methyl 5-(4-(aminomethyl)phenyl)-1-(3,4-dichlorophenyl)-1H-pyrazole-3-carboxylate

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: methyl 5-(4-(aminomethyl)phenyl)-1-(3,4-dichlorophenyl)-1H-pyrazole-3-carboxylate
• 英文别名: Methyl 5-[4-(aminomethyl)phenyl]-1-(3,4-dichlorophenyl)pyrazole-3-carboxylate；methyl 5-[4-(aminomethyl)phenyl]-1-(3,4-dichlorophenyl)pyrazole-3-carboxylate
• 化学式: C₁₈H₁₅Cl₂N₃O₂
• 分子量: 376.242
• InChiKey: WKKFCTHLGJNSGC-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.9
• 重原子数：
  25
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.11
• 拓扑面积：
  70.1
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  methyl 5-(4-(aminomethyl)phenyl)-1-(3,4-dichlorophenyl)-1H-pyrazole-3-carboxylate 在 劳森试剂 、 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 N,N-二异丙基乙胺 、 lithium hydroxide 作用下， 以 四氢呋喃 、 N,N-二甲基甲酰胺 为溶剂， 反应 12.17h， 生成 5-(4-((4-(5-carboxyfuran-2-yl)-2-chlorophenylthioamido)methyl)phenyl)-1-(3,4-dichlorophenyl)-1H-pyrazole-3-carboxylic acid
  参考文献：
  名称：

  Diphenylpyrazoles as Replication Protein A Inhibitors

  摘要：

  Replication Protein A is the primary eukaryotic ssDNA binding protein that has a central role in initiating the cellular response to DNA damage. RPA recruits multiple proteins to sites of DNA damage via the N-terminal domain of the 70 kDa subunit (RPA70N). Here we describe the optimization of a diphenylpyrazole carboxylic acid series of inhibitors of these RPA-protein interactions. We evaluated substituents on the aromatic rings as well as the type and geometry of the linkers used to combine fragments, ultimately leading to submicromolar inhibitors of RPA70N protein-protein interactions.

  DOI：

  10.1021/ml5003629
• 作为产物：
  描述：

  3,4-二氯苯肼盐酸盐 在 氨 、 氢气 、 镍 作用下， 以 甲醇 、 乙醇 为溶剂， 反应 2.5h， 生成 methyl 5-(4-(aminomethyl)phenyl)-1-(3,4-dichlorophenyl)-1H-pyrazole-3-carboxylate
  参考文献：
  名称：

  Discovery of a Potent Inhibitor of Replication Protein A Protein–Protein Interactions Using a Fragment-Linking Approach

  摘要：

  Replication protein A (RPA), the major eukaryotic single-stranded DNA (ssDNA)-binding protein, is involved in nearly all cellular DNA transactions. The RPA N-terminal domain (RPA7ON) is a recruitment site for proteins involved in DNA-damage response and repair. Selective inhibition of these protein protein interactions has the potential to inhibit the DNA-damage response and to sensitize cancer cells to DNA-damaging agents without affecting other functions of RPA. To discover a potent, selective inhibitor of the RPA7ON protein protein interactions to test this hypothesis, we used NMR spectroscopy to identify fragment hits that bind to two adjacent sites in the basic cleft of RPA7ON. High-resolution X-ray crystal structures of RPA70N ligand complexes revealed how these fragments bind to RPA and guided the design of linked compounds that simultaneously occupy both sites. We have synthesized linked submicromolar affinity and minimal disruption of RPA's interaction with ssDNA molecules that bind to RPA7ON with ssDNA.

  DOI：

  10.1021/jm401333u

文献信息

• Diphenylpyrazoles as Replication Protein A Inhibitors
  作者：Alex G. Waterson、J. Phillip Kennedy、James D. Patrone、Nicholas F. Pelz、Michael D. Feldkamp、Andreas O. Frank、Bhavatarini Vangamudi、Elaine M. Souza-Fagundes、Olivia W. Rossanese、Walter J. Chazin、Stephen W. Fesik

  DOI：10.1021/ml5003629

  日期：2015.2.12

  Replication Protein A is the primary eukaryotic ssDNA binding protein that has a central role in initiating the cellular response to DNA damage. RPA recruits multiple proteins to sites of DNA damage via the N-terminal domain of the 70 kDa subunit (RPA70N). Here we describe the optimization of a diphenylpyrazole carboxylic acid series of inhibitors of these RPA-protein interactions. We evaluated substituents on the aromatic rings as well as the type and geometry of the linkers used to combine fragments, ultimately leading to submicromolar inhibitors of RPA70N protein-protein interactions.
• Discovery of a Potent Inhibitor of Replication Protein A Protein–Protein Interactions Using a Fragment-Linking Approach
  作者：Andreas O. Frank、Michael D. Feldkamp、J. Phillip Kennedy、Alex G. Waterson、Nicholas F. Pelz、James D. Patrone、Bhavatarini Vangamudi、DeMarco V. Camper、Olivia W. Rossanese、Walter J. Chazin、Stephen W. Fesik

  DOI：10.1021/jm401333u

  日期：2013.11.27

  Replication protein A (RPA), the major eukaryotic single-stranded DNA (ssDNA)-binding protein, is involved in nearly all cellular DNA transactions. The RPA N-terminal domain (RPA7ON) is a recruitment site for proteins involved in DNA-damage response and repair. Selective inhibition of these protein protein interactions has the potential to inhibit the DNA-damage response and to sensitize cancer cells to DNA-damaging agents without affecting other functions of RPA. To discover a potent, selective inhibitor of the RPA7ON protein protein interactions to test this hypothesis, we used NMR spectroscopy to identify fragment hits that bind to two adjacent sites in the basic cleft of RPA7ON. High-resolution X-ray crystal structures of RPA70N ligand complexes revealed how these fragments bind to RPA and guided the design of linked compounds that simultaneously occupy both sites. We have synthesized linked submicromolar affinity and minimal disruption of RPA's interaction with ssDNA molecules that bind to RPA7ON with ssDNA.