2,3-dihydroxy-5,12b-dihydroisoindolo[1,2-a]isoquinolin-8(6H)-one | 1251442-93-9

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 异吲哚及其衍生物
• 英文名称: 2,3-dihydroxy-5,12b-dihydroisoindolo[1,2-a]isoquinolin-8(6H)-one
• 英文别名: 2,3-dihydroxy-6,12b-dihydro-5H-isoindolo[1,2-a]isoquinolin-8-one
• CAS: 1251442-93-9
• 化学式: C₁₆H₁₃NO₃
• 分子量: 267.284
• InChiKey: FWRLMAIFAGODSO-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2
• 重原子数：
  20
• 可旋转键数：
  0
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.19
• 拓扑面积：
  60.8
• 氢给体数：
  2
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  2,3-dihydroxy-5,12b-dihydroisoindolo[1,2-a]isoquinolin-8(6H)-one 在 silver(l) oxide 作用下， 以 1,2-二氯乙烷 为溶剂， 反应 12.0h， 以49%的产率得到2-hydroxy-5,6-dihydroisoindolo[1,2-a]isoquinoline-3,8-dione
  参考文献：
  名称：

  IinQ attenuates systemic inflammatory responses via selectively impairing the Myddosome complex formation upon TLR4 ligation

  摘要：

  A specific small-molecule inhibitor of the TLR4 signaling complex upstream of the IKK would likely provide therapeutic benefit for NF-kappa B-mediated inflammatory disease. We previously identified brazilin as a selective upstream IRK inhibitor targeting the Myddosome complex. In this study, using a cell-based ubiquitination assay for IRAK1 and a chemical library comprising a series of structural analogues of brazilin, a novel small molecule, 2-hydroxy-5,6-dihydroisoindolo[1,2-a]isog,uinoline-3,8-dione(linQ), was identified as a selective and potent inhibitor of IRAK1-dependent NF-kappa B activation upon TLR4 ligation. In RAW264.7 macrophages, IinQ drastically suppressed activation of upstream IKK signaling events including membrane-bound IRAK1 ubiquitination and IRK phosphorylation by the TLR4 ligand, resulting in reduced expression of proinflammatory mediators including IL-6, TNF-alpha, and nitric oxide. Interestingly, IinQ did not suppress NF-kappa B activation via the TLR3 ligand, DNA damaging agents, or a protein kinase C activator, indicating IinQ is specific for TLR4 signaling. Analysis of upstream signaling events further confirmed that linQ disrupts the MyD88-IRAKI-TRAF6 complex formation induced by LPS treatment, without affecting TLR4 oligomerization. Moreover, intravenous administration of IinQ significantly reduced lethality and attenuated systemic inflammatory responses in an in vivo mouse model of endotoxin shock following LPS challenge. Thus, IinQ represents a novel class of brazilin analogues with improved potency and specificity toward disruption of Myddosome complex formation in TLR4 signaling, indicating that IinQ may be a promising therapeutic candidate for the treatment of systemic inflammatory diseases. (C) 2016 Elsevier Inc. All rights reserved.

  DOI：

  10.1016/j.bcp.2016.09.017
• 作为产物：
  描述：

  N-(3,4-dihydroxyphenethyl)phthalimide 在 sodium tetrahydroborate 、 三氟甲磺酸 、 三氟乙酸 作用下， 以 二氯甲烷 为溶剂， 反应 0.75h， 生成 2,3-dihydroxy-5,12b-dihydroisoindolo[1,2-a]isoquinolin-8(6H)-one
  参考文献：
  名称：

  Brønsted acid assisted activation of imide carbonyl group: regioselective synthesis of isoindoloisoquinolinone alkaloid (±)-nuevamine

  摘要：

  用三氟甲磺酸活化酰亚胺羰基有助于苯乙基邻苯二甲酰亚胺的分子内环化，从而得到融合的异吲哚异喹啉酮骨架。利用这种方法，首次成功地进行了异吲哚异喹啉酮生物碱 (±)-nuevamine 的一锅区域选择性合成。

  DOI：

  10.1039/c1ob06349a

文献信息

• Synthesis of isoindolo[1,2-a]isoquinoline and isoindolo[2,1-a]quinoline derivatives via trifluoroacetic acid-mediated cascade reactions
  作者：Zhuo Huang、Yonggang Meng、Yangang Wu、Chuanjun Song、Junbiao Chang

  DOI：10.1016/j.tet.2021.132280

  日期：2021.7

  Condensation of methyl 2-acylbenzoates with 2-arylethanamines or 2-acylanilines in the presence of trifluoroacetic acid resulted in the formation of isoindolo[1,2-a]isoquinolines or isoindolo[2,1-a]quinolines, respectively, in moderate to excellent isolated yields.

  甲基2-acylbenzoates与2- arylethanamines或在三氟乙酸的存在下2- acylanilines的缩合导致形成异吲哚基的[1,2一]异喹啉或异吲哚基[2,1-一个〕喹啉，分别在中度至优良的分离产率。
• Discovery of new tetrahydroisoquinolines as potent and selective LSD1 inhibitors for the treatment of MLL-rearranged leukemia
  作者：Chao Yang、Yuan Fang、Yaxuan Hu、Tiantian Tian、Guochao Liao

  DOI：10.1016/j.ejmech.2023.115516

  日期：2023.9

  performed the design, synthesis, and extensive structure-activity relationship (SAR) studies based on our previously discovered natural LSD1 inhibitor, higenamine. We found that the tetracyclic tetrahydroisoquinoline FY-21 is a potent and selective inhibitor of LSD1 (IC = 340 nM). FY-21 inhibited leukemia cell proliferation and colony formation and increased the level of p53 expression. Meanwhile,

  组蛋白赖氨酸特异性去甲基酶 1 (LSD1) 是癌症治疗的一个有前景的靶点。在这里，我们基于我们之前发现的天然 LSD1 抑制剂去甲乌药碱进行了设计、合成和广泛的构效关系 (SAR) 研究。我们发现四环四氢异喹啉 FY-21 是一种有效的选择性 LSD1 抑制剂 (IC = 340 nM)。 FY-21 抑制白血病细胞增殖和集落形成并增加 p53 表达水平。同时，FY-21 降低了转录因子 HOXA9 和 MEIS1 的 mRNA 水平。此外，FY-21显着诱导白血病细胞分化。研究表明FY-21可延长白血病小鼠的存活率。总的来说，FY-21是一种有效的、选择性的LSD1抑制剂，可以作为开发用于治疗AML的新型高效LSD1抑制剂的先导化合物。
• Brønsted acid assisted activation of imide carbonyl group: regioselective synthesis of isoindoloisoquinolinone alkaloid (±)-nuevamine
  作者：Jayaraman Selvakumar、Chinnasamy Ramaraj Ramanathan

  DOI：10.1039/c1ob06349a

  日期：——

  Activation of imide carbonyl group with trifluoromethanesulfonic acid facilitates the intramolecular cyclization of phenethylphthalimides to give a fused isoindoloisoquinolinone skeleton. The first one pot regioselective synthesis of isoindoloisoquinolinone alkaloid (±)-nuevamine has been successfully executed using this methodology.

  用三氟甲磺酸活化酰亚胺羰基有助于苯乙基邻苯二甲酰亚胺的分子内环化，从而得到融合的异吲哚异喹啉酮骨架。利用这种方法，首次成功地进行了异吲哚异喹啉酮生物碱 (±)-nuevamine 的一锅区域选择性合成。
• IinQ attenuates systemic inflammatory responses via selectively impairing the Myddosome complex formation upon TLR4 ligation
  作者：Kidong Kang、Minho Won、Jae-Min Yuk、Chan-Yong Park、Hee Sun Byun、Kyeong Ah Park、So-Ra Lee、Young-Goo Kang、Han-Ming Shen、Ill Young Lee、Gang Min Hur

  DOI：10.1016/j.bcp.2016.09.017

  日期：2016.12

  A specific small-molecule inhibitor of the TLR4 signaling complex upstream of the IKK would likely provide therapeutic benefit for NF-kappa B-mediated inflammatory disease. We previously identified brazilin as a selective upstream IRK inhibitor targeting the Myddosome complex. In this study, using a cell-based ubiquitination assay for IRAK1 and a chemical library comprising a series of structural analogues of brazilin, a novel small molecule, 2-hydroxy-5,6-dihydroisoindolo[1,2-a]isog,uinoline-3,8-dione(linQ), was identified as a selective and potent inhibitor of IRAK1-dependent NF-kappa B activation upon TLR4 ligation. In RAW264.7 macrophages, IinQ drastically suppressed activation of upstream IKK signaling events including membrane-bound IRAK1 ubiquitination and IRK phosphorylation by the TLR4 ligand, resulting in reduced expression of proinflammatory mediators including IL-6, TNF-alpha, and nitric oxide. Interestingly, IinQ did not suppress NF-kappa B activation via the TLR3 ligand, DNA damaging agents, or a protein kinase C activator, indicating IinQ is specific for TLR4 signaling. Analysis of upstream signaling events further confirmed that linQ disrupts the MyD88-IRAKI-TRAF6 complex formation induced by LPS treatment, without affecting TLR4 oligomerization. Moreover, intravenous administration of IinQ significantly reduced lethality and attenuated systemic inflammatory responses in an in vivo mouse model of endotoxin shock following LPS challenge. Thus, IinQ represents a novel class of brazilin analogues with improved potency and specificity toward disruption of Myddosome complex formation in TLR4 signaling, indicating that IinQ may be a promising therapeutic candidate for the treatment of systemic inflammatory diseases. (C) 2016 Elsevier Inc. All rights reserved.