2′-chlorobiphenyl-3,4-diamine | 471240-29-6

• 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: 2′-chlorobiphenyl-3,4-diamine
• 英文别名: 2'-chlorobiphenyl-3,4-diamine；4-(2-Chlorophenyl)benzene-1,2-diamine
• CAS: 471240-29-6
• 化学式: C₁₂H₁₁ClN₂
• 分子量: 218.686
• InChiKey: AIVMLHDMIYGJNR-UHFFFAOYSA-N

物化性质

• 沸点：
  381.2±32.0 °C(Predicted)
• 密度：
  1.277±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.3
• 重原子数：
  15
• 可旋转键数：
  1
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.0
• 拓扑面积：
  52
• 氢给体数：
  2
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  1-ethyl-3-(N-(ethylcarbamoyl)-C-methylsulfanylcarbonimidoyl)urea 、 2′-chlorobiphenyl-3,4-diamine 在 溶剂黄146 作用下， 以 水 为溶剂， 反应 5.0h， 以38%的产率得到1-(6-(2-chlorophenyl)-1H-benzo[d]imidazol-2-yl)-3-ethylurea
  参考文献：
  名称：

  Discovery of New Benzothiazole-Based Inhibitors of Breakpoint Cluster Region-Abelson Kinase Including the T315I Mutant

  摘要：

  The existence of drug resistance caused by mutations in the break-point cluster region-Abelson tyrosine kinase (Bcr-Abl) kinase domain remains a clinical challenge due to limited effective treatment options for chronic myeloid leukemia (CML). Herein we report a novel series of benzothiazole-based inhibitors that are effective against wild-type and T315I mutant Bcr-Abl kinases. The original hit compound, nocodazole, was extensively modified through a structure-based drug design strategy, especially by varying the groups at the C2 and C6 positions of the scaffold. In addition, the introduction of water-solubilizing groups at the terminal ethyl group resulted in enhanced physicochemical properties and potency in cellular inhibition. Several compounds inhibited the kinase activity of both wild-type Bcr-Abl and the T315I mutant with IC50 values in the picomolar range and exhibited good antiproliferative effects on Ba/F3 cell lines transformed with either wild-type or T315I mutant Bcr-Abl.

  DOI：

  10.1021/jm301891t
• 作为产物：
  描述：

  2-氯苯基硼酸 、 4-溴邻苯二胺 在 1,1'-双(二苯膦基)二茂铁二氯化钯(II)二氯甲烷复合物 、 potassium carbonate 作用下， 以 1,4-二氧六环 、 水 为溶剂， 反应 1.5h， 生成 2′-chlorobiphenyl-3,4-diamine
  参考文献：
  名称：

  Discovery of New Benzothiazole-Based Inhibitors of Breakpoint Cluster Region-Abelson Kinase Including the T315I Mutant

  摘要：

  The existence of drug resistance caused by mutations in the break-point cluster region-Abelson tyrosine kinase (Bcr-Abl) kinase domain remains a clinical challenge due to limited effective treatment options for chronic myeloid leukemia (CML). Herein we report a novel series of benzothiazole-based inhibitors that are effective against wild-type and T315I mutant Bcr-Abl kinases. The original hit compound, nocodazole, was extensively modified through a structure-based drug design strategy, especially by varying the groups at the C2 and C6 positions of the scaffold. In addition, the introduction of water-solubilizing groups at the terminal ethyl group resulted in enhanced physicochemical properties and potency in cellular inhibition. Several compounds inhibited the kinase activity of both wild-type Bcr-Abl and the T315I mutant with IC50 values in the picomolar range and exhibited good antiproliferative effects on Ba/F3 cell lines transformed with either wild-type or T315I mutant Bcr-Abl.

  DOI：

  10.1021/jm301891t

文献信息

• Discovery of Picomolar ABL Kinase Inhibitors Equipotent for Wild Type and T315I Mutant via Structure-Based de Novo Design
  作者：Hwangseo Park、Seunghee Hong、Jinhee Kim、Sungwoo Hong

  DOI：10.1021/ja311756u

  日期：2013.6.5

  Although the constitutively activated break-point cluster region-Abelson (ABL) tyrosine kinase is known to cause chronic myelogenous leukemia (CML), the prevalence of drug-resistant ABL mutants has made it difficult to develop effective anti-CML drugs. With the aim to identify new lead compounds for anti-CML drugs, we carried out a structure-based de novo design using the scoring function improved by implementing an accurate solvation free energy term. This approach led to the identification of ABL inhibitors equipotent for the wild type and the most drug-resistant T315I mutant of ABL at the picomolar level. Decomposition analysis of the binding free energy showed that a decrease in the desolvation cost for binding in the ATP-binding site could be as important as the strengthening of enzyme-inhibitor interaction to enhance the potency of an ABL inhibitor with structural modifications. A similar energetic feature was also observed in free energy perturbation (FEP) calculations. Consistent with the previous experimental and computational studies, the hydrogen bond interactions with the backbone groups of Met318 proved to be the most significant binding forces to stabilize the inhibitors in the ATP-binding sites of the wild type and T315I mutant. The results of molecular dynamics simulations indicated that the dynamic stabilities of the hydrogen bonds between the inhibitors and Met318 should also be considered in designing the potent common inhibitors of the wild-type and T315I mutant of ABL.
• TRIBENZIMIDAZOLES USEFUL AS TOPOISOMERASE I INHIBITORS
  申请人：RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY

  公开号：EP0839140A1

  公开（公告）日：1998-05-06
• [EN] TRIBENZIMIDAZOLES USEFUL AS TOPOISOMERASE I INHIBITORS<br/>[FR] UTILISATION DE TRISBENZIMIDAZOLS EN TANT QU'INHIBITEURS DE LA TOPOISOMERASE I
  申请人：RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY

  公开号：WO1996036612A1

  公开（公告）日：1996-11-21

  (EN) The present invention provides anti-neoplastic topoisomerase I inhibitors of formula (I) wherein Ar is (C6-C12)aryl or (5- to 12-membered) heteroaryl comprising 1-3 N, S or non peroxyde O, wherein N is unsubstituted or is substituted with (C1-C4)alkyl; X is H, CN, CHO, OH, acetyl, CF3, O(C1-C4)alkyl, NO2, NH2, halogen or halo-(C1-C4)alkyl; each Y is individually H, (C1-C4)alkyl or aralkyl; Y' is H or (C1-C4)alkyl; n is 0 or 1; and each Z is individually H, (C1-C4)alkyl, halogen or halo(C1-C4)alkyl; or a pharmaceutically acceptable salt thereof.(FR) Cette invention concerne des inhibiteurs anti-néoplasiques de la topoisomérase I, de la formule (I), ou un sel de ceux-ci acceptable du point de vue pharmaceutique. Dans cette formule, Ar représente un aryle en C6-C12 ou un hétéroaryle (comportant de 5 à 12 éléments) comprenant 1-3 N, S ou O non peroxydé, N n'étant pas substitué ou substitué par alkyle en C1-C4, X représente H, CN, CHO, OH, acétyle, CF3, O(C1-C4)alkyle, NO2, NH2, halogène ou haloalkyle (C1-C4); chaque Y est individuellement H, alkyle (C1-C4) ou aralkyle, Y' représente H ou alkyle (C1-C4), n vaut 0 ou 1 et chaque Z est individuellement H, alkyle (C1-C4), halogène ou haloalkyle (C1-C4).
• Discovery of New Benzothiazole-Based Inhibitors of Breakpoint Cluster Region-Abelson Kinase Including the T315I Mutant
  作者：Seunghee Hong、Jinhee Kim、Sun-Mi Yun、Hyunseung Lee、Yoonsu Park、Soon-Sun Hong、Sungwoo Hong

  DOI：10.1021/jm301891t

  日期：2013.5.9

  The existence of drug resistance caused by mutations in the break-point cluster region-Abelson tyrosine kinase (Bcr-Abl) kinase domain remains a clinical challenge due to limited effective treatment options for chronic myeloid leukemia (CML). Herein we report a novel series of benzothiazole-based inhibitors that are effective against wild-type and T315I mutant Bcr-Abl kinases. The original hit compound, nocodazole, was extensively modified through a structure-based drug design strategy, especially by varying the groups at the C2 and C6 positions of the scaffold. In addition, the introduction of water-solubilizing groups at the terminal ethyl group resulted in enhanced physicochemical properties and potency in cellular inhibition. Several compounds inhibited the kinase activity of both wild-type Bcr-Abl and the T315I mutant with IC50 values in the picomolar range and exhibited good antiproliferative effects on Ba/F3 cell lines transformed with either wild-type or T315I mutant Bcr-Abl.