7,7'-diazaindirubin | 1181864-25-4

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡咯并吡啶类
• 英文名称: 7,7'-diazaindirubin
• 英文别名: 3-(3-oxo-1H-pyrrolo[2,3-b]pyridin-2-ylidene)-1H-pyrrolo[2,3-b]pyridin-2-one
• CAS: 1181864-25-4
• 化学式: C₁₄H₈N₄O₂
• 分子量: 264.243
• InChiKey: OHHPMLZAKKJNOQ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.45
• 重原子数：
  20.0
• 可旋转键数：
  0.0
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.0
• 拓扑面积：
  83.98
• 氢给体数：
  2.0
• 氢受体数：
  5.0

反应信息

• 作为产物：
  描述：

  7-氮杂吲哚 在 过氧化氢异丙苯 、 溶剂黄146 、 molybdenum hexacarbonyl 作用下， 反应 24.0h， 以79%的产率得到7,7'-diazaindirubin
  参考文献：
  名称：

  靛类化合物的可调合成：通过温度靶向靛玉红

  摘要：

  3-吲哚酚自发转化为靛蓝是用于生产靛蓝染料的成熟工艺。最近的研究表明，一些吲哚在与六羰基钼和过氧化枯基反应时，会通过吲哚酚中间体，通过竞争机制产生大量靛玉红。将该系统调节至较低温度可以进行仔​​细调整，从而在一般过程中选择性地生产靛玉红。对吲哚的系统分析表明，缺电子吲哚在 5 和 7 位被取代时效果良好。相比之下，6-取代的富电子吲哚给出了最好的结果，而卤代吲哚在所有情况下都效果良好。该过程对通常具有反应性的含羰基化合物（例如醛和羧酸）表现出广泛的官能团耐受性。

  DOI：

  10.1039/d2ra00400c

文献信息

• 7-azaindirubins, 7'-azaindirubins, 7-7'-diazaindirubin and the corresponding 3'-oxime ether derivates: production thereof, their production and use as a medicament
  申请人：Technische Universität Kaiserslautern

  公开号：EP2199292A1

  公开（公告）日：2010-06-23

  The present invention relates to 7-azaindirubins (1), 7'-azaindirubins (2), and 7,7'-diaza-indirubins (3), wherein E, R1 and R2 have the meanings detailed in the description, their production and use as a medicament for treating cancer, neurodegenerative diseases, bipolar disorders, inflammatory and infectious diseases, including viral diseases. Depending on structure, these indirubins act as inhibitors of various kinases involved in tumor cell growth, and, most notably, as inhibitors of human tumor cell proliferation. As compared to indirubins bearing identical substituents but no hetero atoms in position 7 and 7', the activity of the compounds according to the present invention is increased and the propensity to get metabolized by CYP450s is reduced, resulting in improved metabolic stability.

  本发明涉及7-azaindirubins（1）、7'-azaindirubins（2）和7,7'-二氮杂吲哚（3），其中E、R1和R2的含义在描述中有详细说明，它们的制备和用作治疗癌症、神经退行性疾病、躁郁症、炎症和传染病，包括病毒性疾病的药物。根据结构的不同，这些吲哚作为抑制与肿瘤细胞生长有关的各种激酶的作用，尤其是作为人类肿瘤细胞增殖的抑制剂。与携带相同取代基但在位置7和7'没有杂原子的吲哚相比，根据本发明的化合物的活性增加，且通过CYP450酶代谢的倾向减少，从而提高了代谢稳定性。
• Exploring an anomaly: the synthesis of 7,7′-diazaindirubin through a 7-azaindoxyl intermediate
  作者：James A. Shriver、Katelyn R. Wang、Andrew C. Patterson、James R. DeYoung、Richard J. Lipsius

  DOI：10.1039/d0ra07144g

  日期：——

  Generation of 7-azaindoxyl under acidic conditions leads exclusively to 7,7′-diazaindirubin over 7,7′-diazaindigo through a condensation pathway.

  在酸性条件下生成7-氮氧自由基，仅通过缩合途径形成7,7'-二氮吲哚鲁宾，而不是7,7'-二氮吲哥。
• 7,7′-Diazaindirubin—A small molecule inhibitor of casein kinase 2 in vitro and in cells
  作者：Xinlai Cheng、Karl-Heinz Merz、Sandra Vatter、Jochen Christ、Stefan Wölfl、Gerhard Eisenbrand

  DOI：10.1016/j.bmc.2013.11.031

  日期：2014.1

  Aza- and diaza-bisindoles were synthesized by coupling of 7-azaisatin, 7-azaoxindol, 7-azaindoxyl acetate, and their non-aza counterparts, respectively. Whereas 7,7'-diazaindigo (10) and 7,7'-diazaisoindigo (11) did not show antiproliferative activity in several human tumor cell lines up to 100 mu M, 7-azaindirubin (12) and 7'-azaindirubin (13) were more active than the parent molecule, indirubin, in LXFL529L cells (human large cell lung tumor xenograft), and 7,7'-diazaindirubin (14) was exhibiting substantially enhanced growth inhibitory activity in these cells. In the NCI 60 cell line panel, 14 displayed antiproliferative activity preferentially in certain melanoma and non-small cell lung cancer cells. In contrast to the potent serine/threonine/tyrosine kinase inhibition observed for indirubins, kinase inhibition profiling of 14 in 220 kinases revealed largely a loss of kinase inhibitory activity towards most kinases, with retained inhibitory activity for just a few kinases. At 1 mu M concentration, especially casein kinases CK1 gamma 3, CK2 alpha, CK2 alpha 2, and SIK were inhibited by more than 50%. In cell-based assays, 14 markedly affected CK2-mediated signaling in various human tumor cells. In MCF7 cells, 14 induced cell cycle arrest at G1 and G2/M and apoptosis, whereas CK2-deficient MCF7 cells were resistant. These findings reveal a novel key mechanism of action for 14, suggesting primarily CK2 inhibition to be causally related to growth inhibition of human tumor cells. (C) 2013 Elsevier Ltd. All rights reserved.
• A tunable synthesis of indigoids: targeting indirubin through temperature
  作者：James A. Shriver、Kaylie S. Kaller、Ally L. Kinsey、Katelyn R. Wang、Summer R. Sterrenberg、Madison K. Van Vors、Joshua T. Cheek、John S. Horner

  DOI：10.1039/d2ra00400c

  日期：——

  with molybdenum hexacarbonyl and cumyl peroxide, proceed through an indoxyl intermediate to produce significant amounts of indirubin through a competing mechanism. Modulation of this system to lower temperatures allows for careful tuning, leading to selective production of indirubins in a general process. A systematic assay of indoles show that electron deficient indoles work well when substituted at the

  3-吲哚酚自发转化为靛蓝是用于生产靛蓝染料的成熟工艺。最近的研究表明，一些吲哚在与六羰基钼和过氧化枯基反应时，会通过吲哚酚中间体，通过竞争机制产生大量靛玉红。将该系统调节至较低温度可以进行仔​​细调整，从而在一般过程中选择性地生产靛玉红。对吲哚的系统分析表明，缺电子吲哚在 5 和 7 位被取代时效果良好。相比之下，6-取代的富电子吲哚给出了最好的结果，而卤代吲哚在所有情况下都效果良好。该过程对通常具有反应性的含羰基化合物（例如醛和羧酸）表现出广泛的官能团耐受性。