(5-methoxy-1-methyl-1H-indol-3-yl)-oxo-acetyl chloride | 16382-43-7

• 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-methoxy-1-methyl-1H-indol-3-yl)-oxo-acetyl chloride
• 英文别名: 2-(5-Methoxy-1-methylindol-3-yl)-2-oxoacetyl chloride
• CAS: 16382-43-7
• 化学式: C₁₂H₁₀ClNO₃
• 分子量: 251.669
• InChiKey: ZJUGTCYOQGGMJF-UHFFFAOYSA-N

物化性质

• 沸点：
  428.6±48.0 °C(Predicted)
• 密度：
  1.33±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.4
• 重原子数：
  17
• 可旋转键数：
  3
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.17
• 拓扑面积：
  48.3
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  (5-methoxy-1-methyl-1H-indol-3-yl)-oxo-acetyl chloride 在 potassium tert-butylate 作用下， 以 四氢呋喃 、 乙醚 、 乙醇 为溶剂， 生成 3-(benzofuran-3-yl)-4-(5-methoxy-1-methyl-1H-indol-3-yl)pyrrole-2,5-dione
  参考文献：
  名称：

  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

  摘要：

  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.

  DOI：

  10.1021/ja068969w
• 作为产物：
  描述：

  5-甲氧基吲哚 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-methoxy-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

• Substituted pyrroles
  申请人：Hoffmann-La Roche Inc.

  公开号：US06228877B1

  公开（公告）日：2001-05-08

  Compounds of the formula wherein R1 and R1′ are independently alkyl, aryl, alkenyl or alkynyl; R2 and R2′ are independently hydrogen, alkyl, aralkyl, alkoxyalkyl, hydroxyalkyl, haloalkyl, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, acylaminoalkyl, alkylsulphonylaminoalkyl, arylsulphonyl-aminoalkyl, mercaptoalkyl, alkylthioalkyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl, alkylthio or alkylsulphinyl; R4, R5, R6, R7, R4′, R5′, R6′, and R7′ each independently are hydrogen, CO2R9, CH2OR10, CHO, CH2NR11R12, CON(R13)2, halogen, cyano, aryl, alkyl, hydroxy, alkoxy, aryloxy, haloalkyl, nitro, amino, aralkyloxy, acylamino, monoalkylamino, dialkylamino, thio, alkyl, alkylsulphinyl, alkylsulphonyl, arylsulphinyl, azide, phosphate or phosphonate provided that at least one of R4, R5, R6 and R7 and at least one of R4′, R5′, R6′, and R7′ are other than hydrogen, with the proviso that when R6 is methoxy, R5 or R5′ are not methoxy; R8 is alkyl or aryl; R9 is alkyl or aryl; R10 is hydrogen, alkyl or aryl; R11 and R12 are independently hydrogen, alkyl, aryl, aralkyl or acyl; R13 is hydrogen, alkyl, aryl or aralkyl; and one of X and Y signifies O and the other signifies O, S, (H,OH) or (H,H); as well as pharmaceutically acceptable prodrugs or pharmaceutically acceptable salts of acidic compounds of formula I with bases and or basic compounds of formula I with acids are antiproliferative agents useful in the treatment of cancer.

  化合物的公式为其中R1和R1'分别独立地为烷基、芳基、烯基或炔基；R2和R2'分别独立地为氢、烷基、芳基烷基、烷氧基烷基、羟基烷基、卤代烷基、氨基烷基、单烷基氨基烷基、双烷基氨基烷基、酰胺基烷基、烷基磺酰胺基烷基、芳基磺酰胺基烷基、巯基烷基、烷硫基烷基、羧基烷基、烷氧羰基烷基、氨基羰基烷基、烷硫基或烷基亚磺酰基；R4、R5、R6、R7、R4'、R5'、R6'和R7'各自独立地为氢、CO2R9、CH2OR10、CHO、CH2NR11R12、CON(R13)2、卤素、氰基、芳基、烷基、羟基、烷氧基、芳氧基、卤代烷基、硝基、氨基、芳基氧基、酰胺基、单烷基氨基、双烷基氨基、硫基、烷基、烷基亚磺酰基、烷基磺酰基、芳基亚磺酰基、偶氮基、磷酸酯或膦酸酯，但至少有R4、R5、R6和R7中的一个和R4'、R5'、R6'和R7'中的一个不是氢，如果R6是甲氧基，则R5或R5'不是甲氧基；R8为烷基或芳基；R9为烷基或芳基；R10为氢、烷基或芳基；R11和R12独立地为氢、烷基、芳基、芳基烷基或酰基；R13为氢、烷基、芳基或芳基烷基；X和Y中的一个表示O，另一个表示O、S、(H,OH)或(H,H)；以及公式I的酸性化合物的药学上可接受的前药或与酸的公式I的碱性化合物的药学上可接受的盐是抗增殖剂，可用于癌症的治疗。
• Serotonergic alpha-oxoacetamides
  申请人：Syntex (U.S.A.) Inc.

  公开号：US05192770A1

  公开（公告）日：1993-03-09

  .alpha.-Oxoacetamides of the formula R.sup.1 C(O)C(O)NR.sup.2 R.sup.3 in which R.sup.1 is optionally substituted phenyl, 1-indolyl, 2,3-dihydro-1-indolyl, 1-benzimidazolidinonyl, 3-benzofuranyl, 3-benzothiophenyl, 3-indolyl, and 1,2-alkano-3-indolyl; R.sup.2 is selected from: ##STR1## and R.sup.3 is selected from hydrogen or lower alkyl; and the pharmaceutically acceptable salts, individual isomers, mixtures of isomers, processes for preparation, compositions, and methods of use thereof.

  该文献描述了式为R.sup.1 C(O)C(O)NR.sup.2 R.sup.3的.alpha.-羰基乙酰胺，其中R.sup.1为可选取代的苯基、1-吲哚基、2,3-二氢-1-吲哚基、1-苯并咪唑啉基、3-苯并呋喃基、3-苯并硫杂苯基、3-吲哚基和1,2-烷基-3-吲哚基；R.sup.2选自：##STR1## R.sup.3选自氢或低碳基；以及其药学上可接受的盐、单体异构体、异构体混合物、制备过程、组合物和使用方法。
• 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
• Substituierte Pyrrole
  申请人：F. HOFFMANN-LA ROCHE AG

  公开号：EP0328026A1

  公开（公告）日：1989-08-16

  Pyrrole der allgemeinen Formel worin R¹, R², R³, R⁴, R⁵, R⁶, R⁷, X und Y die in der Beschreibung angegebene Bedeutung haben sind verwendbar bei der Behandlung oder Prophylaxe von inflammatorischen, immunologischen, bronchopulmonären oder cardiovaskulären Krankheiten. Sie werden ausgehend von entsprechend substituierten Furanen oder von auf andere Weise substituierten Pyrrolen hergestellt.

  通式如下的吡咯 其中 R¹、R²、R³、R⁴、R⁵、R⁶、R⁷、X 和 Y 具有说明中给出的含义，可用于治疗或预防炎症、免疫学、支气管肺病或心血管疾病。 它们由适当取代的呋喃或其他取代的吡咯制备而成。