methyl (E)-3-(6-fluoro-1H-indol-3-yl)acrylate | 1316695-38-1

• 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: methyl (E)-3-(6-fluoro-1H-indol-3-yl)acrylate
• 英文别名: methyl (E)-3-(6-fluoro-1H-indol-3-yl)prop-2-enoate
• CAS: 1316695-38-1
• 化学式: C₁₂H₁₀FNO₂
• 分子量: 219.215
• InChiKey: CKXVPLTXKONPSQ-GORDUTHDSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.4
• 重原子数：
  16
• 可旋转键数：
  3
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.08
• 拓扑面积：
  42.1
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  methyl (E)-3-(6-fluoro-1H-indol-3-yl)acrylate 在 水 、 potassium hydroxide 作用下， 以 乙醇 为溶剂， 反应 1.0h， 以82%的产率得到(E)-3-(6-fluoro-1H-indol-3-yl)acrylic acid
  参考文献：
  名称：

  Tryptophan 2,3-Dioxygenase (TDO) Inhibitors. 3-(2-(Pyridyl)ethenyl)indoles as Potential Anticancer Immunomodulators

  摘要：

  Tryptophan catabolism mediated by indoleamine 2,3-dioxygenase (IDO) is an important mechanism of peripheral immune tolerance contributing to tumoral immune resistance. IDO inhibition is thus an active area of research in drug development. Recently, our group has shown that tryptophan 2,3-dioxygenase (TDO), an unrelated hepatic enzyme also catalyzing the first step of tryptophan degradation, is also expressed in many tumors and that this expression prevents tumor rejection by locally depleting tryptophan. Herein, we report a structure- activity study on a series of 3-(2-(pyridyl)ethenyl)indoles. More than 70 novel derivatives were synthesized, and their TDO inhibitory potency was evaluated. The rationalization of the structure-activity relationships (SARs) revealed essential features to attain high TDO inhibition and notably a dense H-bond network mainly involving His(55) and Thr(254) residues. Our study led to the identification of a very promising compound (58) displaying good TDO inhibition (K-i = 5.5 mu M), high selectivity, and good oral bioavailability. Indeed, 58 was chosen for preclinical evaluation.

  DOI：

  10.1021/jm2006782
• 作为产物：
  描述：

  6-氟吲哚 、 丙烯酸甲酯（MA） 在 palladium diacetate 、 copper(II) acetate monohydrate 作用下， 以 二甲基亚砜 、 N,N-二甲基甲酰胺 为溶剂， 反应 18.0h， 以79%的产率得到methyl (E)-3-(6-fluoro-1H-indol-3-yl)acrylate
  参考文献：
  名称：

  Tryptophan 2,3-Dioxygenase (TDO) Inhibitors. 3-(2-(Pyridyl)ethenyl)indoles as Potential Anticancer Immunomodulators

  摘要：

  Tryptophan catabolism mediated by indoleamine 2,3-dioxygenase (IDO) is an important mechanism of peripheral immune tolerance contributing to tumoral immune resistance. IDO inhibition is thus an active area of research in drug development. Recently, our group has shown that tryptophan 2,3-dioxygenase (TDO), an unrelated hepatic enzyme also catalyzing the first step of tryptophan degradation, is also expressed in many tumors and that this expression prevents tumor rejection by locally depleting tryptophan. Herein, we report a structure- activity study on a series of 3-(2-(pyridyl)ethenyl)indoles. More than 70 novel derivatives were synthesized, and their TDO inhibitory potency was evaluated. The rationalization of the structure-activity relationships (SARs) revealed essential features to attain high TDO inhibition and notably a dense H-bond network mainly involving His(55) and Thr(254) residues. Our study led to the identification of a very promising compound (58) displaying good TDO inhibition (K-i = 5.5 mu M), high selectivity, and good oral bioavailability. Indeed, 58 was chosen for preclinical evaluation.

  DOI：

  10.1021/jm2006782

文献信息

• 10.1021/acs.joc.4c00929
  作者：Xiong, Shu-Shu、Jian, Cui、Mo, Yan-Qing、Hu, Wei、He, Yong-Ke、Ren, Bao-Yi、Yang, Yu-Ming、Li, Shaoyu

  DOI：10.1021/acs.joc.4c00929

  日期：——

  contrast to the well-developed hydrogen functionalization. Current exploration on [4 + 2] cyclization of vinylpyridines mainly relies on extremely high temperatures and the LUMO activation of vinylpyridines using boron trifluoride as a strong Lewis acid. Herein, we established a phosphoric acid-catalyzed [4 + 2] cyclization reaction of 3-vinyl-1H-indoles and 2-vinylpyridines by means of the LUMO/HOMO

  与成熟的氢官能化相比，基于环化策略的乙烯基吡啶双官能化仍然罕见且不发达。目前对乙烯基吡啶[4+2]环化的探索主要依赖于极高的温度和使用三氟化硼作为强路易斯酸对乙烯基吡啶的LUMO活化。在此，我们通过LUMO/HOMO双功能激活模型建立了磷酸催化的3-乙烯基-1H-吲哚和2-乙烯基吡啶的[4+2]环化反应。该方案具有反应条件温和、官能团耐受性高、底物兼容性广、非对映选择性高等特点，能够高效构建各种功能化吡啶取代四氢咔唑，在药物发现方面具有突出的潜力。
• Tryptophan 2,3-Dioxygenase (TDO) Inhibitors. 3-(2-(Pyridyl)ethenyl)indoles as Potential Anticancer Immunomodulators
  作者：Eduard Dolušić、Pierre Larrieu、Laurence Moineaux、Vincent Stroobant、Luc Pilotte、Didier Colau、Lionel Pochet、Benoît Van den Eynde、Bernard Masereel、Johan Wouters、Raphaël Frédérick

  DOI：10.1021/jm2006782

  日期：2011.8.11

  Tryptophan catabolism mediated by indoleamine 2,3-dioxygenase (IDO) is an important mechanism of peripheral immune tolerance contributing to tumoral immune resistance. IDO inhibition is thus an active area of research in drug development. Recently, our group has shown that tryptophan 2,3-dioxygenase (TDO), an unrelated hepatic enzyme also catalyzing the first step of tryptophan degradation, is also expressed in many tumors and that this expression prevents tumor rejection by locally depleting tryptophan. Herein, we report a structure- activity study on a series of 3-(2-(pyridyl)ethenyl)indoles. More than 70 novel derivatives were synthesized, and their TDO inhibitory potency was evaluated. The rationalization of the structure-activity relationships (SARs) revealed essential features to attain high TDO inhibition and notably a dense H-bond network mainly involving His(55) and Thr(254) residues. Our study led to the identification of a very promising compound (58) displaying good TDO inhibition (K-i = 5.5 mu M), high selectivity, and good oral bioavailability. Indeed, 58 was chosen for preclinical evaluation.
• Aerobic C–H Olefination of Indoles via a Cross-Dehydrogenative Coupling in Continuous Flow
  作者：Hannes P. L. Gemoets、Volker Hessel、Timothy Noël

  DOI：10.1021/ol502910e

  日期：2014.11.7

  Herein, we report the first site-selective, Pd(II)-catalyzed, cross-dehydrogenative Heck reaction of indoles in micro flow. By use of a capillary microreactor, we were able to boost the intrinsic kinetics to accelerate former hour-scale reaction conditions in batch to the minute range in flow. The synergistic use of microreactor technology and oxygen, as both terminal oxidant and mixing motif, highlights the sustainable aspect of this process.