7-Chloro-8-hydroxy-3-oxo-11,16-dioxa-2,4,19,21-tetrazatricyclo[15.3.1.05,10]henicosa-1(20),5,7,9,17(21),18-hexaene-18-carbonitrile | 1000807-33-9

• 分子结构分类: 有机化合物 - 苯类化合物 - 酚类
• 英文名称: 7-Chloro-8-hydroxy-3-oxo-11,16-dioxa-2,4,19,21-tetrazatricyclo[15.3.1.05,10]henicosa-1(20),5,7,9,17(21),18-hexaene-18-carbonitrile
• 英文别名: 7-chloro-8-hydroxy-3-oxo-11,16-dioxa-2,4,19,21-tetrazatricyclo[15.3.1.05,10]henicosa-1(20),5,7,9,17(21),18-hexaene-18-carbonitrile
• CAS: 1000807-33-9
• 化学式: C₁₆H₁₄ClN₅O₄
• 分子量: 375.771
• InChiKey: LBIUHSYVFSGYOS-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.8
• 重原子数：
  26
• 可旋转键数：
  0
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.25
• 拓扑面积：
  129
• 氢给体数：
  3
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  7-Chloro-8-hydroxy-3-oxo-11,16-dioxa-2,4,19,21-tetrazatricyclo[15.3.1.05,10]henicosa-1(20),5,7,9,17(21),18-hexaene-18-carbonitrile 、 1-溴-3-甲氧基丙烷 在 caesium carbonate 作用下， 生成 7-Chloro-8-(3-methoxypropoxy)-3-oxo-11,16-dioxa-2,4,19,21-tetrazatricyclo[15.3.1.05,10]henicosa-1(20),5,7,9,17(21),18-hexaene-18-carbonitrile
  参考文献：
  名称：

  Macrocyclic ureas as potent and selective Chk1 inhibitors: An improved synthesis, kinome profiling, structure–activity relationships, and preliminary pharmacokinetics

  摘要：

  A new series of potent macrocyclic urea-based Chk1 inhibitors are described. A detailed SAR study on the 4-position of the phenyl ring of the 14-member macrocyclic ureas 1a and d led to the identification of the potent Chk1 inhibitors 2, 5-7, 10, 13, 14, 19-21, 25, 27, and 31-34. These compounds significantly sensitize tumor cells to the DNA-damaging antitumor agent doxorubicin in a cell-based assay and efficiently abrogate the doxorubicin-induced G2/M and camptothecin-induced S checkpoints, indicating that the potent biological activities of these compounds are mechanism-based through Chk1 inhibition. Kinome pro. ling analysis of a representative macrocyclic urea 25 against a panel of 120 kinases indicates that these novel macrocyclic ureas are highly selective Chk1 inhibitors. Preliminary PK studies of 1a and b suggest that the 14-member macrocyclic inhibitors may possess better PK properties than their 15-member counterparts. An improved synthesis of 2 and 20 by using 2-(trimethylsilyl) ethoxycarbonyl (Teoc) to protect the amino group not only readily provided the desired compounds in pure form but also facilitated the scale up of potent compounds for various biological studies. (c) 2007 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2007.09.063
• 作为产物：
  描述：

  在 盐酸 作用下， 以 1,4-二氧六环 、 乙醇 、 二氯甲烷 为溶剂， 以95%的产率得到7-Chloro-8-hydroxy-3-oxo-11,16-dioxa-2,4,19,21-tetrazatricyclo[15.3.1.05,10]henicosa-1(20),5,7,9,17(21),18-hexaene-18-carbonitrile
  参考文献：
  名称：

  Macrocyclic ureas as potent and selective Chk1 inhibitors: An improved synthesis, kinome profiling, structure–activity relationships, and preliminary pharmacokinetics

  摘要：

  A new series of potent macrocyclic urea-based Chk1 inhibitors are described. A detailed SAR study on the 4-position of the phenyl ring of the 14-member macrocyclic ureas 1a and d led to the identification of the potent Chk1 inhibitors 2, 5-7, 10, 13, 14, 19-21, 25, 27, and 31-34. These compounds significantly sensitize tumor cells to the DNA-damaging antitumor agent doxorubicin in a cell-based assay and efficiently abrogate the doxorubicin-induced G2/M and camptothecin-induced S checkpoints, indicating that the potent biological activities of these compounds are mechanism-based through Chk1 inhibition. Kinome pro. ling analysis of a representative macrocyclic urea 25 against a panel of 120 kinases indicates that these novel macrocyclic ureas are highly selective Chk1 inhibitors. Preliminary PK studies of 1a and b suggest that the 14-member macrocyclic inhibitors may possess better PK properties than their 15-member counterparts. An improved synthesis of 2 and 20 by using 2-(trimethylsilyl) ethoxycarbonyl (Teoc) to protect the amino group not only readily provided the desired compounds in pure form but also facilitated the scale up of potent compounds for various biological studies. (c) 2007 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2007.09.063

文献信息

• Macrocyclic ureas as potent and selective Chk1 inhibitors: An improved synthesis, kinome profiling, structure–activity relationships, and preliminary pharmacokinetics
  作者：Zhi-Fu Tao、Zehan Chen、Mai-Ha Bui、Peter Kovar、Eric Johnson、Jennifer Bouska、Haiying Zhang、Saul Rosenberg、Thomas Sowin、Nan-Horng Lin

  DOI：10.1016/j.bmcl.2007.09.063

  日期：2007.12

  A new series of potent macrocyclic urea-based Chk1 inhibitors are described. A detailed SAR study on the 4-position of the phenyl ring of the 14-member macrocyclic ureas 1a and d led to the identification of the potent Chk1 inhibitors 2, 5-7, 10, 13, 14, 19-21, 25, 27, and 31-34. These compounds significantly sensitize tumor cells to the DNA-damaging antitumor agent doxorubicin in a cell-based assay and efficiently abrogate the doxorubicin-induced G2/M and camptothecin-induced S checkpoints, indicating that the potent biological activities of these compounds are mechanism-based through Chk1 inhibition. Kinome pro. ling analysis of a representative macrocyclic urea 25 against a panel of 120 kinases indicates that these novel macrocyclic ureas are highly selective Chk1 inhibitors. Preliminary PK studies of 1a and b suggest that the 14-member macrocyclic inhibitors may possess better PK properties than their 15-member counterparts. An improved synthesis of 2 and 20 by using 2-(trimethylsilyl) ethoxycarbonyl (Teoc) to protect the amino group not only readily provided the desired compounds in pure form but also facilitated the scale up of potent compounds for various biological studies. (c) 2007 Elsevier Ltd. All rights reserved.