5-(3-(4-bromophenyl)-5-(2-chloro-7-ethoxyquinolin-3-yl)-4,5-dihydro-1H-pyrazol-1-yl)-5-oxopentanoic acid

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 喹啉及其衍生物
• 英文名称: 5-(3-(4-bromophenyl)-5-(2-chloro-7-ethoxyquinolin-3-yl)-4,5-dihydro-1H-pyrazol-1-yl)-5-oxopentanoic acid
• 英文别名: 5-[5-(4-Bromophenyl)-3-(2-chloro-7-ethoxyquinolin-3-yl)-3,4-dihydropyrazol-2-yl]-5-oxopentanoic acid
• 化学式: C₂₅H₂₃BrClN₃O₄
• 分子量: 544.832
• InChiKey: BBEILKGKJBLZAZ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.7
• 重原子数：
  34
• 可旋转键数：
  8
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.28
• 拓扑面积：
  92.1
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  N-(3-氨丙基)吗啉 、 5-(3-(4-bromophenyl)-5-(2-chloro-7-ethoxyquinolin-3-yl)-4,5-dihydro-1H-pyrazol-1-yl)-5-oxopentanoic acid 在 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 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 18.5h， 以80%的产率得到5-(3-(4-bromophenyl)-5-(2-chloro-7-ethoxyquinolin-3-yl)-4,5-dihydro-1H-pyrazol-1-yl)-N-(3-morpholinopropyl)-5-oxopentanamide
  参考文献：
  名称：

  Structure-Guided Optimization of Replication Protein A (RPA)–DNA Interaction Inhibitors

  摘要：

  Replication protein A (RPA) is the major human single stranded DNA (ssDNA)-binding protein, playing essential roles in DNA replication, repair, recombination, and DNA-damage response (DDR). Inhibition of RPA-DNA interactions represents a therapeutic strategy for cancer drug discovery and has great potential to provide single agent anticancer activity and to synergize with both common DNA damaging chemotherapeutics and newer targeted anticancer agents. In this letter, a new series of analogues based on our previously reported TDRL-551 (4) compound were designed to improve potency and physicochemical properties. Molecular docking studies guided molecular insights, and further SAR exploration led to the identification of a series of novel compounds with low micromolar RPA inhibitory activity, increased solubility, and excellent cellular up-take. Among a series of analogues, compounds 43, 44, 45, and 46 hold promise for further development of novel anticancer agents.

  DOI：

  10.1021/acsmedchemlett.9b00440
• 作为产物：
  描述：

  间氨基苯乙醚 在 4-二甲氨基吡啶 、 一水合肼 、 N,N-二异丙基乙胺 、 sodium hydroxide 、 三氯氧磷 作用下， 以 乙醇 、 二氯甲烷 、 氯仿 、 水 为溶剂， 反应 10.34h， 生成 5-(3-(4-bromophenyl)-5-(2-chloro-7-ethoxyquinolin-3-yl)-4,5-dihydro-1H-pyrazol-1-yl)-5-oxopentanoic acid
  参考文献：
  名称：

  Structure-Guided Optimization of Replication Protein A (RPA)–DNA Interaction Inhibitors

  摘要：

  Replication protein A (RPA) is the major human single stranded DNA (ssDNA)-binding protein, playing essential roles in DNA replication, repair, recombination, and DNA-damage response (DDR). Inhibition of RPA-DNA interactions represents a therapeutic strategy for cancer drug discovery and has great potential to provide single agent anticancer activity and to synergize with both common DNA damaging chemotherapeutics and newer targeted anticancer agents. In this letter, a new series of analogues based on our previously reported TDRL-551 (4) compound were designed to improve potency and physicochemical properties. Molecular docking studies guided molecular insights, and further SAR exploration led to the identification of a series of novel compounds with low micromolar RPA inhibitory activity, increased solubility, and excellent cellular up-take. Among a series of analogues, compounds 43, 44, 45, and 46 hold promise for further development of novel anticancer agents.

  DOI：

  10.1021/acsmedchemlett.9b00440

文献信息

• [EN] REPLICATION PROTEIN A (RPA)-DNA INTERACTION INHIBITORS<br/>[FR] INHIBITEURS DE L'INTERACTION PROTÉINE A DE RÉPLICATION (RPA)-ADN
  申请人：UNIV INDIANA TRUSTEES

  公开号：WO2021119242A1

  公开（公告）日：2021-06-17

  This invention relates to RPA compounds or pharmaceutically acceptable salts thereof, and for the use of the compounds to treat cancer.

  这项发明涉及RPA化合物或其药用盐，以及利用这些化合物治疗癌症的用途。
• Materials and method for inhibiting replication protein A and uses thereof
  申请人：INDIANA UNIVERSITY RESEARCH AND TECHNOLOGY CORPORATION

  公开号：US10774063B2

  公开（公告）日：2020-09-15

  Targeting uncontrolled cell proliferation and resistance to DNA damaging chemotherapeutics with at least one reagent has significant potential in cancer treatment. Replication Protein A, the eukaryotic single-strand (ss) DNA binding protein, is essential for genomic maintenance and stability via roles in both DNA replication and repair. Reported herein are small molecules that inhibit the in vitro, in vivo, and cellular ssDNA binding activity of RPA, thereby disrupting the eukaryotic cell cycle, inducing cytotoxicity and increasing the efficacy of chemotherapeutic agents damage DNA, and/or disrupt its replication and/or function. These results provide new insights into the mechanism of RPA-ssDNA interactions in chromosome maintenance and stability. This represents a molecularly targeted eukaryotic DNA binding inhibitor and demonstrates the utility of targeting a protein-DNA interaction as a means of studying the cell cycle and providing a therapeutic strategy for cancer treatment.

  用至少一种试剂来靶向不受控制的细胞增殖和对 DNA 损伤性化疗药物的抗性，在癌症治疗中具有巨大的潜力。复制蛋白 A 是真核生物单链（ss）DNA 结合蛋白，通过在 DNA 复制和修复中发挥作用，对基因组的维护和稳定至关重要。本文报告的小分子能抑制 RPA 在体外、体内和细胞内的 ssDNA 结合活性，从而扰乱真核细胞周期，诱导细胞毒性，提高化疗药物对 DNA 的损伤和/或破坏其复制和/或功能的疗效。这些结果为研究 RPA-ssDNA 在染色体维护和稳定性中的相互作用机制提供了新的视角。这代表了一种分子靶向真核生物 DNA 结合抑制剂，证明了靶向蛋白质-DNA 相互作用是研究细胞周期的一种手段，并为癌症治疗提供了一种治疗策略。
• Structure-Guided Optimization of Replication Protein A (RPA)–DNA Interaction Inhibitors
  作者：Navnath S. Gavande、Pamela S. VanderVere-Carozza、Katherine S. Pawelczak、Tyler L. Vernon、Matthew R. Jordan、John J. Turchi

  DOI：10.1021/acsmedchemlett.9b00440

  日期：2020.6.11

  Replication protein A (RPA) is the major human single stranded DNA (ssDNA)-binding protein, playing essential roles in DNA replication, repair, recombination, and DNA-damage response (DDR). Inhibition of RPA-DNA interactions represents a therapeutic strategy for cancer drug discovery and has great potential to provide single agent anticancer activity and to synergize with both common DNA damaging chemotherapeutics and newer targeted anticancer agents. In this letter, a new series of analogues based on our previously reported TDRL-551 (4) compound were designed to improve potency and physicochemical properties. Molecular docking studies guided molecular insights, and further SAR exploration led to the identification of a series of novel compounds with low micromolar RPA inhibitory activity, increased solubility, and excellent cellular up-take. Among a series of analogues, compounds 43, 44, 45, and 46 hold promise for further development of novel anticancer agents.