(5-fluoro-1-methyl-1H-indol-3-yl)-oxo-acetyl chloride | 396091-17-1

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吲哚及其衍生物
• 英文名称: (5-fluoro-1-methyl-1H-indol-3-yl)-oxo-acetyl chloride
• 英文别名: 2-(5-Fluoro-1-methylindol-3-yl)-2-oxoacetyl chloride
• CAS: 396091-17-1
• 化学式: C₁₁H₇ClFNO₂
• 分子量: 239.633
• InChiKey: SDHMSWQRQVPHFP-UHFFFAOYSA-N

物化性质

• 沸点：
  397.4±45.0 °C(Predicted)
• 密度：
  1.41±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.5
• 重原子数：
  16
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.09
• 拓扑面积：
  39.1
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  (5-fluoro-1-methyl-1H-indol-3-yl)-oxo-acetyl chloride 在 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 sodium hydroxide 作用下， 以 四氢呋喃 、 N,N-二甲基甲酰胺 为溶剂， 反应 12.75h， 生成 (5-fluoro-1-methyl-1H-indol-3-yl)[3-(5-methoxy-1H-indol-3-yl)-1,2,4-oxadiazol-5-yl]methanone
  参考文献：
  名称：

  具有抗胰腺癌细胞增殖活性的 1,2,4-恶二唑 Topsentin 类似物，靶向 GSK3β 激酶

  摘要：

  高效合成了一系列新的topsentin类似物，其中天然铅的中心咪唑环被1,2,4-恶二唑部分取代。所有衍生物均针对美国国家癌症研究所 (NCI-60) 细胞系面板的抗增殖活性进行了预筛选。在各种胰腺导管腺癌 (PDAC) 细胞系中进一步研究了五种最有效的化合物，包括 SUIT-2、Capan-1 和 Panc-1 细胞，引发 EC 50微摩尔和亚微摩尔范围内的值，与细胞迁移的显着减少有关。这些显着的结果可能是由于这些新的 topsentin 类似物对上皮-间质转化标志物的影响，包括 SNAIL-1/2 和金属蛋白酶-9。此外，Annexin V-FITC 和碘化丙啶染色后的流式细胞术分析表明，这些衍生物增强了 PDAC 细胞的凋亡。与这些数据保持一致，PathScan 细胞内信号传导和 ELISA 阵列显示 caspase-3 和 PARP 的裂解以及 GSK3β 磷酸化的显着抑制，表明该

  DOI：

  10.1002/cmdc.202000752
• 作为产物：
  描述：

  5-氟吲哚 在 三(3,6-二氧杂庚基)胺 、 potassium tert-butylate 作用下， 以 乙醚 、 甲苯 为溶剂， 反应 4.0h， 生成 (5-fluoro-1-methyl-1H-indol-3-yl)-oxo-acetyl chloride
  参考文献：
  名称：

  具有抗胰腺癌细胞增殖活性的 1,2,4-恶二唑 Topsentin 类似物，靶向 GSK3β 激酶

  摘要：

  高效合成了一系列新的topsentin类似物，其中天然铅的中心咪唑环被1,2,4-恶二唑部分取代。所有衍生物均针对美国国家癌症研究所 (NCI-60) 细胞系面板的抗增殖活性进行了预筛选。在各种胰腺导管腺癌 (PDAC) 细胞系中进一步研究了五种最有效的化合物，包括 SUIT-2、Capan-1 和 Panc-1 细胞，引发 EC 50微摩尔和亚微摩尔范围内的值，与细胞迁移的显着减少有关。这些显着的结果可能是由于这些新的 topsentin 类似物对上皮-间质转化标志物的影响，包括 SNAIL-1/2 和金属蛋白酶-9。此外，Annexin V-FITC 和碘化丙啶染色后的流式细胞术分析表明，这些衍生物增强了 PDAC 细胞的凋亡。与这些数据保持一致，PathScan 细胞内信号传导和 ELISA 阵列显示 caspase-3 和 PARP 的裂解以及 GSK3β 磷酸化的显着抑制，表明该

  DOI：

  10.1002/cmdc.202000752

文献信息

• 3-indolyl-4-phenyl-1H-pyrrole-2,5-dione derivatives as inhibitors of glycogen synthase kinase-3beta
  申请人：——

  公开号：US20020052397A1

  公开（公告）日：2002-05-02

  This invention relates to inhibitors of glycogen synthase kinase- 3 &bgr;, methods of treating diseases characterized by an excess of Th 2 cytokines, and to 3 -indolyl- 4 -phenyl- 1 H-pyrrole- 2,5 -dione derivatives of Formula (I): 1 that are inhibitors of glycogen synthase kinase - 3 &bgr;, pharmaceutical compositions containing them, methods for their use and methods for preparing these compounds.

  这项发明涉及抑制糖原合成酶激酶-3β的方法，用于治疗由Th2细胞因子过多引起的疾病，以及3-吲哚基-4-苯基-1H-吡咯-2,5-二酮衍生物的化合物(I)的方法：这些化合物是糖原合成酶激酶-3β的抑制剂，包含它们的药物组合物，使用它们的方法以及制备这些化合物的方法。
• Methods for increasing bone formation using inhibitors of glycogen synthase kinase-3 betta
  申请人：Syntex (U.S.A.) LLC

  公开号：US20030176484A1

  公开（公告）日：2003-09-18

  This invention relates to the use of inhibitors of glycogen synthase kinase-3&bgr; to increase bone formation.

  这项发明涉及利用糖原合成激酶-3β抑制剂来增加骨形成。
• Structural Manipulations of Marine Natural Products Inspire a New Library of 3-Amino-1,2,4-Triazine PDK Inhibitors Endowed with Antitumor Activity in Pancreatic Ductal Adenocarcinoma
  作者：Daniela Carbone、Michele De Franco、Camilla Pecoraro、Davide Bassani、Matteo Pavan、Stella Cascioferro、Barbara Parrino、Girolamo Cirrincione、Stefano Dall’Acqua、Stefania Sut、Stefano Moro、Valentina Gandin、Patrizia Diana

  DOI：10.3390/md21050288

  日期：——

  Pancreatic ductal adenocarcinoma (PDAC) is one of the main aggressive types of cancer, characterized by late prognosis and drug resistance. Among the main factors sustaining PDAC progression, the alteration of cell metabolism has emerged to have a key role in PDAC cell proliferation, invasion, and resistance to standard chemotherapeutic agents. Taking into account all these factors and the urgency in evaluating novel options to treat PDAC, in the present work we reported the synthesis of a new series of indolyl-7-azaindolyl triazine compounds inspired by marine bis-indolyl alkaloids. We first assessed the ability of the new triazine compounds to inhibit the enzymatic activity of pyruvate dehydrogenase kinases (PDKs). The results showed that most of derivatives totally inhibit PDK1 and PDK4. Molecular docking analysis was executed to predict the possible binding mode of these derivatives using ligand-based homology modeling technique. Evaluation of the capability of new triazines to inhibit the cell growth in 2D and 3D KRAS-wild-type (BxPC-3) and KRAS-mutant (PSN-1) PDAC cell line, was carried out. The results showed the capacity of the new derivatives to reduce cell growth with a major selectivity against KRAS-mutant PDAC PSN-1 on both cell models. These data demonstrated that the new triazine derivatives target PDK1 enzymatic activity and exhibit cytotoxic effects on 2D and 3D PDAC cell models, thus encouraging further structure manipulation for analogs development against PDAC.

  胰腺导管腺癌（PDAC）是主要的侵袭性癌症类型之一，具有预后晚和耐药性强的特点。在维持 PDAC 进展的主要因素中，细胞新陈代谢的改变已成为 PDAC 细胞增殖、侵袭和对标准化疗药物产生耐药性的关键因素。考虑到所有这些因素以及评估治疗 PDAC 的新方案的紧迫性，我们在本研究中报告了受海洋双吲哚生物碱启发合成的一系列新的吲哚基-7-氮杂吲哚基三嗪化合物。我们首先评估了新三嗪化合物抑制丙酮酸脱氢酶激酶（PDKs）酶活性的能力。结果表明，大多数衍生物能完全抑制 PDK1 和 PDK4。利用基于配体的同源建模技术进行了分子对接分析，以预测这些衍生物可能的结合模式。研究还评估了新型三嗪类化合物在二维和三维 KRAS 野生型（BxPC-3）和 KRAS 突变型（PSN-1）PDAC 细胞系中抑制细胞生长的能力。结果表明，新衍生物能够降低两种细胞模型中 KRAS 突变型 PDAC PSN-1 的细胞生长，并对其具有较大的选择性。这些数据表明，新的三嗪衍生物以 PDK1 酶活性为靶点，在二维和三维 PDAC 细胞模型上表现出细胞毒性作用，从而鼓励了针对 PDAC 类似物开发的进一步结构操作。
• Discovery of the 3-Amino-1,2,4-triazine-Based Library as Selective PDK1 Inhibitors with Therapeutic Potential in Highly Aggressive Pancreatic Ductal Adenocarcinoma
  作者：Daniela Carbone、Michele De Franco、Camilla Pecoraro、Davide Bassani、Matteo Pavan、Stella Cascioferro、Barbara Parrino、Girolamo Cirrincione、Stefano Dall’Acqua、Stefano Moro、Valentina Gandin、Patrizia Diana

  DOI：10.3390/ijms24043679

  日期：——

  aggressiveness and resistance. Dichloroacetic acid (DCA) is the first PDK inhibitor that has entered phase II clinical; however, several side effects associated with weak anticancer activity and excessive drug dose (100 mg/kg) have led to its limitation in clinical application. Building upon a molecular hybridization approach, a small library of 3-amino-1,2,4-triazine derivatives has been designed,

  丙酮酸脱氢酶激酶 (PDK) 是丝氨酸/苏氨酸激酶，直接参与改变癌细胞代谢，导致癌症侵袭性和耐药性。二氯乙酸（DCA）是第一个进入II期临床的PDK抑制剂；然而，抗癌活性弱和药物剂量过高（100 mg/kg）相关的一些副作用导致其在临床应用中受到限制。基于分子杂交方法，设计、合成了一个小型 3-氨基-1,2,4-三嗪衍生物文库，并使用计算机、体外和体内测定对其 PDK 抑制活性进行了表征。生化筛选表明所有合成的化合物都是PDK的有效亚型选择性抑制剂。因此，分子模型研究表明，许多配体可以正确放置在 PDK1 的 ATP 结合位点内。有趣的是，2D 和 3D 细胞研究揭示了它们在低微摩尔剂量下诱导癌细胞死亡的能力，对人类胰腺 KRAS 突变癌细胞极其有效。细胞机制研究证实它们能够阻碍 PDK/PDH 轴，从而导致代谢/氧化还原细胞损伤，并最终引发癌细胞凋亡。值得注意的是，在高度侵袭性和转移性 Kras
• Structure-Based Design Leads to the Identification of Lithium Mimetics That Block Mania-like Effects in Rodents. Possible New GSK-3β Therapies for Bipolar Disorders
  作者：Alan P. Kozikowski、Irina N. Gaisina、Hongbin Yuan、Pavel A. Petukhov、Sylvie Y. Blond、Allison Fedolak、Barbara Caldarone、Paul McGonigle

  DOI：10.1021/ja068969w

  日期：2007.7.1

  More than two million American adults, or approximately one percent of the population 18 years or older, suffer from bipolar disorder. Current treatments include the so-called "mood stabilizers," lithium and valproic acid. Both are relatively dated drugs that are only partially effective and produce various undesirable side effects including weight gain. Based upon continued efforts to understand the molecular target for lithium, it now appears that specific inhibitors of the enzyme glycogen synthase kinase-3 beta (GSK-3 beta) may mimic the therapeutic action of mood stabilizers and might therefore allow for the design of improved drugs for treating patients with bipolar disorder as well as certain neurodegenerative disorders. Furthermore, the pro-apoptotic properties of the GSK-3 enzyme suggest the possible use of such inhibitors as neuroprotective agents. In fact, neuroprotection may contribute to the treatment of mood disorders. The present chemistry, modeling, and biology efforts have identified 3-benzofuranyl-4-indolylmaleimides as potent and relatively selective GSK-3 beta inhibitors. The best ligand in this series (having a K-i value of 4.6 nM against GSK-3 beta) was studied in a novel mouse model of mania that has recently been validated with several clinically effective mood stabilizers. This study presents the first demonstration of the efficacy of a GSK-3 beta inhibitor in this mouse model of mania. Selective brain penetrable GSK-3 ligands like those described herein become valuable research tools in better defining the role of this multifaceted kinase in both physiological and pathophysiological events.