8-hydroxy-3-methyl-5-oxo-2,3,4,5-tetrahydro-1H-chromeno[3,4-c]pyridine-7-carbaldehyde | 1607803-45-1

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并吡喃
• 英文名称: 8-hydroxy-3-methyl-5-oxo-2,3,4,5-tetrahydro-1H-chromeno[3,4-c]pyridine-7-carbaldehyde
• 英文别名: 8-hydroxy-3-methyl-5-oxo-2,4-dihydro-1H-chromeno[3,4-c]pyridine-7-carbaldehyde
• CAS: 1607803-45-1
• 化学式: C₁₄H₁₃NO₄
• 分子量: 259.262
• InChiKey: AIQJUHLNDAWJNC-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1
• 重原子数：
  19
• 可旋转键数：
  1
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.29
• 拓扑面积：
  66.8
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  8-hydroxy-3-methyl-5-oxo-2,3,4,5-tetrahydro-1H-chromeno[3,4-c]pyridine-7-carbaldehyde 、 乙酰肼 在 溶剂黄146 作用下， 以 乙醇 为溶剂， 反应 3.0h， 以83%的产率得到(E)-N'-((8-hydroxy-3-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridin-7-yl)methylene)acetohydrazide
  参考文献：
  名称：

  [EN] SUBSTITUTED CHROMENONES, IRE1 INHIBITORS, AND METHODS OF USING SAME
  [FR] CHROMÉNONES SUBSTITUÉES, INHIBITEURS D'IRE1 ET PROCÉDÉS D'UTILISATION ASSOCIÉS

  摘要：

  本发明包括有用于抑制IRE1/XBP-1途径的取代香豆素。在某些实施方式中，本发明的化合物抑制IRE1的RNase活性。在其他实施方式中，本发明的化合物用于治疗或预防涉及ER应激反应激活的癌症。本发明还涉及在某些方面的发现，即分泌型IgM（sIgM）可以通过将髓样来源的抑制细胞（MDSCs）招募到不同的肿瘤模型中，如但不限于固体肿瘤（如肺癌）和具有高水平分泌IgM的肿瘤。在某些实施方式中，由B细胞或CLL细胞产生的sIgM可以促进肿瘤中MDSCs的积累。在其他实施方式中，抑制IRE1/XBP-1途径可以消除、最小化或减少肿瘤中的MDSC水平。

  公开号：

  WO2019195135A1
• 作为产物：
  描述：

  7-(1,3-二恶烷-2-基)-1,2,3,4-四氢-8-羟基-5H-[1]苯并吡喃并[3,4-c]吡啶-5-一 在 palladium on activated charcoal 、 氢气 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 水 为溶剂， 反应 3.5h， 生成 8-hydroxy-3-methyl-5-oxo-2,3,4,5-tetrahydro-1H-chromeno[3,4-c]pyridine-7-carbaldehyde
  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
• 作为试剂：
  描述：

  7-(1,3-二恶烷-2-基)-1,2,3,4-四氢-8-羟基-5H-[1]苯并吡喃并[3,4-c]吡啶-5-一 、 四氢呋喃 、 聚合甲醛 、 盐酸 在 钯 甲醇 、 8-hydroxy-3-methyl-5-oxo-2,3,4,5-tetrahydro-1H-chromeno[3,4-c]pyridine-7-carbaldehyde 、 二氯甲烷 、 Sodium sulfate-III 、 silica gel 、 chloroform methanol 作用下， 以 1,4-二氧六环 、 水 为溶剂， 反应 3.5h， 以afforded 30 as a white powder (35 mg, 67%)的产率得到8-hydroxy-3-methyl-5-oxo-2,3,4,5-tetrahydro-1H-chromeno[3,4-c]pyridine-7-carbaldehyde
  参考文献：
  名称：

  INHIBITORS OF THE IRE-1/XBP-1 PATHWAY AND METHODS OF USING THEREOF

  摘要：

  本文披露了具有公式所述的XBP-1/IRE-1抑制剂。还披露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。此外，还披露了一种遗传XBP-1敲除癌症小鼠模型。在更进一步的方面，所披露的主题涉及用于治疗患者的肿瘤和炎症性疾病的方法。例如，本文披露了将公式所述的化合物或组合物的有效量给予患有肿瘤疾病（例如B细胞慢性淋巴细胞白血病（CLL））并需要治疗的患者的方法。XBP-1缺乏会导致白血病细胞获得对其生存不利的表型，例如受损的BCR信号传导能力和增加的S1 P1表面表达。

  公开号：

  US20160083361A1

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。
• Inhibitors of the IRE-1/XBP-1 pathway and methods of using thereof
  申请人：H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE, INC.

  公开号：US10323013B2

  公开（公告）日：2019-06-18

  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 S1P1.

  所公开的是具有本文所公开式的 XBP-1/IRE-1 抑制剂。还公开了制造和使用这些抑制剂治疗癌症，特别是 B 细胞癌症的方法。还公开了一种遗传 XBP-1 基因敲除癌症小鼠模型。在更多方面，所公开的主题涉及治疗患者肿瘤和炎症性疾病的方法。例如，本文公开的方法是将有效量的本文公开的化合物或组合物施用给患有肿瘤疾病（例如B细胞慢性淋巴细胞白血病（CLL））且需要治疗的患者。XBP-1 缺乏会导致白血病细胞获得不利于其存活的表型，如 BCR 信号转导能力受损和 S1P1 表面表达增加。
• Structural Tailoring of a Novel Fluorescent IRE-1 RNase Inhibitor to Precisely Control Its Activity
  作者：Andong Shao、Chang Won Kang、Chih-Hang Anthony Tang、Christopher F. Cain、Qin Xu、Claire M. Phoumyvong、Juan R. Del Valle、Chih-Chi Andrew Hu

  DOI：10.1021/acs.jmedchem.9b00269

  日期：2019.6.13

  Activation of the IRE-1/XBP-1 pathway has been linked to many human diseases. We report a novel fluorescent tricyclic chromenone inhibitor, D-F07, in which we incorporated a 9-methoxy group onto the chromenone core to enhance its potency and masked the aldehyde to achieve long-term efficacy. Protection of the aldehyde as a 1,3-dioxane acetal led to strong fluorescence emitted by the coumarin chromophore, enabling D-F07 to be tracked inside the cell. We installed a photolabile structural cage on the hydroxy group of D-F07 to generate PC-D-F07. Such a modification significantly stabilized the 1,3-dioxane acetal protecting group, allowing for specific stimulus-mediated control of inhibitory activity. Upon photoactivation, the re-exposed hydroxy group on D-F07 triggered the aldehyde-protecting 1,3-dioxane acetal to slowly decompose, leading to the inhibition of the RNase activity of IRE-1. Our novel findings will also allow for spatiotemporal control of the inhibitory effect of other salicylaldehyde-based compounds currently in development.
• Substituted Chromenones, IRE1 Inhibitors, and Methods of Using Same
  申请人：The Wistar Institute

  公开号：US20210008043A1

  公开（公告）日：2021-01-14

  The present invention includes substituted chromenones that are useful to inhibit the IRE1/XBP-1 pathway. In certain embodiments, the compounds of the invention inhibit IRE1's RNase activity. In other embodiments, the compounds of the invention are useful to treat or prevent a cancer that involve activation of the ER stress response. The invention also relates, in certain aspects, to the discovery that secretory IgM (sIgM) can orchestrate an immunosuppressive microenvironment by recruiting myeloid-derived suppressor cells (MDSCs) into different tumor models, such as but not limited to solid tumors (such as but not limited to lung cancer) and tumors that have high levels of secreted IgM. In certain embodiments, sIgM produced by B cells or CLL cells can contribute to the accumulation of MDSCs in a tumor. In other embodiments, inhibition of the IRE1/XBP-1 pathway can ablate, minimize, or reduce MDSC levels in a tumor.
• 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.