1-(6-methoxy-3′-nitro-[1,1′-biphenyl]-3-yl)-3-(8-methyl-7-((1-methylpiperidin-4-yl)oxy)-2-oxo-2H-chromen-3-yl)urea | 1535221-83-0

• 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: 1-(6-methoxy-3′-nitro-[1,1′-biphenyl]-3-yl)-3-(8-methyl-7-((1-methylpiperidin-4-yl)oxy)-2-oxo-2H-chromen-3-yl)urea
• 英文别名: 1-[4-Methoxy-3-(3-nitrophenyl)phenyl]-3-[8-methyl-7-(1-methylpiperidin-4-yl)oxy-2-oxochromen-3-yl]urea；1-[4-methoxy-3-(3-nitrophenyl)phenyl]-3-[8-methyl-7-(1-methylpiperidin-4-yl)oxy-2-oxochromen-3-yl]urea
• CAS: 1535221-83-0
• 化学式: C₃₀H₃₀N₄O₇
• 分子量: 558.591
• InChiKey: CWNQGKLTGVWZDZ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5
• 重原子数：
  41
• 可旋转键数：
  6
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.27
• 拓扑面积：
  135
• 氢给体数：
  2
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  1-(6-methoxy-3′-nitro-[1,1′-biphenyl]-3-yl)-3-(8-methyl-7-((1-methylpiperidin-4-yl)oxy)-2-oxo-2H-chromen-3-yl)urea 在 palladium on activated charcoal 、 氢气 作用下， 以 甲醇 为溶剂， 反应 4.0h， 以85%的产率得到1-(3′-amino-6-methoxy-[1,1′-biphenyl]-3-yl)-3-(8-methyl-7-((1-methylpiperidin-4-yl)oxy)-2-oxo-2H-chromen-3-yl)urea
  参考文献：
  名称：

  Exploiting Conformational Dynamics in Drug Discovery: Design of C-Terminal Inhibitors of Hsp90 with Improved Activities

  摘要：

  The interaction that occurs between molecules is a dynamic process that impacts both structural and conformational properties of the ligand and the ligand binding site. Herein, we investigate the dynamic cross-talk between a protein and the ligand as a source for new opportunities in ligand design. Analysis of the formation/disappearance of protein pockets produced in response to a first-generation inhibitor assisted in the identification of functional groups that could be introduced onto scaffolds to facilitate optimal binding, which allowed for increased binding with previously uncharacterized regions. MD simulations were used to elucidate primary changes that occur in the Hsp90 C-terminal binding pocket in the presence of first-generation ligands. This data was then used to design ligands that adapt to these receptor conformations, which provides access to an energy landscape that is not visible in a static model. The newly synthesized compounds demonstrated antiproliferative activity at similar to 150 nM concentration. The method identified herein may be used to design chemical probes that provide additional information on structural variations of Hsp90 C-terminal binding site.

  DOI：

  10.1021/ci4005767
• 作为产物：
  描述：

  3-碘-4-甲氧基苯甲酸甲酯 在 (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride 、 叠氮磷酸二苯酯 、 potassium carbonate 、 三乙胺 、 sodium hydroxide 作用下， 以 甲醇 、 二氯甲烷 、 水 、 乙腈 、 苯 为溶剂， 反应 45.0h， 生成 1-(6-methoxy-3′-nitro-[1,1′-biphenyl]-3-yl)-3-(8-methyl-7-((1-methylpiperidin-4-yl)oxy)-2-oxo-2H-chromen-3-yl)urea
  参考文献：
  名称：

  Exploiting Conformational Dynamics in Drug Discovery: Design of C-Terminal Inhibitors of Hsp90 with Improved Activities

  摘要：

  The interaction that occurs between molecules is a dynamic process that impacts both structural and conformational properties of the ligand and the ligand binding site. Herein, we investigate the dynamic cross-talk between a protein and the ligand as a source for new opportunities in ligand design. Analysis of the formation/disappearance of protein pockets produced in response to a first-generation inhibitor assisted in the identification of functional groups that could be introduced onto scaffolds to facilitate optimal binding, which allowed for increased binding with previously uncharacterized regions. MD simulations were used to elucidate primary changes that occur in the Hsp90 C-terminal binding pocket in the presence of first-generation ligands. This data was then used to design ligands that adapt to these receptor conformations, which provides access to an energy landscape that is not visible in a static model. The newly synthesized compounds demonstrated antiproliferative activity at similar to 150 nM concentration. The method identified herein may be used to design chemical probes that provide additional information on structural variations of Hsp90 C-terminal binding site.

  DOI：

  10.1021/ci4005767

文献信息

• Coumarin based Hsp90 inhibitors with urea and ether substituents
  申请人：University of Kansas

  公开号：US10030006B2

  公开（公告）日：2018-07-24

  Compounds of the formulas: wherein: R1-R4, X1, Y1, and A are as defined herein are provided. Pharmaceutical compositions of the compounds are also provided. In some aspects, these compounds are are useful for the treatment of a disease or disorder. In some embodiments, the disease or disorder is a proliferative disease such as cancer.

  提供了以下式子的化合物： 其中：提供了 R1-R4、X1、Y1 和 A 如本文所定义的化合物。还提供了这些化合物的药物组合物。在某些方面，这些化合物可用于治疗疾病或紊乱。在某些实施方案中，疾病或紊乱是增殖性疾病，如癌症。
• COUMARIN BASED HSP90 INHIBITORS WITH UREA AND ETHER SUBSTITUENTS
  申请人：THE UNIVERSITY OF KANSAS

  公开号：US20160289217A1

  公开（公告）日：2016-10-06

  Compounds of the formulas: wherein: R 1 -R 4 , X 1 , Y 1 , and A are as defined herein are provided. Pharmaceutical compositions of the compounds are also provided. In some aspects, these compounds are are useful for the treatment of a disease or disorder. In some embodiments, the disease or disorder is a proliferative disease such as cancer.
• [EN] COUMARIN BASED HSP90 INHIBITORS WITH UREA AND ETHER SUBSTITUENTS<br/>[FR] INHIBITEURS HSP90 À BASE DE COUMARINE À SUBSTITUANTS D'URÉE ET D'ÉTHER
  申请人：UNIV KANSAS

  公开号：WO2015070238A2

  公开（公告）日：2015-05-14

  Compounds of the formulas: wherein: R1-R4, X1, Y1, and A are as defined herein are provided. Pharmaceutical compositions of the compounds are also provided. In some aspects, these compounds are are useful for the treatment of a disease or disorder. In some embodiments, the disease or disorder is a proliferative disease such as cancer.
• Exploiting Conformational Dynamics in Drug Discovery: Design of C-Terminal Inhibitors of Hsp90 with Improved Activities
  作者：Elisabetta Moroni、Huiping Zhao、Brian S. J. Blagg、Giorgio Colombo

  DOI：10.1021/ci4005767

  日期：2014.1.27

  The interaction that occurs between molecules is a dynamic process that impacts both structural and conformational properties of the ligand and the ligand binding site. Herein, we investigate the dynamic cross-talk between a protein and the ligand as a source for new opportunities in ligand design. Analysis of the formation/disappearance of protein pockets produced in response to a first-generation inhibitor assisted in the identification of functional groups that could be introduced onto scaffolds to facilitate optimal binding, which allowed for increased binding with previously uncharacterized regions. MD simulations were used to elucidate primary changes that occur in the Hsp90 C-terminal binding pocket in the presence of first-generation ligands. This data was then used to design ligands that adapt to these receptor conformations, which provides access to an energy landscape that is not visible in a static model. The newly synthesized compounds demonstrated antiproliferative activity at similar to 150 nM concentration. The method identified herein may be used to design chemical probes that provide additional information on structural variations of Hsp90 C-terminal binding site.