4,9-dibromo-2,7-bis(3-morpholinopropyl)benzo[lmn][3,8]phenanthroline-1,3,6,8-(2H,7H)-tetraone | 1429028-92-1

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡啶及其衍生物
• 英文名称: 4,9-dibromo-2,7-bis(3-morpholinopropyl)benzo[lmn][3,8]phenanthroline-1,3,6,8-(2H,7H)-tetraone
• 英文别名: 2,9-dibromo-6,13-bis(3-morpholin-4-ylpropyl)-6,13-diazatetracyclo[6.6.2.04,16.011,15]hexadeca-1,3,8,10,15-pentaene-5,7,12,14-tetrone
• CAS: 1429028-92-1
• 化学式: C₂₈H₃₀Br₂N₄O₆
• 分子量: 678.377
• InChiKey: QRVSPVLHVNWIMI-UHFFFAOYSA-N

物化性质

• 沸点：
  787.6±60.0 °C(Predicted)
• 密度：
  1.616±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.6
• 重原子数：
  40
• 可旋转键数：
  8
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  99.7
• 氢给体数：
  0
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  4,9-dibromo-2,7-bis(3-morpholinopropyl)benzo[lmn][3,8]phenanthroline-1,3,6,8-(2H,7H)-tetraone 在 (2-dicyclohexylphosphino-2’,4’,6’-triisopropyl-1,1 ‘-biphenyl)[2-(2’-amino-1,1‘-biphenyl)]palladium(II) methanesulfonate 、 potassium carbonate 作用下， 以 1,4-二氧六环 、 水 、 甲苯 为溶剂， 反应 19.0h， 生成 4-(4-(morpholinomethyl)phenyl)-2,7-bis(3-morpholinopropyl)-9-((2-(pyrrolidin-1-yl)ethyl)amino)benzo[lmn][3,8]phenanthroline-1,3,6,8(2H,7H)-tetraone
  参考文献：
  名称：

  Asymmetrically Substituted Quadruplex-Binding Naphthalene Diimide Showing Potent Activity in Pancreatic Cancer Models

  摘要：

  Targeting of genomic quadruplexes is an approach to treating complex human cancers. We describe a series of tetrasubstituted naphthalene diimide (ND) derivatives with a phenyl substituent directly attached to the ND core. The lead compound (SOP1812) has 10 times superior cellular and in vivo activity compared with previous ND compounds and nanomolar binding to human quadruplexes. The pharmacological properties of SOP1812 indicate good bioavailability, which is consistent with the in vivo activity in xenograft and genetic models for pancreatic cancer. Transcriptome analysis shows that it down-regulates several cancer gene pathways, including Wnt/beta-catenin signaling.

  DOI：

  10.1021/acsmedchemlett.0c00317
• 作为产物：
  描述：

  1,4,5,8-萘四甲酸酐 在 硫酸 、 溶剂黄146 、 1,3-二溴-1,3,5-三嗪-2,4,6-三酮 作用下， 反应 5.0h， 生成 4,9-dibromo-2,7-bis(3-morpholinopropyl)benzo[lmn][3,8]phenanthroline-1,3,6,8-(2H,7H)-tetraone
  参考文献：
  名称：

  胰腺癌细胞中萘二酰亚胺G-四链体配体作为端粒靶向剂的基于结构的设计和评估

  摘要：

  具有正电荷末端的四取代萘二酰亚胺（ND）衍生物是人端粒和基因启动子DNA四链体的有效稳定剂，可在体外和体内抑制人癌细胞的生长。本研究报告使用基于结构的设计增强了早期ND化合物的药理特性。具有人类端粒分子内四链体的三个复合物的晶体结构表明，四个强碱性N-甲基-哌嗪基团中的两个可以被碱性较低的吗啉基团取代，而在四链体的凹槽中没有分子间相互作用的损失。这些新化合物与人端粒四链体DNA保持高度亲和力，但对带有MIC PaCa-2胰腺癌细胞系的效力要高10倍，并带有IC50个值约为10 nM。铅化合物诱导细胞衰老，但在抑制细胞增殖所需的纳摩尔剂量水平上，不抑制端粒酶活性。对用先导化合物处理的MIA PaCa-2细胞进行的基因阵列qPCR分析显示，显着剂量依赖性地调节了不同基因的子集，包括强烈诱导DNA损伤应答基因CDKN1A，DDIT3，GADD45A / G和PPM1D，以及抑制涉及端粒维持的基因，包括hPOT1和PARP1。

  DOI：

  10.1021/jm301899y

文献信息

• Structure-Based Design and Evaluation of Naphthalene Diimide G-Quadruplex Ligands As Telomere Targeting Agents in Pancreatic Cancer Cells
  作者：Marialuisa Micco、Gavin W. Collie、Aaron G. Dale、Stephan A. Ohnmacht、Ingrida Pazitna、Mekala Gunaratnam、Anthony P. Reszka、Stephen Neidle

  DOI：10.1021/jm301899y

  日期：2013.4.11

  charged termini are potent stabilizers of human telomeric and gene promoter DNA quadruplexes and inhibit the growth of human cancer cells in vitro and in vivo. The present study reports the enhancement of the pharmacological properties of earlier ND compounds using structure-based design. Crystal structures of three complexes with human telomeric intramolecular quadruplexes demonstrate that two of the

  具有正电荷末端的四取代萘二酰亚胺（ND）衍生物是人端粒和基因启动子DNA四链体的有效稳定剂，可在体外和体内抑制人癌细胞的生长。本研究报告使用基于结构的设计增强了早期ND化合物的药理特性。具有人类端粒分子内四链体的三个复合物的晶体结构表明，四个强碱性N-甲基-哌嗪基团中的两个可以被碱性较低的吗啉基团取代，而在四链体的凹槽中没有分子间相互作用的损失。这些新化合物与人端粒四链体DNA保持高度亲和力，但对带有MIC PaCa-2胰腺癌细胞系的效力要高10倍，并带有IC50个值约为10 nM。铅化合物诱导细胞衰老，但在抑制细胞增殖所需的纳摩尔剂量水平上，不抑制端粒酶活性。对用先导化合物处理的MIA PaCa-2细胞进行的基因阵列qPCR分析显示，显着剂量依赖性地调节了不同基因的子集，包括强烈诱导DNA损伤应答基因CDKN1A，DDIT3，GADD45A / G和PPM1D，以及抑制涉及端粒维持的基因，包括hPOT1和PARP1。
• Rapid Telomere Reduction in Cancer Cells Induced by G-Quadruplex-Targeting Copper Complexes
  作者：Zhen Yu、Kevin D. Fenk、Derrick Huang、Sambuddha Sen、J. A. Cowan

  DOI：10.1021/acs.jmedchem.9b00215

  日期：2019.5.23

  series of Cu complexes has been designed as selective artificial nucleases that degrade G-quadruplex telomeric DNA and exhibit selective DNA binding affinity and cleavage reactivity toward G-quadruplex telomeric DNA over duplex DNA. In contrast to protein-based nucleases that usually lack membrane permeability, significant cellular uptake and nuclear localization of these Cu complexes was observed

  端粒的长度决定了哺乳动物细胞的复制能力。端粒的连续减少至极短的长度可导致细胞衰老，这不可逆地阻止了细胞进一步的细胞分裂。已经设计了一系列的Cu复合物作为选择性的人工核酸酶，其降解G-四链体端粒DNA并显示出选择性的DNA结合亲和力和相对于双链体DNA的对G-四链体端粒DNA的切割反应性。与通常缺乏膜通透性的基于蛋白质的核酸酶相反，观察到这些铜络合物的显着细胞摄取和核定位。在仅孵育1天后，还观察到癌细胞的端粒快速减少，而DNA片段的缺失表明非选择性DNA裂解的水平较低。
• The influence of positional isomerism on G-quadruplex binding and anti-proliferative activity of tetra-substituted naphthalene diimide compounds
  作者：Sheila Mpima、Stephan A. Ohnmacht、Maria Barletta、Jarmila Husby、Luke C. Pett、Mekala Gunaratnam、Stephen T. Hilton、Stephen Neidle

  DOI：10.1016/j.bmc.2013.05.027

  日期：2013.10

  The synthesis together with biophysical and biological evaluation of a series of tetra-substituted naphthalene diimide (ND) compounds, are presented. These compounds are positional isomers of a recently-described series of quadruplex-binding ND derivatives, in which the two N-methyl-piperidine-alkyl side-chains have now been interchanged with the positions of side-chains bearing a range of end-groups. Molecular dynamics simulations of a pair of positional isomers are in accord with the quadruplex stabilization and biological data for these compounds. Analysis of structure-activity data indicates that for compounds where the side-chains are not of equivalent length then the positional isomers described here tend to have improved cell proliferation potency and in some instances, superior quadruplex stabilization ability. (C) 2013 Elsevier Ltd. All rights reserved.
• Targeting Multiple Effector Pathways in Pancreatic Ductal Adenocarcinoma with a G-Quadruplex-Binding Small Molecule
  作者：Chiara Marchetti、Katherine G. Zyner、Stephan A. Ohnmacht、Mathew Robson、Shozeb M. Haider、Jennifer P. Morton、Giovanni Marsico、Tam Vo、Sarah Laughlin-Toth、Ahmed A. Ahmed、Gloria Di Vita、Ingrida Pazitna、Mekala Gunaratnam、Rachael J. Besser、Ana C. G. Andrade、Seckou Diocou、Jeremy A. Pike、David Tannahill、R. Barbara Pedley、T. R. Jeffry Evans、W. David Wilson、Shankar Balasubramanian、Stephen Neidle

  DOI：10.1021/acs.jmedchem.7b01781

  日期：2018.3.22

  Human pancreatic ductal adenocarcinoma (PDAC) involves the dysregulation of multiple signaling pathways. A novel approach to the treatment of PDAC is described, involving the targeting of cancer genes in PDAC pathways having over-representation of Gquadruplexes, using the trisubstituted naphthalene diimide quadruplexbinding compound 2,7-bis(3-morpholinopropyl)-4-((2-(pyrrolidin-1-yl)ethyl)amino)benzo [lmn] [3,8] phenanthroline-1,3,6,8 (2H,7H)-tetraone (CM03). This compound has been designed by computer modeling, is a potent inhibitor of cell growth in PDAC cell lines, and has anticancer activity in PDAC models, with a superior profile compared to gemcitabine, a commonly used therapy. Whole-transcriptome RNA-seq methodology has been used to analyze the effects of this quadruplexbinding small molecule on global gene expression. This has revealed the down-regulation of a large number of genes, rich in putative quadruplex elements and involved in essential pathways of PDAC survival, metastasis, and drug resistance. The changes produced by CM03 represent a global response to the complexity of human PDAC and may be applicable to other currently hard-to-treat cancers.
• US20140275062A1
  申请人：——

  公开号：——

  公开（公告）日：——