2,4,5,6,7-五溴-1H-苯并咪唑 | 16865-25-1

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并咪唑类
• 中文名称: 2,4,5,6,7-五溴-1H-苯并咪唑
• 英文名称: 2,4,5,6,7-pentabromo-1H-benzimidazole
• 英文别名: TBI；2,4, 5,6,7-pentabromobenzimidazole；2,4,5,6,7-Pentabromo-1H-benzo[d]imidazole
• CAS: 16865-25-1
• 化学式: C₇HBr₅N₂
• 分子量: 512.618
• InChiKey: RKIBZFOZIJTIJU-UHFFFAOYSA-N

物化性质

• 熔点：
  269-270 °C(Solv: methanol (67-56-1); water (7732-18-5))
• 沸点：
  541.3±60.0 °C(Predicted)
• 密度：
  2.912±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  5.3
• 重原子数：
  14
• 可旋转键数：
  0
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.0
• 拓扑面积：
  28.7
• 氢给体数：
  1
• 氢受体数：
  1

安全信息

• 海关编码：
  2933990090

反应信息

• 作为反应物：
  描述：

  2,4,5,6,7-五溴-1H-苯并咪唑 在 氨 作用下， 以 甲醇 为溶剂， 以36%的产率得到Tetrabrom-2-aminobenzimidazol
  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：

  1H-苯并咪唑-2-硫醇 在 氢溴酸 、 溴 、 溶剂黄146 作用下， 以 水 为溶剂， 反应 34.0h， 生成 2,4,5,6,7-五溴-1H-苯并咪唑
  参考文献：
  名称：

  新型人蛋白激酶CK2和PIM-1双重抑制剂的合成及抗癌活性

  摘要：

  CK2 和 PIM-1 是丝氨酸/苏氨酸激酶，参与许多重要过程的调节，例如增殖、分化和凋亡。抑制 CK2 和 PIM-1 激酶活性已被证明可以通过诱导细胞凋亡来显着降低癌细胞的活力。设计并合成了一系列新型亲本 DMAT 氨基醇衍生物作为有效的双重 CK2/PIM-1 抑制剂。伴随着对重组CK2和PIM-1的抑制研究，获得的化合物对三种人癌细胞系，即急性淋巴细胞白血病(CCRF-CEM)、人慢性粒细胞白血病(K-562)、使用 MTT 测定评估乳腺癌 (MCF-7) 以及非癌细胞 (Vero)。通过基于流式细胞术的测定研究了用最具活性的化合物和先导化合物处理后的细胞凋亡和细胞周期进程的诱导。此外，分别通过定性/定量荧光测定和蛋白质印迹法评估了 K-562 细胞中的自噬诱导以及所有测试细胞系中 CK2 和 PIM-1 的细胞内抑制。在新开发的抑制剂中，1,1,1-三氟-3-[(4,5,6,7-

  DOI：

  10.3390/pharmaceutics15071991

文献信息

• From a MMP2/CK2 multitarget approach to the identification of potent and selective MMP13 inhibitors
  作者：Miryam Pastor、José María Zapico、Claire Coderch、Maciej Maslyk、Rostyslav Panchuk、Beatriz de Pascual-Teresa、Ana Ramos

  DOI：10.1039/c8ob02990c

  日期：——

  MMP2/CK2 dual targeting inhibitors. We have followed a rational drug design approach based on our experience in the selective inhibition of these two enzymes. We have successfully obtained highly active MMP2 (10, IC50 = 70 nM; 11, IC50 = 100 nM) and CK2 (16a, IC50 = 500 nM) inhibitors. However, structural fine tuning of these small molecules to simultaneously target both enzymes turned out to be an unattainable

  在本文中，我们描述了我们在寻找MMP2 / CK2双重靶向抑制剂方面的努力。我们根据选择性抑制这两种酶的经验，采用了合理的药物设计方法。我们已经成功获得了高活性的MMP2（10，IC 50 = 70 nM; 11，IC 50 = 100 nM）和CK2（16a，IC 50 = 500 nM）抑制剂。然而，对这些小分子进行结构微调以同时靶向两种酶被证明是无法实现的目标。出乎意料的是，我们很幸运地发现了新的选择性MMP13抑制剂（10，IC 50 = 3.7 nM和11，IC 50= 5.6 nM）的TBB衍生支架。这些化合物构成了进一步优化的有趣起点。
• [EN] NEW DERIVATIVES OF 4, 5, 6, 7-TETRABROMOBENZIMIDAZOLE AND METHOD OF THEIR PREPARATION<br/>[FR] NOUVEAUX DERIVES DE 4, 5, 6, 7-TETRABROMOBENZIMIDAZOLE ET PROCEDE POUR LES PREPARER
  申请人：FUNDACJA ROZWOJU DIAGNOSTYKI I

  公开号：WO2005092866A1

  公开（公告）日：2005-10-06

  New derivatives of 4, 5, 6, 7-tetrabromobenzimidazole of formula (I); wherein R1 is hydrogen or aliphatic group, R2 is aliphatic group optionally substituted with hydrogen or substituent such as hydroxyl group or substituted amino group and method of their preparation.

  4, 5, 6, 7-四溴苯并咪唑的新衍生物的公式(I)；其中R1是氢或脂肪基团，R2是脂肪基团，可选地取代为氢或诸如羟基或取代氨基等取代基，以及其制备方法。
• Multitarget Anticancer Agents Based on Histone Deacetylase and Protein Kinase CK2 Inhibitors
  作者：Regina Martínez、Bruno Di Geronimo、Miryam Pastor、José María Zapico、Claire Coderch、Rostyslav Panchuk、Nadia Skorokhyd、Maciej Maslyk、Ana Ramos、Beatriz de Pascual-Teresa

  DOI：10.3390/molecules25071497

  日期：——

  The design of multitarget drugs (MTDs) has become an innovative approach for the search of effective treatments in complex diseases such as cancer. In this work, we communicate our efforts in the design of multi-targeting histone deacetylase (HDAC) and protein kinase CK2 inhibitors as a novel therapeutic strategy against cancer. Using tetrabromobenzotriazole (TBB) and 2-dimethylamino-4,5,6,7-tetrabromo-benzimidazole (DMAT) as scaffolds for CK2 inhibition, and a hydroxamate to coordinate the zinc atom present in the active site of HDAC (zinc binding group, ZBG), new multitarget inhibitors have been designed and synthesized. According to the in vitro assays, N-Hydroxy-6-(4,5,6,7-tetrabromo-2-(dimethylamino)-1H-benzo[d]imidazol-1-yl)hexanamide (11b) is the most interesting compound, with IC50 values of 0.66; 1.46 and 3.67 µM. for HDAC6; HDAC1 and CK2; respectively. Cellular assays on different cancer cell lines rendered promising results for N-Hydroxy-8-(4,5,6,7-tetrabromo-2-(dimethylamino)-1H-benzo[d]imidazol-1-yl)octanamide (11d). This inhibitor presented the highest cytotoxic activity, proapoptotic capability, and the best mitochondria-targeting and multidrug-circumventing properties, thus being the most promising drug candidate for further in vivo studies.

  多靶点药物（MTDs）的设计已经成为在复杂疾病如癌症中寻找有效治疗方法的创新途径。在这项工作中，我们介绍了我们在设计多靶点组蛋白去乙酰化酶（HDAC）和蛋白激酶CK2抑制剂方面的努力，作为一种新的抗癌治疗策略。使用四溴苯并三唑（TBB）和2-二甲基氨基-4,5,6,7-四溴苯并咪唑（DMAT）作为CK2抑制的支架，并使用一个羟肟酸基团来配位HDAC活性位点中的锌原子（锌结合基团，ZBG），设计并合成了新的多靶点抑制剂。根据体外实验，N-羟基-6-(4,5,6,7-四溴-2-(二甲基氨基)-1H-苯并[d]咪唑-1-基)己酰胺（11b）是最有趣的化合物，其HDAC6；HDAC1和CK2的IC50值分别为0.66；1.46和3.67微米。对不同癌细胞系的细胞实验为N-羟基-8-(4,5,6,7-四溴-2-(二甲基氨基)-1H-苯并[d]咪唑-1-基)辛酰胺（11d）提供了有希望的结果。该抑制剂表现出最高的细胞毒活性、促凋亡能力，以及最佳的靶向线粒体和多药耐受性，因此是最有前景的药物候选化合物，值得进一步进行体内研究。
• A compound, a process for its preparation, a pharmaceutical composition, use of a compound, a method for modulating or regulating serine/threonine kinases and a serine/threonine kinases modulating agent
  申请人：SELVITA S.A.

  公开号：EP2366695A1

  公开（公告）日：2011-09-21

  The subject of the inventions are a compound, a process for its preparation, a pharmaceutical composition, use of a compound, a method for modulating or regulating serine/threonine kinases and a serine/threonine kinases modulating agent. The present invention relates to novel small-molecule compounds with kinase inhibitory activity, having superior properties as pharmaceutical agents, production method thereof and uses thereof. In particular, this invention relates to new derivatives of tetrabromobenzimidazole with serine/threonine kinases inhibitory properties, preferably selected from the group of Pim, HIPK, DYRK and CLK kinases, which exhibits superior pharmacological actions, and can be useful for the treatment of disease conditions, especially cancers depending on serine/threonine kinases, such as leukemias and prostate cancer.

  这些发明的主题是一种化合物，其制备方法，一种药物组合物，一种化合物的用途，一种调节丝氨酸/苏氨酸激酶的方法和丝氨酸/苏氨酸激酶调节剂。本发明涉及具有激酶抑制活性的新型小分子化合物，具有作为药物剂的优越性能，其生产方法及用途。具体而言，本发明涉及新型四溴苯并咪唑衍生物，具有丝氨酸/苏氨酸激酶抑制性质，优选来自Pim、HIPK、DYRK和CLK激酶组的，表现出优越的药理作用，并可用于治疗疾病状况，尤其是依赖于丝氨酸/苏氨酸激酶的癌症，如白血病和前列腺癌。
• DERIVATIVES OF TETRABROMOBENZIMIDAZOLE, A PROCESS FOR THE PREPARATION THEREOF, A PHARMACEUTICAL COMPOSITION COMPRISING THE SAME, A METHOF OF USING THE SAME, A METHOD FOR MODULATING OR REGULATING SERINE/THREONINE KINASES, AND SERINE/THREONINE KINASES MODULATING AGENT
  申请人：Brzozka Krzysztof

  公开号：US20110112091A1

  公开（公告）日：2011-05-12

  A derivative of tetrabromobenzimidazole, a process for the preparation thereof, a pharmaceutical composition, a method for using the same, a method for modulating or regulating serine/threonine kinases, and a serine/threonine kinases modulating agent. The invention relates to novel small-molecule compounds with kinase inhibitory activity, having superior properties as pharmaceutical agents, production method thereof and uses thereof. In particular, this invention relates to new derivatives of tetrabromobenzimidazole with Pim kinases inhibitory properties, which exhibits superior pharmacological actions, and can be useful for the treatment of disease conditions, especially cancers depending on Pim kinases, such as leukemias and prostate cancer.

  一种四溴苯并咪唑的衍生物，其制备方法，一种药物组合物，一种使用该衍生物的方法，一种调节丝氨酸/苏氨酸激酶的方法，以及一种丝氨酸/苏氨酸激酶调节剂。该发明涉及具有激酶抑制活性的新型小分子化合物，具有作为药物剂的优越性能，其生产方法和用途。具体而言，本发明涉及具有Pim激酶抑制性能的四溴苯并咪唑的新衍生物，表现出卓越的药理作用，并可用于治疗疾病，特别是依赖于Pim激酶的白血病和前列腺癌等癌症。