pyrido[2',3':4,5]pyrimido[1,2-α]indole-5,11-dione

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡啶并嘧啶类
• 英文名称: pyrido[2',3':4,5]pyrimido[1,2-α]indole-5,11-dione
• 英文别名: 4-azatryptanthrin；4b,9,10-Triaza-benzo[b]fluorene-5,11-dione；2,4,10-triazatetracyclo[8.7.0.03,8.011,16]heptadeca-1,3(8),4,6,11,13,15-heptaene-9,17-dione
• 化学式: C₁₄H₇N₃O₂
• 分子量: 249.228
• InChiKey: GTMWBKWHXVFTCH-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.3
• 重原子数：
  19
• 可旋转键数：
  0
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.0
• 拓扑面积：
  62.6
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  pyrido[2',3':4,5]pyrimido[1,2-α]indole-5,11-dione 在 盐酸羟胺 作用下， 生成 4-aza-6-oximotryptanthrin
  参考文献：
  名称：

  Antimicrobial Activity of Tryptanthrins in Escherichia coli

  摘要：

  Tryptanthrins have potential therapeutic activity against a wide variety of pathogenic organisms, although little is known about their mechanism. Activity against Escherichia colt, however, has not been examined. The effects of tryptanthrin (indolo[2,1-b]quinazolin-6,12-dione) and nine derivatives on growth, survival, and mutagenesis in E. colt were examined. Analogues with a nitrogen atom at the 4-position of tryptanthrin stopped log phase growth of E. coli cultures at concentrations as low as 5 mu M. Tryptanthrins decreased viability during incubation with cells in buffer by factors of 10(-2) to < 10(-6) at 0.2-40 mu M. Derivatives with an oxime group at the 6-position exhibited the greatest bactericidal activity. Most tryptanthrins were not mutagenic in several independent assays, although the 4-aza and 4 aza-8-fluoro derivatives increased frameshift mutations about 22- and 4-fold, respectively. Given the structure of trypanthrins, binding to DNA may occur by intercalation. From analysis using a sensitive linking number assay, several tryptanthrins, especially the 4-aza and 6-oximo derivatives, intercalate into DNA.

  DOI：

  10.1021/jm901847f
• 作为产物：
  描述：

  2-羟基亚氨基-n-苯乙酰胺 在 硫酸 、 1,8-二氮杂双环[5.4.0]十一碳-7-烯 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 生成 pyrido[2',3':4,5]pyrimido[1,2-α]indole-5,11-dione
  参考文献：
  名称：

  色胺菊酯及其衍生物的发现及其通过细胞凋亡和自噬途径体外抗 NSCLC 的活性。

  摘要：

  在这项研究中，合成了一系列新型色胺酮衍生物，并评估了它们对选定的人类癌细胞系，即肺癌 (A549)、慢性粒细胞白血病 (K562)、前列腺 (PC3) 和活细胞 (HepG2) 的抑制活性使用甲基噻唑基四唑鎓比色法 (MTT) 测定。在测试的化合物中，化合物 C1 对 A549 细胞系表现出良好的抑制作用，IC50 值为 0.55 ± 0.33 µM。通过细胞迁移实验观察细胞形态学结果表明，C1处理可显着抑制A549细胞的迁移。此外，经C1处理后，A549细胞表现出典型的凋亡形态和明显的自噬。此外，细胞凋亡和线粒体膜电位的检测表明，C1通过调节Bcl2家族成员的水平并破坏线粒体膜电位来诱导A549细胞凋亡。化合物C1还抑制细胞周期蛋白D1的表达并增加A549细胞中p21的表达，以剂量依赖的方式诱导细胞周期停滞在G2/M期。进一步的机制研究发现，C1 显着增加了从 LC3-I 到 LC3-II

  DOI：

  10.3390/ijms24021450

文献信息

• Cytotoxicity and reversal of multidrug resistance by tryptanthrin-derived indoloquinazolines
  作者：Sung-tsai Yu、Ji-wang Chern、Tzer-ming Chen、Yi-fan Chiu、Hui-ting Chen、Yen-hui Chen

  DOI：10.1038/aps.2009.198

  日期：2010.2

  To evaluate the effects and elucidate the mechanisms of a series of indoloquinazolines as novel anticancer agents. Condensation of the substituted isatoic anhydride with the substituted isatin was performed to prepare compounds 1–4, followed by adding malononitrile to prepare compounds 5–7. Cytotoxicity was measured by MTT assays. Apoptosis induction was evaluated using DNA fragmentation, cell cycle assay, caspase 3/7 activity and Western blot. Compounds 3, 4, and 5 display cytotoxicity against MCF-7, HeLa, SKOV3, and A498 cancer cells. DNA ladders appear in cells treated with compounds 3, 4, and 5. Within those, compound 4 exhibits the greatest activity in regards to sub-G1 accumulations in the cell cycle and the activation of caspase-3/7. Furthermore, Fas and Fas ligand levels are elevated by compound 4, implying that the apoptosis is in part mediated through the signals. On the other hand, compounds 1 and 7 display chemosensitizing activity since cytotoxicity of doxorubicine and etoposide is enhanced in combination with compound 1 and 7, respectively, in MCF-7/adr (doxorubicin-resistant) and MCF-7/vp (etoposide-resistant). The cytotoxicity of indoloquinazolines is structure-dependent rather than cell type-dependent due to the similar degree of cytotoxicity induced by the individual compounds in all four cell lines. Further modification of the tryptanthrin skeleton is important to develop novel anticancer agents bearing either cytotoxicity against MCF-7 cells or drug resistance reversal in MCF-7/adr and MCF-7/vp.

  评估一系列吲哚喹唑啉类化合物作为新型抗癌剂的效果并阐明其作用机制。将取代的异酸酐与取代的靛红进行缩合，制备出化合物 1â4 ，然后加入丙二腈，制备出化合物 5â7 。细胞毒性通过 MTT 试验测定。凋亡诱导采用 DNA 断裂、细胞周期测定、caspase 3/7 活性和 Western 印迹法进行评估。化合物 3、4 和 5 对 MCF-7、HeLa、SKOV3 和 A498 癌细胞具有细胞毒性。经化合物 3、4 和 5 处理的细胞出现 DNA 梯状。其中，化合物 4 在细胞周期的亚 G1 累积和 caspase-3/7 激活方面表现出最大的活性。此外，化合物 4 还提高了 Fas 和 Fas 配体的水平，这意味着细胞凋亡部分是通过信号介导的。另一方面，化合物 1 和 7 显示出化疗增敏活性，因为在 MCF-7/adr（对多柔比星耐药）和 MCF-7/vp（对依托泊苷耐药）中，多柔比星和依托泊苷的细胞毒性分别与化合物 1 和 7 结合使用时会增强。吲哚喹唑啉类化合物的细胞毒性是结构依赖性的，而不是细胞类型依赖性的，这是因为单个化合物在所有四种细胞系中诱导的细胞毒性程度相似。要开发出对 MCF-7 细胞具有细胞毒性或可逆转 MCF-7/adr 和 MCF-7/vp 耐药性的新型抗癌剂，进一步修饰胰黄素骨架非常重要。
• Antimalarial and antiproliferative pharmacophore models, novel tryptanthrin compounds having increased solubility, and methods of making and using thereof
  申请人：——

  公开号：US20040033934A1

  公开（公告）日：2004-02-19

  Disclosed herein is a pharmacophore model for antimalarial activity and methods of making and using thereof. The pharmacophore comprises two hydrogen bond acceptor (lipid) functions and two hydrophobic (aromatic) functions. The pharmacophore model was made using a test set of tryptanthrin compounds which exhibit antimalarial activity. Also disclosed are tryptanthrin compounds having greater solubility and bioactivity as compared to prior art tryptanthrin compounds and methods of making and using thereof. Also disclosed are methods of treating malaria in a subject.

  本文揭示了一种抗疟药物活性的药效团模型及其制备和使用方法。该药效团包括两个氢键受体（脂肪）功能和两个疏水（芳香）功能。该药效团模型是使用一组具有抗疟活性的色胺类化合物试验集制备的。还揭示了具有比先前技术的色胺类化合物更高溶解度和生物活性的色胺类化合物及其制备和使用方法。还揭示了治疗受体内疟疾的方法。
• Use of tryptanthrin compounds for immune potentiation
  申请人：Chiron Corporation

  公开号：US20040241192A1

  公开（公告）日：2004-12-02

  The invention provides immunostimulatory compositions and methods of administration thereof. Also provided are methods of administering a tryptanthrin compound in an effective amount to enhance the immune response of a subject to an antigen. Also provided are methods of administering an effective amount of a tryptanthrin to stimulate the immune response in a subject for the treatment of cancer. Further provided are methods of administering a tryptanthrin compounds as an immunotherapeutic in the treatment of infectious diseases.

  该发明提供了免疫刺激性组合物及其给药方法。还提供了一种给予色胺酸酸衍生物有效量的方法，以增强受体对抗原的免疫反应。还提供了一种给予有效量色胺酸酸衍生物的方法，以刺激受体的免疫反应，用于治疗癌症。此外，还提供了一种给予色胺酸酸衍生物作为免疫治疗剂治疗传染病的方法。
• USE OF TRYPTANTHRIN COMPOUNDS FOR IMMUNE POTENTIATION
  申请人：VALIANTE Nicholas M.

  公开号：US20120244182A1

  公开（公告）日：2012-09-27

  The invention provides immunostimulatory compositions and methods of administration thereof. Also provided are methods of administering a tryptanthrin compound in an effective amount to enhance the immune response of a subject to an antigen. Also provided are methods of administering an effective amount of a tryptanthrin to stimulate the immune response in a subject for the treatment of cancer. Further provided are methods of administering a tryptanthrin compounds as an immunotherapeutic in the treatment of infectious diseases.

  本发明提供了免疫刺激组合物及其给药方法。还提供了一种给予吲哚丹宁化合物有效量的方法，以增强受体对抗原的免疫反应。还提供了一种给予有效量的吲哚丹宁化合物的方法，以刺激受体对癌症的免疫反应。此外，还提供了将吲哚丹宁化合物作为免疫治疗剂治疗传染病的方法。
• <i>N</i>-Carboxyanhydrides directly from amino acids and carbon dioxide and their tandem reactions to therapeutic alkaloids
  作者：Thi V. Tran、Yi Shen、Hieu D. Nguyen、Shijie Deng、Hootan Roshandel、Mason M. Cooper、Jose R. Watson、Jeffery A. Byers、Paula L. Diaconescu、Loi H. Do

  DOI：10.1039/d2gc03507c

  日期：——

  versatile N-carboxyanhydrides (NCAs) directly from amino acids and CO2 using n-propylphosphonic anhydride. Most of the NCAs were isolated with >95% purity after simple workup, avoiding the need for tedious purification procedures typically required using conventional methods. Because the reagents and conditions employed are mild, tandem reactions with moisture-sensitive NCAs were carried out to transform

  我们报告了使用正丙基膦酸酐直接从氨基酸和 CO 2制备综合通用的N-羧基酸酐 (NCA) 。大多数 NCA 在简单的后处理后以 > 95% 的纯度被分离出来，避免了使用传统方法通常需要的繁琐纯化程序的需要。由于所使用的试剂和条件温和，因此与对水分敏感的 NCA 进行串联反应，将它们在一锅中转化为药用生物碱色胺菊酯和 Phaitanthrin A。定性分析表明，我们的 NCA 合成方法比直接或间接使用剧毒气体光气的传统方法更环保。