6-chloro-7-((2-morpholin-4-yl)ethylamino)quinoline-5,8-dione | 383907-43-5

• 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: 6-chloro-7-((2-morpholin-4-yl)ethylamino)quinoline-5,8-dione
• 英文别名: NSC 663284；6-chloro-7-((2-(4-morpholinyl)ethyl)amino)-5,8-quinolinedione；6-chloro-7-[[2-(4-morpholinyl)ethyl]amino]-5,8-quinolinedione；6-chloro-7-(2-morpholin-4-yl-ethylamino)quinoline-5,8-dione；NSC-663284；NSC663284；6-chloro-7-(2-morpholin-4-ylethylamino)quinoline-5,8-dione
• CAS: 383907-43-5
• 化学式: C₁₅H₁₆ClN₃O₃
• 分子量: 321.763
• InChiKey: BMKPVDQDJQWBPD-UHFFFAOYSA-N

物化性质

• 沸点：
  478.8±45.0 °C(Predicted)
• 密度：
  1.41±0.1 g/cm3(Predicted)
• 溶解度：
  二甲基亚砜：16 毫克/毫升

计算性质

• 辛醇/水分配系数(LogP)：
  1.4
• 重原子数：
  22
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.4
• 拓扑面积：
  71.5
• 氢给体数：
  1
• 氢受体数：
  6

制备方法与用途

生物活性

NSC 663284 是一种有效的、细胞可渗透的且不可逆的 Cdc25 dual specificity phosphatase 抑制剂，对 Cdc25B2 的 IC50 值为 0.21 μM。它表现出与 Cdc25A、Cdc25B2 和 Cdc25C 的混合竞争动力学，相应的 Ki 值分别为 29 nM、95 nM 和 89 nM。此外，NSC 663284 通过与 SET 结构域（Kd 为 370 nM）的相互作用抑制 NSD2 酶的活性（IC50 值为 170 nM）。

靶点

• IC50: 0.21 μM (Cdc25B2)

体外研究

NSC 663284 在 NCI 60 细胞人类肿瘤 panel 中的平均 IC50 值为 1.5 ± 0.6 μM。在人乳腺癌 MDA-MB-435 和 MDA-N 细胞中，其 IC50 值分别为 0.2 μM；在培养的人乳腺 MCF-7 细胞中的 IC50 值为 1.7 μM。

与 VHR (IC50 = 4.0 μM) 或 PTP1B (IC50 > 4.0 μM) 相比，NSC 663284 对 Cdc25B2 的 IC50 值分别低约 20 倍和 450 倍。

体内研究

通过静脉注射 (2, 3, 和 5 mg/kg) NSC 663284 可抑制 SCID 小鼠皮下人结肠 HT29 异种移植物的生长。单次给药 5 mg/kg 后，NSC 663284 在血液和组织中不可检测的时间超过 5 分钟。在肿瘤携带 SCID 小鼠接受 NSC 663284 治疗后，HT29 肿瘤中的谷胱甘肽浓度显著降低，并且这种减少持续时间更长，谷胱甘肽水平低于肝脏和肾脏的相应减少。

反应信息

• 作为产物：
  描述：

  5-氨基-8-羟基喹啉 在 盐酸 、 sodium chlorate 、 N,N-二异丙基乙胺 作用下， 以 二氯甲烷 、 水 为溶剂， 反应 4.0h， 生成 6-chloro-7-((2-morpholin-4-yl)ethylamino)quinoline-5,8-dione 、 DA 3003-2
  参考文献：
  名称：

  6-Regioisomeric 5,8-quinolinediones as potent CDC25 inhibitors against colorectal cancers

  摘要：

  DOI：

  10.1016/j.ejmech.2023.115505
• 作为试剂：
  描述：

  氧气 在 3,3,3-膦三基三丙酸 、 乙二胺四乙酸 、 6-chloro-7-((2-morpholin-4-yl)ethylamino)quinoline-5,8-dione 作用下， 以 aq. buffer 为溶剂， 反应 0.33h， 生成 双氧水
  参考文献：
  名称：

  将无效的对苯二酚转换为高效的活性氧生成器：泛素特异性蛋白酶2抑制，电催化和定量

  摘要：

  作用方式：通过泛素特异性蛋白酶2（USP2）抑制，循环伏安法首次证明了对醌中独特模式N-C = O-N对于有效生成活性氧（ROS）的重要性，电催化和化学发光研究。

  DOI：

  10.1002/cbic.201700330

文献信息

• Compound capable of cytoskeleton and induction of cell elongation and process for synthesizing the same
  申请人：Chao Jui-I

  公开号：US20080015221A1

  公开（公告）日：2008-01-17

  A compound capable of cytoskeleton and induction of cell elongation, 7-chloro-6-piperidin-1-yl-quinoline-5,8-dione with a chemical formula of C 14 H 13 CIN 2 O 2 , is designated as PT-262. The PT-262 can induce cell elongation by stabilization of the F-actin and induction of the abnormal actin polymerization in cancer cells, further, the PT-262 possesses antitumor activity and can block survival pathway of the cancer cells, resulting in cancer cells apoptosis, and the PT-262 can induce growth arrest and inhibition of cell cycle. PT-262 stabilizes cancer cells cytoskeleton that results in an irreversible cell elongation, decreases the levels of cyclin B1 and phospho-cdc2 proteins, and inhibits the survival signal pathway of Ras-ERK proteins. The PT-262 also inhibits the mitochondrial membrane potential and induces the caspase-3 activation and apoptosis in the cancer cells.

  一种具有细胞骨架和诱导细胞延长能力的化合物，化学式为C14H13CIN2O2的7-氯-6-哌啶-1-基喹啉-5,8-二酮被指定为PT-262。PT-262可以通过稳定F-肌动蛋白和诱导癌细胞中异常肌动蛋白聚合来诱导细胞延长，此外，PT-262具有抗肿瘤活性，可以阻断癌细胞的生存途径，导致癌细胞凋亡，PT-262还可以诱导生长停滞和抑制细胞周期。PT-262稳定了癌细胞的细胞骨架，导致不可逆的细胞延长，降低了细胞周期素B1和磷酸化cdc2蛋白的水平，并抑制了Ras-ERK蛋白的生存信号途径。PT-262还抑制了线粒体膜电位，诱导了癌细胞中caspase-3的激活和凋亡。
• Use of a Compound in Obtaining Cytoskeleton Blockage and Cell Elongation
  申请人：CHAO Jui-I

  公开号：US20100093794A1

  公开（公告）日：2010-04-15

  A use of a compound in obtaining cytoskeleton and cell elongation is disclosed, the compound is 7-chloro-6-piperidin-1-yl-quinoline-5,8-dione with a chemical formula of C 14 H 13 CIN 2 O 2 , is designated as PT-262. The PT-262 can induce cell elongation by stabilization of the F-actin and induction of the abnormal actin polymerization in cancer cells, further, the PT-262 possesses antitumor activity and can block survival pathway of the cancer cells, resulting in cancer cells apoptosis, and the PT-262 can induce growth arrest and inhibition of cell cycle. PT-262 stabilizes cancer cells cytoskeleton that results in an irreversible cell elongation, decreases the levels of cyclin B1 and phospho-cdc2 proteins, and inhibits the survival signal pathway of Ras-ERK proteins. The PT-262 also inhibits the mitochondrial membrane potential and induces the caspase-3 activation and apoptosis in the cancer cells.

  本文揭示了一种利用化合物获得细胞骨架和细胞延伸的方法，该化合物是7-氯-6-哌啶-1-基喹啉-5,8-二酮，化学式为C14H13CIN2O2，被指定为PT-262。PT-262能够通过稳定F-actin和诱导癌细胞中异常的肌动蛋白聚合来诱导细胞延伸，此外，PT-262具有抗肿瘤活性，可以阻断癌细胞的生存途径，导致癌细胞凋亡，并且PT-262可以诱导细胞生长停滞和细胞周期抑制。PT-262稳定癌细胞的细胞骨架，导致不可逆的细胞延伸，降低cyclin B1和磷酸化cdc2蛋白的水平，并抑制Ras-ERK蛋白的生存信号通路。PT-262还抑制线粒体膜电位，在癌细胞中诱导caspase-3激活和凋亡。
• Discovery and Biological Evaluation of a New Family of Potent Inhibitors of the Dual Specificity Protein Phosphatase Cdc25
  作者：John S. Lazo、Diana C. Aslan、Eileen C. Southwick、Kathleen A. Cooley、Alexander P. Ducruet、Beomjun Joo、Andreas Vogt、Peter Wipf

  DOI：10.1021/jm0102046

  日期：2001.11.1

  The Cdc25 dual specificity phosphatases have central roles in coordinating cellular signaling processes and cell proliferation, but potent and selective inhibitors are lacking. We experimentally examined the 1990 compound National Cancer Institute Diversity Set and then computationally selected from their 140 000 compound repository 30 quinolinediones of which 8 had in vitro mean inhibitory concentrations < 1 muM. The most potent was 6-chloro-7-(2-morpholin-4-ylethylamino)quinoline-5,8-dione (NSC 663284), which was 20- and 450-fold more selective against Cdc25B(2) as compared with VHR or PTP1B phosphatases, respectively. NSC 663284 exhibited mixed competitive kinetics against Cdc25A, Cdc25B(2), and Cdc25C with K-i values of 29, 95, and 89 nM, respectively. As compared with NSC 663284, the regioisomer 7-chloro-6-(2-morpholin-4-ylethylamino)quinoline-5,8-dione was 3-fold less active against Cdc25B(2) in vitro and less potent as a growth inhibitor of human breast cancer cells. Computational electrostatic potential mapping suggested the need for an electron-deficient 7-position for maximal inhibitor activity. Using a chemical complementation assay, we found that NSC 663284 blocked cellular Erk dephosphorylation caused by ectopic Cdc25A expression.
• [EN] INHIBITORS OF CANCER STEM CELLS<br/>[FR] INHIBITEURS DE CELLULES SOUCHES CANCÉREUSES
  申请人：UNIV PITTSBURGH

  公开号：WO2011130677A1

  公开（公告）日：2011-10-20

  A method of treating cancer in a subject, comprising co-administering to the subject (a) a therapeutically effective amount of at least one compound that selectively targets cancer stem cells, wherein the compound is selected from an indenoisoquinoline compound, a naphthoquinone compound, a quinolinedione compound, bouvardin, A-77636, rottlerin, or CGP-74514A, or a pharmaceutically acceptable salt or ester thereof, and (b) a therapeutically effective amount of at least one anti-cancer agent.
• 6-Regioisomeric 5,8-quinolinediones as potent CDC25 inhibitors against colorectal cancers
  作者：Iin Narwanti、Zih-Yao Yu、Bidyadhar Sethy、Mei-Jung Lai、Hsueh-Yun Lee、Popazova Olena、Sung-Bau Lee、Jing-Ping Liou

  DOI：10.1016/j.ejmech.2023.115505

  日期：2023.10