(E)-3-(3-(4-bromophenyl)acryloyl)-6-chloro-4-phenylquinolin-2(1H)-one | 1449373-34-5

• 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: (E)-3-(3-(4-bromophenyl)acryloyl)-6-chloro-4-phenylquinolin-2(1H)-one
• 英文别名: 3-[(2E)-3-(4-Bromophenyl)prop-2-enoyl]-6-chloro-4-phenyl-1,2-dihydroquinolin-2-one；3-[(E)-3-(4-bromophenyl)prop-2-enoyl]-6-chloro-4-phenyl-1H-quinolin-2-one
• CAS: 1449373-34-5
• 化学式: C₂₄H₁₅BrClNO₂
• 分子量: 464.746
• InChiKey: WRQUKEGHXPUPAP-MDWZMJQESA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.8
• 重原子数：
  29
• 可旋转键数：
  4
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.0
• 拓扑面积：
  46.2
• 氢给体数：
  1
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  (E)-3-(3-(4-bromophenyl)acryloyl)-6-chloro-4-phenylquinolin-2(1H)-one 在 一水合肼 作用下， 以 四氢呋喃 、 乙醇 为溶剂， 反应 1.5h， 生成 4-(5-(4-bromophenyl)-3-(6-chloro-2-oxo-4-phenyl-1,2-dihydroquinolin-3-yl)-4,5-dihydro-1H-pyrazol-1-yl)-4-oxobutanoic acid
  参考文献：
  名称：

  Synthetic Lethality in Pancreatic Cancer: Discovery of a New RAD51-BRCA2 Small Molecule Disruptor That Inhibits Homologous Recombination and Synergizes with Olaparib

  摘要：

  Synthetic lethality is an innovative framework for discovering novel anticancer drug candidates. One example is the use of PARP inhibitors (PARPi) in oncology patients with BRCA mutations. Here, we exploit a new paradigm based on the possibility of triggering synthetic lethality using only small organic molecules (dubbed "fully small-molecule-induced synthetic lethality"). We exploited this paradigm to target pancreatic cancer, one of the major unmet needs in oncology. We discovered a dihydroquinolone pyrazoline-based molecule (35d) that disrupts the RAD51-BRCA2 protein-protein interaction, thus mimicking the effect of BRCA2 mutation. 35d inhibits the homologous recombination in a human pancreatic adenocarcinoma cell line. In addition, it synergizes with olaparib (a PARPi) to trigger synthetic lethality. This strategy aims to widen the use of PARPi in BRCA-competent and olaparib-resistant cancers, making fully small-molecule-induced synthetic lethality an innovative approach toward unmet oncological needs.

  DOI：

  10.1021/acs.jmedchem.9b01526
• 作为产物：
  描述：

  2-氨基-5-氯二苯甲酮 在 potassium hydroxide 作用下， 以 乙醇 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 19.75h， 生成 (E)-3-(3-(4-bromophenyl)acryloyl)-6-chloro-4-phenylquinolin-2(1H)-one
  参考文献：
  名称：

  Synthetic Lethality in Pancreatic Cancer: Discovery of a New RAD51-BRCA2 Small Molecule Disruptor That Inhibits Homologous Recombination and Synergizes with Olaparib

  摘要：

  Synthetic lethality is an innovative framework for discovering novel anticancer drug candidates. One example is the use of PARP inhibitors (PARPi) in oncology patients with BRCA mutations. Here, we exploit a new paradigm based on the possibility of triggering synthetic lethality using only small organic molecules (dubbed "fully small-molecule-induced synthetic lethality"). We exploited this paradigm to target pancreatic cancer, one of the major unmet needs in oncology. We discovered a dihydroquinolone pyrazoline-based molecule (35d) that disrupts the RAD51-BRCA2 protein-protein interaction, thus mimicking the effect of BRCA2 mutation. 35d inhibits the homologous recombination in a human pancreatic adenocarcinoma cell line. In addition, it synergizes with olaparib (a PARPi) to trigger synthetic lethality. This strategy aims to widen the use of PARPi in BRCA-competent and olaparib-resistant cancers, making fully small-molecule-induced synthetic lethality an innovative approach toward unmet oncological needs.

  DOI：

  10.1021/acs.jmedchem.9b01526

文献信息

• [EN] COMPOUNDS AND COMPOSITIONS FOR THE TREATMENT OF TUMORS<br/>[FR] COMPOSÉS ET COMPOSITIONS POUR LE TRAITEMENT DE TUMEURS
  申请人：FONDAZIONE ST ITALIANO TECNOLOGIA

  公开号：WO2021116999A1

  公开（公告）日：2021-06-17

  The present invention relates to compounds of Formula (Ia) or pharmaceutically acceptable salts, hydrates, solvates, clathrates, polymorphs, stereoisomers thereof. It further discloses a pharmaceutical composition comprising compounds of Formula (Ia) and the use of compounds of Formula (Ib), in particular for the use in the treatment of diseases or disorders wherein disrupting Rad51-BRCA2 interaction is beneficial.

  本发明涉及式(Ia)的化合物或药学上可接受的盐、水合物、溶剂合物、包合物、多晶型、立体异构体，还揭示了包含式(Ia)的化合物的药物组合物以及利用式(Ib)的化合物，特别是用于治疗破坏Rad51-BRCA2相互作用有益的疾病或紊乱的用途。
• Structure–Activity Relationships and Pharmacophore Model of a Noncompetitive Pyrazoline Containing Class of GluN2C/GluN2D Selective Antagonists
  作者：Timothy M. Acker、Alpa Khatri、Katie M. Vance、Cathryn Slabber、John Bacsa、James P. Snyder、Stephen F. Traynelis、Dennis C. Liotta

  DOI：10.1021/jm400652r

  日期：2013.8.22

  Here we describe the synthesis and structure-activity relationship for a class of pyrazoline-containing dihydroquinolone negative allosteric modulators of the NMDA receptor that show strong subunit selectivity for GluN2C- and GluN2D-containing receptors over GluN2A- and GluN2B-containing receptors. Several members of this class inhibit NMDA receptor responses in the nanomolar range and are more than 50-fold selective over GluN1/GluN2A and GluN1/GluN2B NMDA receptors, as well as AMPA, kainate, GABA, glycine, nicotinic, serotonin, and purinergic receptors. Analysis of the purified enantiomers of one of the more potent and selective compounds shows that the S-enantiomer is both more potent and more selective than the R-enantiomer. The S-enantiomer had an IC50 of 0.17-0.22 mu M at GluN2D- and GluN2C-containing receptors, respectively, and showed over 70-fold selectivity over other NMDA receptor subunits. The subunit selectivity of this class of compounds should be useful in defining the role of GluN2C- and GluN2D-containing receptors in specific brain circuits in both physiological and pathophysiological conditions.
• Synthetic Lethality in Pancreatic Cancer: Discovery of a New RAD51-BRCA2 Small Molecule Disruptor That Inhibits Homologous Recombination and Synergizes with Olaparib
  作者：Greta Bagnolini、Domenico Milano、Marcella Manerba、Fabrizio Schipani、Jose Antonio Ortega、Dario Gioia、Federico Falchi、Andrea Balboni、Fulvia Farabegoli、Francesca De Franco、Janet Robertson、Roberto Pellicciari、Isabella Pallavicini、Sebastiano Peri、Saverio Minucci、Stefania Girotto、Giuseppina Di Stefano、Marinella Roberti、Andrea Cavalli

  DOI：10.1021/acs.jmedchem.9b01526

  日期：2020.3.12

  Synthetic lethality is an innovative framework for discovering novel anticancer drug candidates. One example is the use of PARP inhibitors (PARPi) in oncology patients with BRCA mutations. Here, we exploit a new paradigm based on the possibility of triggering synthetic lethality using only small organic molecules (dubbed "fully small-molecule-induced synthetic lethality"). We exploited this paradigm to target pancreatic cancer, one of the major unmet needs in oncology. We discovered a dihydroquinolone pyrazoline-based molecule (35d) that disrupts the RAD51-BRCA2 protein-protein interaction, thus mimicking the effect of BRCA2 mutation. 35d inhibits the homologous recombination in a human pancreatic adenocarcinoma cell line. In addition, it synergizes with olaparib (a PARPi) to trigger synthetic lethality. This strategy aims to widen the use of PARPi in BRCA-competent and olaparib-resistant cancers, making fully small-molecule-induced synthetic lethality an innovative approach toward unmet oncological needs.