allyl-8-hydroxy-7-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-chromeno [3,4-c] pyridine3(2H)-carboxylate | 1607803-64-4

• 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: allyl-8-hydroxy-7-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-chromeno [3,4-c] pyridine3(2H)-carboxylate
• 英文别名: Allyl 8-hydroxy-7-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-chromeno[3,4-c]pyridine-3(2H)-carboxylate；prop-2-enyl 8-hydroxy-7-(hydroxymethyl)-5-oxo-2,4-dihydro-1H-chromeno[3,4-c]pyridine-3-carboxylate
• CAS: 1607803-64-4
• 化学式: C₁₇H₁₇NO₆
• 分子量: 331.325
• InChiKey: FGFNZDKQPAEEPZ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.2
• 重原子数：
  24
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.29
• 拓扑面积：
  96.3
• 氢给体数：
  2
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  allyl-8-hydroxy-7-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-chromeno [3,4-c] pyridine3(2H)-carboxylate 在 氯化亚砜 作用下， 以 二氯甲烷 为溶剂， 反应 5.5h， 以67%的产率得到prop-2-enyl 7-(chloromethyl)-8-hydroxy-5-oxo-2,4-dihydro-1H-chromeno[3,4-c]pyridine-3-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
• 作为产物：
  描述：

  3-(allyloxycarbonylamino)propionic acid 在 吡啶 、 4-二甲氨基吡啶 、 sodium tetrahydroborate 、 乙酸酐 、 N,N'-二异丙基碳二亚胺 作用下， 以 甲醇 、 甲烷磺酸 、 二氯甲烷 、 乙腈 为溶剂， 反应 49.17h， 生成 allyl-8-hydroxy-7-(hydroxymethyl)-5-oxo-4,5-dihydro-1H-chromeno [3,4-c] pyridine3(2H)-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。
• 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：US20160083361A1

  公开（公告）日：2016-03-24

  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。
• 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。
• 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.