7-methoxy-9-ethyl-1-methyl-β-carboline

• 分子结构分类: 有机化合物 - 生物碱及其衍生物 - 哈马拉生物碱
• 英文名称: 7-methoxy-9-ethyl-1-methyl-β-carboline
• 英文别名: N-Ethylharmine；9-ethyl-7-methoxy-1-methylpyrido[3,4-b]indole
• 化学式: C₁₅H₁₆N₂O
• 分子量: 240.305
• InChiKey: IPKUPGYEVPMEEL-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.8
• 重原子数：
  18
• 可旋转键数：
  2
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.27
• 拓扑面积：
  27
• 氢给体数：
  0
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  7-methoxy-9-ethyl-1-methyl-β-carboline 在 氢溴酸 、 sodium hydride 、 溶剂黄146 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 生成 7-isopropoxy-9-ethyl-1-methyl-β-carboline
  参考文献：
  名称：

  Synthesis and structure–activity relationships of harmine derivatives as potential antitumor agents

  摘要：

  Harmine, a naturally occurring beta-carboline alkaloid, showed good antitumor activities together with remarkable neurotoxic effects in animal models. In order to search for novel leading compounds endowed with better antitumor activities and less neurotoxicities, a series of harmine derivatives were designed and synthesized by modification of position-2, 7 and 9 of beta-carboline nucleus, and their cytotoxic activities against human tumor cell lines were investigated. Acute toxicities and antitumor activities of the selected compounds in mice were also evaluated. Structure activity relationships studies confirmed that (1) the 7-methoxy structural moiety was the pharmacophore responsible for the neurotoxic effects of this class of compounds; (2) the substituents in position-2 and 9 played a vital role in modulation of their antitumor activities. (C) 2012 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2012.11.045
• 作为产物：
  描述：

  四氢骆驼蓬碱 在 5%-palladium/activated carbon 、 sodium hydride 作用下， 以 5,5-dimethyl-1,3-cyclohexadiene 、 N,N-二甲基甲酰胺 为溶剂， 反应 36.0h， 生成 7-methoxy-9-ethyl-1-methyl-β-carboline
  参考文献：
  名称：

  N 9取代的香豆素衍生物作为潜在抗癌药的合成及生物学评价

  摘要：

  合成了一系列N 9取代的harmine衍生物，并评估了它们对一组癌细胞系的抗癌活性，它们的凋亡诱导作用以及它们的细胞周期效应。结果表明，N 9取代的甜菜碱衍生物具有抗癌作用。尤其是N 9-卤代烷基衍生物9a - 9c和N 9-酰基氨基甜菜碱衍生物11c和11d，其IC 50为值小于1μM的抗A-549和/或MCF-7细胞系的效力比阿霉素强。此外，结构-活性关系（SARs）表明，在甜菜碱的N 9位引入卤代烷基或苯磺酰基可以显着提高抗癌活性。活性最高的化合物（11d）导致细胞周期停滞在G2 / M期，并以剂量​​依赖性方式诱导细胞凋亡。

  DOI：

  10.1016/j.bmcl.2016.06.087

文献信息

• Synthesis and structure-activity relationships of asymmetric dimeric β-carboline derivatives as potential antitumor agents
  作者：Liang Guo、Wei Chen、Rihui Cao、Wenxi Fan、Qin Ma、Jie Zhang、Bin Dai

  DOI：10.1016/j.ejmech.2018.02.003

  日期：2018.3

  series of newly asymmetric dimeric β-carbolines with a spacer of 4–6 methylene units between the indole nitrogen and the harmine oxygen were synthesized. Structures of all the novel synthesized compounds were confirmed by their spectral and analytical studies. All of the synthesized compounds were screened for their in vitro cytotoxic activity against nine cancer cell lines. The results revealed that

  合成了一系列新的不对称的二聚β-咔啉，它们在吲哚氮和氨苄基氧之间具有一个4-6个亚甲基单元的间隔。通过光谱和分析研究证实了所有新型合成化合物的结构。筛选所有合成的化合物对九种癌细胞系的体外细胞毒活性。结果表明，化合物7c，7o和7s对测试的肿瘤细胞系表现出最高的细胞毒活性，IC 50值小于20μM。还评估了所选化合物在小鼠中的急性毒性和抗肿瘤功效，并且化合物7o表现出有效的抗肿瘤活性，肿瘤抑制率超过40％。伤口愈合试验显示了HT-29细胞运动性的特定损伤，这提示了化合物7o的抗转移潜力。此外，化合物7o在鸡绒膜尿囊膜（CAM）分析中具有明显的血管生成抑制作用。初步的结构-活性关系（SAR）分析表明：（1）吲哚环N 9位的3-苯基丙基取代基是最合适的产生有效细胞毒性剂的基团；（2）间隔物长度影响抗肿瘤能力，并且四个亚甲基单元是更有利的。
• Synthesis, acute toxicities, and antitumor effects of novel 9-substituted β-carboline derivatives
  作者：Rihui Cao、Qi Chen、Xuerui Hou、Hongsheng Chen、Huaji Guan、Yan Ma、Wenlie Peng、Anlong Xu

  DOI：10.1016/j.bmc.2004.06.038

  日期：2004.9

  A series of novel 9-substituted beta-carboline derivatives was synthesized from harmine and l-tryptophan, respectively. Cytotoxic activities of these compounds in vitro were investigated. The results showed that most compounds of 9-substituted beta-carboline derivatives had more remarkable cytotoxic activities in vitro than their corresponding parent compounds. Acute toxicities and antitumor effects

  分别从甜蜜素和色氨酸合成了一系列新颖的9-取代的β-咔啉衍生物。研究了这些化合物在体外的细胞毒活性。结果表明，大多数9-取代的β-咔啉衍生物的化合物在体外具有比其相应母体化合物更显着的细胞毒活性。还检查了选定的β-咔啉衍生物在小鼠中的急性毒性和抗肿瘤作用。结果表明，位置9处的短烷基或苄基取代基显着提高了抗肿瘤活性，位置3处的乙氧羰基或羧基取代基显着降低了这些β-咔啉衍生物的急性毒性和神经毒性。而且，与其他化合物相比，在第3位具有烷氧基羰基或羧基取代基且在第9位具有短烷基或苄基取代基的化合物均表现出更显着的抗肿瘤活性以及较低的急性毒性和神经毒性。发现分别在第9位和第3位具有正丁基和羧基取代基的化合物8c具有最高的抗肿瘤作用和最低的急性毒性和神经毒性。这些数据表明：（1）β-咔啉衍生物第9位和第3位的适当取代基可能在确定其增强的抗肿瘤活性以及降低的急性毒性和神经毒性作用方面起着至关重要的作用；
• Exploring Kinase Inhibition Properties of 9H-pyrimido[5,4-b]- and [4,5-b]indol-4-amine Derivatives
  作者：Yvonnick Loidreau、Carole Dubouilh-Benard、Marie-Renée Nourrisson、Nadège Loaëc、Laurent Meijer、Thierry Besson、Pascal Marchand

  DOI：10.3390/ph13050089

  日期：——

  We previously highlighted the interest in 6,5,6-fused tricyclic analogues of 4-aminoquinazolines as kinase inhibitors in the micromolar to the nanomolar range of IC50 values. For the generation of chemical libraries, the formamide-mediated cyclization of the cyanoamidine precursors was carried out under microwave irradiation in an eco-friendly approach. In order to explore more in-depth the pharmacological interest in such tricyclic skeletons, the central five member ring, i.e., thiophène or furan, was replaced by a pyrrole to afford 9H-pyrimido[5,4-b]- and [4,5-b]indol-4-amine derivatives inspired from harmine. The inhibitory potency of the final products was determined against four protein kinases (CDK5/p25, CK1δ/ε, GSK3α/β, and DYRK1A). As a result, we have identified promising compounds targeting CK1δ/ε and DYRK1A and displaying micromolar and submicromolar IC50 values.

  我们先前强调了6,5,6-融合三环类4-氨基喹唑啉作为激酶抑制剂在微摩尔到纳摩尔范围内的IC50值的兴趣。为了生成化学库，使用甲酰胺介导的氰基胺前体的环化反应在微波辐射下进行，采用环保的方法。为了更深入地探索这种三环骨架的药理学兴趣，中心的五元环，即噻吩或呋喃，被替换为吡咯，以制备受到harmine启发的9H-嘧啶并[5,4-b]-和[4,5-b]吲哚-4-胺衍生物。最终产品的抑制效力被测定对四种蛋白激酶（CDK5/p25、CK1δ/ε、GSK3α/β和DYRK1A）。结果，我们已经确定了有前途的化合物，靶向CK1δ/ε和DYRK1A，显示微摩尔和亚微摩尔的IC50值。
• Synthesis, crystal structure, and reactive oxygen species (ROS) inhibition of N– and O–linked triazole analogues of harmine
  作者：Shazia Iqbal、Maria A. Khan、Almas Jabeen、Sammer Yousuf、Fatima Zafar、Farhana Batool、Muhammad Uzair Ganatra、Fatima Z. Basha

  DOI：10.1016/j.molstruc.2022.132796

  日期：2022.8

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• Harmine derivatives, intermediates used in their preparations, preparation processes and use therefo
  申请人：Wu Jialin

  公开号：US20090227619A1

  公开（公告）日：2009-09-10

  This invention relates to compounds of general formula (I), wherein R 1 , R 2 , R 3 , R 4 and R 5 are as defined in the specification; intermediates used in their preparation, preparation processes and use thereof. The present invention produces new harmine derivatives with enhanced antitumour activity and lower nervous system toxicity by structurally modification of the parent structure of β-carboline of harmines at position 1, 2, 3, 7 and 9. The compounds of the present invention can be prepared easily with high yield. They can be used in manufacture of a variety of antitumour medicines and medicines used in treatment of tumour diseases in combination of light or radiation therapy.

  本发明涉及一般式（I）的化合物，其中R1、R2、R3、R4和R5如规范中所定义；用于它们的制备的中间体，制备方法和使用。本发明通过在β-噻吩类似物的母体结构的1、2、3、7和9位进行结构修饰，产生具有增强抗肿瘤活性和较低神经系统毒性的新的harmine衍生物。本发明的化合物可以轻松高产制备。它们可以用于制造各种抗肿瘤药物和用于结合光或放射治疗治疗肿瘤疾病的药物。