allyl-9-formyl-10-hydroxy-7-oxo-2,3,5,6-tetrahydro-1H-chromeno[3,4-d]azocine-4(7H)-carboxylate | 1607803-39-3

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 香豆素及其衍生物
• 英文名称: allyl-9-formyl-10-hydroxy-7-oxo-2,3,5,6-tetrahydro-1H-chromeno[3,4-d]azocine-4(7H)-carboxylate
• 英文别名: Prop-2-enyl 6-formyl-5-hydroxy-9-oxo-8-oxa-12-azatricyclo[8.6.0.02,7]hexadeca-1(10),2(7),3,5-tetraene-12-carboxylate；prop-2-enyl 6-formyl-5-hydroxy-9-oxo-8-oxa-12-azatricyclo[8.6.0.02,7]hexadeca-1(10),2(7),3,5-tetraene-12-carboxylate
• CAS: 1607803-39-3
• 化学式: C₁₉H₁₉NO₆
• 分子量: 357.363
• InChiKey: QLXJRUHYMGPSSJ-UHFFFAOYSA-N

物化性质

• 沸点：
  563.0±50.0 °C(predicted)
• 密度：
  1.37±0.1 g/cm3(Temp: 20 °C; Press: 760 Torr)(predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.2
• 重原子数：
  26
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.32
• 拓扑面积：
  93.1
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  5-{[(prop-2-en-1-yloxy)carbonyl]amino}pentanoic acid 在 4-二甲氨基吡啶 、 溶剂黄146 、 N,N'-二异丙基碳二亚胺 作用下， 以 甲烷磺酸 、 二氯甲烷 为溶剂， 反应 42.5h， 生成 allyl-9-formyl-10-hydroxy-7-oxo-2,3,5,6-tetrahydro-1H-chromeno[3,4-d]azocine-4(7H)-carboxylate
  参考文献：
  名称：

  Synthesis of Novel Tricyclic Chromenone-Based Inhibitors of IRE-1 RNase Activity

  摘要：

  Inositol-requiring enzyme 1 (IRE-1) is a kinase/RNase ER stress sensor that is activated in response to excessive accumulation of unfolded proteins, hypoxic conditions, calcium imbalance, and other stress stimuli. Activation of IRE-1 RNase function exerts a cytoprotective effect and has been implicated in the progression of cancer via increased expression of the transcription factor XBP-1s. Here, we describe the synthesis and biological evaluation of novel chromenone-based covalent inhibitors of IRE-1. Preparation of a family of 8-formyltetrahydrochromeno[3,4-c]pyridines was achieved via a Duff formylation that is attended by an unusual cyclization reaction. Biological evaluation in vitro and in whole cells led to the identification of 30 as a potent inhibitor of IRE-1 RNase activity and XBP-1s expression in wild type B cells and human mantle cell lymphoma cell lines.

  DOI：

  10.1021/jm5002452

文献信息

• [EN] INHIBITORS OF THE IRE-1/XBP-1 PATHWAY AND METHODS OF USING THEREOF<br/>[FR] INHIBITEURS DE LA VOIE IRE-1/XBP-1 ET PROCÉDÉS D'UTILISATION ASSOCIÉS
  申请人：H LEE MOFFITT CANCER CT & RES

  公开号：WO2014176348A1

  公开（公告）日：2014-10-30

  Disclosed are XBP-1/IRE-1 inhibitors having formula disclosed herein. Methods of making and using these inhibitors for the treatment of cancer, in particular B cell cancers, are also disclosed. Also disclosed is a genetic XBP-1 -knockout cancer mouse model. In still further aspects, the disclosed subject matter relates to methods for treating oncological and inflammatory disorders in a patient. For example, disclosed herein are methods whereby an effective amount of a compound or composition disclosed herein is administered to a patient having an oncological disorder, for example B-cell chronic lymphocytic leukemia (CLL), and who is in need of treatment thereof. XBP-1 deficiency causes leukemic cells to acquire phenotypes that are disadvantageous for their survival, such as compromised BCR signaling capability and increased surface expression of S1 P1.

  本公开了具有以下公开的化学式的XBP-1/IRE-1抑制剂。还公开了制备和使用这些抑制剂治疗癌症，特别是B细胞癌症的方法。还公开了一种基因XBP-1敲除的癌症小鼠模型。此外，所公开的主题还涉及治疗患者的肿瘤和炎症性疾病的方法。例如，本文公开了一种方法，根据该方法，向需要治疗的患有肿瘤性疾病（例如B细胞慢性淋巴细胞白血病（CLL））的患者施用本文公开的化合物或组合物的有效量。XBP-1缺乏导致白血病细胞获得对其生存不利的表型，例如受损的BCR信号传导能力和S1P1的表面表达增加。
• Synthesis of Novel Tricyclic Chromenone-Based Inhibitors of IRE-1 RNase Activity
  作者：Sujeewa Ranatunga、Chih-Hang Anthony Tang、Chang Won Kang、Crystina L. Kriss、Bernhard J. Kloppenburg、Chih-Chi Andrew Hu、Juan R. Del Valle

  DOI：10.1021/jm5002452

  日期：2014.5.22

  Inositol-requiring enzyme 1 (IRE-1) is a kinase/RNase ER stress sensor that is activated in response to excessive accumulation of unfolded proteins, hypoxic conditions, calcium imbalance, and other stress stimuli. Activation of IRE-1 RNase function exerts a cytoprotective effect and has been implicated in the progression of cancer via increased expression of the transcription factor XBP-1s. Here, we describe the synthesis and biological evaluation of novel chromenone-based covalent inhibitors of IRE-1. Preparation of a family of 8-formyltetrahydrochromeno[3,4-c]pyridines was achieved via a Duff formylation that is attended by an unusual cyclization reaction. Biological evaluation in vitro and in whole cells led to the identification of 30 as a potent inhibitor of IRE-1 RNase activity and XBP-1s expression in wild type B cells and human mantle cell lymphoma cell lines.