2-[(E)-2-(2,6-dichlorophenyl)ethenyl]-5-methoxy-1H-indole | 622861-16-9

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吲哚及其衍生物
• 英文名称: 2-[(E)-2-(2,6-dichlorophenyl)ethenyl]-5-methoxy-1H-indole
• CAS: 622861-16-9
• 化学式: C₁₇H₁₃Cl₂NO
• 分子量: 318.202
• InChiKey: MFKBUJSWENHBGR-FNORWQNLSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.6
• 重原子数：
  21
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.06
• 拓扑面积：
  25
• 氢给体数：
  1
• 氢受体数：
  1

反应信息

• 作为反应物：
  描述：

  2-[(E)-2-(2,6-dichlorophenyl)ethenyl]-5-methoxy-1H-indole 在 2,3-二氯-5,6-二氰基-1,4-苯醌 、 tin(ll) chloride 作用下， 以 1,4-二氧六环 、 甲苯 为溶剂， 反应 51.0h， 生成 4-(2,6-dichlorophenyl)-9-methoxypyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione
  参考文献：
  名称：

  4-Phenylpyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione Inhibitors of the Checkpoint Kinase Wee1. Structure−Activity Relationships for Chromophore Modification and Phenyl Ring Substitution

  摘要：

  High-throughput screening has identified a novel class of inhibitors of the checkpoint kinase Wee1, which have potential for use in cancer chemotherapy. These inhibitors are based on a 4-phenylpyrrolo[3,4-c]carbazole- 1,3(2H,6H)-dione template and have been shown by X-ray crystallography to bind at the ATP site of the enzyme. An extensive study of the effects of substitution around this template has been carried out, which has identified substituents which lead to improvements in potency and selectivity for Wee1. While retention of the maleimide ring and pendant 4-phenyl group is necessary for potency, replacement of the carbazole nitrogen by oxygen is well tolerated and results in improved Wee1 selectivity against the related checkpoint kinase Chk1. Wee1 potency and selectivity are also enhanced by the incorporation of lipophilic functionality at the 2'-position of the 4-phenyl ring, and Wee1 selectivity against Chk1 is favored by C3-C5 alkyl substitution of the carbazole nitrogen. These studies provide a basis for the design of active analogues of the pyrrolocarbazole lead with improved physical properties.

  DOI：

  10.1021/jm0512591
• 作为产物：
  描述：

  2,6-二氯苄基溴 在 lithium diisopropyl amide 作用下， 以 四氢呋喃 、 环己烷 、 苯 为溶剂， 反应 23.25h， 生成 2-[(E)-2-(2,6-dichlorophenyl)ethenyl]-5-methoxy-1H-indole
  参考文献：
  名称：

  4-Phenylpyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione Inhibitors of the Checkpoint Kinase Wee1. Structure−Activity Relationships for Chromophore Modification and Phenyl Ring Substitution

  摘要：

  High-throughput screening has identified a novel class of inhibitors of the checkpoint kinase Wee1, which have potential for use in cancer chemotherapy. These inhibitors are based on a 4-phenylpyrrolo[3,4-c]carbazole- 1,3(2H,6H)-dione template and have been shown by X-ray crystallography to bind at the ATP site of the enzyme. An extensive study of the effects of substitution around this template has been carried out, which has identified substituents which lead to improvements in potency and selectivity for Wee1. While retention of the maleimide ring and pendant 4-phenyl group is necessary for potency, replacement of the carbazole nitrogen by oxygen is well tolerated and results in improved Wee1 selectivity against the related checkpoint kinase Chk1. Wee1 potency and selectivity are also enhanced by the incorporation of lipophilic functionality at the 2'-position of the 4-phenyl ring, and Wee1 selectivity against Chk1 is favored by C3-C5 alkyl substitution of the carbazole nitrogen. These studies provide a basis for the design of active analogues of the pyrrolocarbazole lead with improved physical properties.

  DOI：

  10.1021/jm0512591

文献信息

• [EN] INHIBITORS OF CHECKPOINT KINASES (WEE1 AND CHK1)<br/>[FR] INHIBITEURS DE CHECKPOINT KINASES (WEE1 ET CHK1)
  申请人：WARNER LAMBERT CO

  公开号：WO2003091255A1

  公开（公告）日：2003-11-06

  This invention relates to pyrrolocarbazole derivatives according formula (I) wherein R1, R2, r7, R8 R9, X and Y are as defined in the specification wherein said derivatives specifically inhibit one or both of the checkpoint kinases Wee1 and Chk1.

  本发明涉及公式（I）中的吡咯并咔唑衍生物，其中R1，R2，r7，R8，R9，X和Y如规范中所定义，其中所述衍生物特异性地抑制检查点激酶Wee1和Chk1中的一个或两个。
• Inhibitors of checkpoint kinases (Wee1 and Chk1)
  申请人：Pfizer Inc

  公开号：US07094798B1

  公开（公告）日：2006-08-22

  This invention relates to pyrrolocarbazole derivatives according formula I wherein R1, R2, R7, R8, R9, X and Y are as defined in the specification wherein said derivatives specifically inhibit one or both of the checkpoint kinases Wee1 and Chk1

  本发明涉及公式I中的吡咯烷并咔唑衍生物，其中R1、R2、R7、R8、R9、X和Y如规范中所定义，其中这些衍生物特异性抑制检查点激酶Wee1和Chk1中的一个或两个。
• Synthesis and structure–activity relationships of N-6 substituted analogues of 9-hydroxy-4-phenylpyrrolo[3,4-c]carbazole-1,3(2H,6H)-diones as inhibitors of Wee1 and Chk1 checkpoint kinases
  作者：Jeff B. Smaill、Edward N. Baker、R. John Booth、Alexander J. Bridges、James M. Dickson、Ellen M. Dobrusin、Ivan Ivanovic、Alan J. Kraker、Ho H. Lee、Elizabeth A. Lunney、Daniel F. Ortwine、Brian D. Palmer、John Quin、Christopher J. Squire、Andrew M. Thompson、William A. Denny

  DOI：10.1016/j.ejmech.2007.07.016

  日期：2008.6

  A series of N-6 substituted 9-hydroxy-4-phenylpyrrolo[3,4-c]carbazole-1,3(2H,6H)-diones were prepared from N-substituted (5-methoxyphenyl)ethenylindoles. The target compounds were tested for their ability to inhibit the G2/M cell cycle checkpoint kinases, Wee1 and Chk1. Analogues with neutral or cationic N-6 side chains were potent dual inhibitors. Acidic side chains provided potent (average IC(50) 0.057 microM) and selective (average ratio 223-fold) Wee1 inhibition. Co-crystal structures of inhibitors bound to Wee1 show that the pyrrolo[3,4-c]carbazole scaffold binds in the ATP-binding site, with N-6 substituents involved in H-bonding to conserved water molecules. HT-29 cells treated with doxorubicin and then target compounds demonstrate an active Cdc2/cyclin B complex, inhibition of the doxorubicin-induced phosphorylation of tyrosine 15 of Cdc2 and abrogation of the G2 checkpoint.
• INHIBITORS OF CHECKPOINT KINASES (WEE1 AND CHK1)
  申请人：WARNER-LAMBERT COMPANY LLC

  公开号：EP1501831A1

  公开（公告）日：2005-02-02
• US7094798B1
  申请人：——

  公开号：US7094798B1

  公开（公告）日：2006-08-22