N,N'-((3,6-dimethoxy-2-nitrophenyl)methylene)diformamide | 19819-19-3

• 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: N,N'-((3,6-dimethoxy-2-nitrophenyl)methylene)diformamide
• 英文别名: N,Na(2)-[(3,6-Dimethoxy-2-nitrophenyl)methylene]bis[formamide]；N-[(3,6-dimethoxy-2-nitrophenyl)-formamidomethyl]formamide
• CAS: 19819-19-3
• 化学式: C₁₁H₁₃N₃O₆
• 分子量: 283.241
• InChiKey: OIQLXOVAENUMOX-UHFFFAOYSA-N

物化性质

• 沸点：
  656.3±55.0 °C(Predicted)
• 密度：
  1.338±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  0.3
• 重原子数：
  20
• 可旋转键数：
  5
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.27
• 拓扑面积：
  123
• 氢给体数：
  2
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  N,N'-((3,6-dimethoxy-2-nitrophenyl)methylene)diformamide 在 盐酸 、 硝酸 、 溶剂黄146 、 锌 作用下， 反应 2.75h， 生成 6,7-二氯喹唑啉-5,8-二酮
  参考文献：
  名称：

  Synthesis and antiproliferative activity of new cytotoxic tri- and tetraazabenzo[3,2-a]fluorene-5,6-dione derivatives

  摘要：

  A new series of substituted tri-/tetraazabenzo[3,2-alpha] fluorene-5,6-diones and their corresponding oxime derivatives have been synthesized and spectroscopically characterized. The antiproliferative activities of all compounds were evaluated on at least three different cell lines. (C) 2013 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2013.08.021
• 作为产物：
  描述：

  2,5-二甲氧基苯甲醛 在 盐酸 、 硝酸 、 乙酸酐 作用下， 反应 2.5h， 生成 N,N'-((3,6-dimethoxy-2-nitrophenyl)methylene)diformamide
  参考文献：
  名称：

  一种新型氧化还原调节剂可诱导 GPX4 介导的依赖铁和活性氧的细胞死亡。

  摘要：

  氧化还原调节剂已被开发为治疗癌症的有吸引力的方法。在此，我们报告了喹唑啉二酮活性氧 (ROS) 诱导剂 QD394 的合成、鉴定和生物学评估，该诱导剂在胰腺癌细胞中具有显着的细胞毒性。QD394 显示出与癌症干性抑制剂 napabucasin 非常相似的转录组学特征。这两种小分子都抑制 STAT3 磷酸化，增加细胞 ROS，并降低 GSH/GSSG 比率。此外，QD394 导致铁和 ROS 依赖性、GPX4 介导的细胞死亡，表明铁死亡是主要机制。重要的是，QD394 降低了 LRPPRC 和 PNPT1 的表达，这两种蛋白质参与线粒体 RNA 分解代谢过程，并且都与胰腺癌患者的总生存期呈负相关。药代动力学指导的先导优化产生了衍生物 QD394-Me，与 QD394 相比，它在小鼠中显示出改善的血浆稳定性和降低的毒性。总体而言，QD394 和 QD394-Me 代表了新型 ROS 诱导药物样化合物，值得进一步开发用于治疗胰腺癌。

  DOI：

  10.1021/acs.jmedchem.0c01016

文献信息

• [EN] SMALL MOLECULE INDUCERS OF REACTIVE OXYGEN SPECIES AND INHIBITORS OF MITOCHONDRIAL ACTIVITY<br/>[FR] INDUCTEURS DE PETITES MOLÉCULES DE DÉRIVES RÉACTIFS DE L'OXYGÈNE ET INHIBITEURS DE L'ACTIVITÉ MITOCHONDRIALE
  申请人：UNIV MICHIGAN REGENTS

  公开号：WO2017155991A1

  公开（公告）日：2017-09-14

  This invention is in the field of medicinal chemistry. In particular, the invention relates to a new class of small-molecules having a quinazolinedione structure which function as reactive oxygen species (ROS) inducers and inhibitors of mitochondrial activity within cancer cells (e.g., pancreatic cancer cells), and their use as therapeutics for the treatment of cancer (e.g., pancreatic cancer) and other diseases.

  这项发明属于药物化学领域。具体来说，该发明涉及一类具有喹唑啉二酮结构的小分子，其作为活性氧（ROS）诱导剂和对癌细胞（例如胰腺癌细胞）内线粒体活性的抑制剂，并将它们用作治疗癌症（例如胰腺癌）和其他疾病的药物。
• Design and Synthesis of Novel Reactive Oxygen Species Inducers for the Treatment of Pancreatic Ductal Adenocarcinoma
  作者：Yuting Kuang、Mario Sechi、Salvatore Nurra、Mats Ljungman、Nouri Neamati

  DOI：10.1021/acs.jmedchem.7b01463

  日期：2018.2.22

  modulators that we previously showed to induce potent growth inhibition in pancreatic ductal adenocarcinoma (PDAC) cell lines. Our lead optimization campaign yielded QD325 as the most potent redox modulator candidate inducing substantial reactive oxygen species (ROS) in PDAC cells. Nascent RNA sequencing following treatments with the QD compounds revealed induction of stress responses in nucleus, endoplasmic

  改变氧化还原稳态可以为胰腺癌的治疗提供独特的治疗机会。喹唑啉二酮（QDs）是新颖的氧化还原调节剂，我们先前已证明在胰腺导管腺癌（PDAC）细胞系中诱导有效的生长抑制作用。我们的领先优化活动使QD325成为最有力的氧化还原调节剂候选物，可在PDAC细胞中诱导大量的活性氧（ROS）。QD化合物处理后的新生RNA测序表明，胰腺癌细胞核，内质网和线粒体中应激反应的诱导。此外，QD化合物诱导Nrf2介导的氧化应激和未折叠的蛋白质反应，如代表性基因（如NQO1，HMOX1，DDIT3和HSPA5。在较高浓度下，量子点通过抑制mtDNA转录并下调mtDNA编码的OXPHOS酶来阻断线粒体功能。重要的是，QD325的治疗在体内具有良好的耐受性，并显着延迟了小鼠的肿瘤生长。我们的研究支持QD325作为PDAC治疗的新疗法的开发。
• Small molecule inducers of reactive oxygen species and inhibitors of mitochondrial activity
  申请人：The Regents of the University of Michigan

  公开号：US10781183B2

  公开（公告）日：2020-09-22

  This invention is in the field of medicinal chemistry. In particular, the invention relates to a new class of small-molecules having a quinazolinedione structure which function as reactive oxygen species (ROS) inducers and inhibitors of mitochondrial activity within cancer cells (e.g., pancreatic cancer cells), and their use as therapeutics for the treatment of cancer (e.g., pancreatic cancer) and other diseases.

  本发明属于药物化学领域。特别是，本发明涉及一类新的具有喹唑啉二酮结构的小分子，它们在癌细胞（如胰腺癌细胞）中可作为活性氧（ROS）诱导剂和线粒体活性抑制剂，并可用作治疗癌症（如胰腺癌）和其他疾病的疗法。
• Targeted Nanoparticles for the Delivery of Novel Bioactive Molecules to Pancreatic Cancer Cells
  作者：Vanna Sanna、Salvatore Nurra、Nicolino Pala、Salvatore Marceddu、Divya Pathania、Nouri Neamati、Mario Sechi

  DOI：10.1021/acs.jmedchem.5b01571

  日期：2016.6.9

  Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with poor prognosis and limited therapeutic options. Therefore, there is an urgent need to identify new, safe, and targeted therapeutics for effective treatment of late as well as early stage disease. Plectin-I (Plec-1) was recently identified as specific biomarker for detecting PDAC at an early stage. We envisioned that multivalent attachment of nanocarriers incorporating certain drugs to Plec-1-derived peptide would increase specific binding affinity and impart high specificity for PDAC cells. Previously, we dicovered a novel class of compounds (e.g., quinazolinediones, QDs) that exert their cytotoxic effects by modulating ROS-mediated cell signaling.. Herein, we prepared novel QD242-encapsulated polymeric nanoparticles (NPs) functionalized with a peptide to selectively bind to Plec-1. Similarly, we prepared QD-based NPs densely decorated with an isatoic anhydride derivative. Furthermore, we evaluated their impact on ligand binding and antiproliferative activity against PDAC cells. The targeted NPs were more potent than the nontargeted constructs in PDAC cells warranting further development.
• 6-Arylamino-7-chloro-quinazoline-5,8-diones as novel cytotoxic and DNA topoisomerase inhibitory agents
  作者：Hyen Joo Park、Young-Shin Kim、Jin Sung Kim、Eun-Jin Lee、You-Jin Yi、Hye Jin Hwang、Myung-Eun Suh、Chung-Kyu Ryu、Sang Kook Lee

  DOI：10.1016/j.bmcl.2004.04.094

  日期：2004.7

  A series of 6-arylamino-7-chloro-quinazoline-5,8-diones were prepared and evaluated for their in vitro cytotoxicity in cultured human cancer cell lines A549 (lung cancer), Col2 (colon cancer), and SNU-638 (stomach cancer). The preliminary structure-activity relationship has been described for providing further development of potent antitumor agents. To further investigate the cytotoxic mechanism, the effects of test compounds on DNA topoisomerase I and II activities have been assessed. (C) 2004 Elsevier Ltd. All rights reserved.