2-2c complex, based on the crystal structure of the CK2-TBB complex suggests that a number of additional apolar contacts between its two methyl groups and hydrophobic residues nearby could account for its superior inhibitory properties. Consequently, 2c is even more susceptible than TBB to mutations of the unique hydrophobic residues V66 and/or I174 to alanine. We propose to adopt 2c as first choice CK2 inhibitor instead of TBB, especially for in cell studies.