2-(2,6-difluorophenyl)-5-(4-methoxyphenyl)-1-oxa-3-azaspiro(5.5)undecane

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 氮杂螺癸烷衍生物
• 英文名称: 2-(2,6-difluorophenyl)-5-(4-methoxyphenyl)-1-oxa-3-azaspiro(5.5)undecane
• 英文别名: 2-(2,6-difluorophenyl)-5-(4-methoxyphenyl)-1-oxa-3-azaspiro[5.5]undecane
• 化学式: C₂₂H₂₅F₂NO₂
• 分子量: 373.443
• InChiKey: AZRZFJCKUHGMNS-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.6
• 重原子数：
  27
• 可旋转键数：
  3
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.45
• 拓扑面积：
  30.5
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  2,6-二氟苯甲醛 、 1-[2-氨基-1-(4-甲氧基苯基)乙基]环己醇 在 potassium carbonate 作用下， 以 甲醇 为溶剂， 生成 2-(2,6-difluorophenyl)-5-(4-methoxyphenyl)-1-oxa-3-azaspiro(5.5)undecane
  参考文献：
  名称：

  Development of a Novel Azaspirane That Targets the Janus Kinase-Signal Transducer and Activator of Transcription (STAT) Pathway in Hepatocellular Carcinoma in Vitro and in Vivo

  摘要：

  Background: Constitutive activation of STAT3 is associated with the progression of hepatocellular carcinoma (HCC), and abrogation of STAT3 signaling is a potential target for HCC treatment. Results: A novel azaspirane modulates the JAK-STAT pathway in HCC. Conclusion: The lead compound induces apoptosis by down-regulating STAT3 signaling. Significance: This investigation reports a novel inhibitor of the JAK-STAT pathway with the potential to target various cancers.Signal transducer and activator of transcription 3 (STAT3) is a transcription factor that regulates genes involved in cell growth, proliferation, and survival, and given its association with many types of cancers, it has recently emerged as a promising target for therapy. In this work, we present the synthesis of N-substituted azaspirane derivatives and their biological evaluation against hepatocellular carcinoma (HCC) cells (IC50 = 7.3 m), thereby identifying 2-(1-(4-(2-cyanophenyl)1-benzyl-1H-indol-3-yl)-5-(4-methoxy-phenyl)-1-oxa-3-azaspiro(5,5) undecane (CIMO) as a potent inhibitor of the JAK-STAT pathway with selectivity over normal LO2 cells (IC50 > 100 m). The lead compound, CIMO, suppresses proliferation of HCC cells and achieves this effect by reducing both constitutive and inducible phosphorylation of JAK1, JAK2, and STAT3. Interestingly, CIMO displayed inhibition of Tyr-705 phosphorylation, which is required for nuclear translocation of STAT3, but it has no effect on Ser-727 phosphorylation. CIMO accumulates cancer cells in the sub-G(1) phase and decreases STAT3 in the nucleus and thereby causes down-regulation of genes regulated via STAT3. Suppression of STAT3 phosphorylation by CIMO and knockdown of STAT3 mRNA using siRNA transfection displayed a similar effect on the viability of HCC cells. Furthermore, CIMO significantly decreased the tumor development in an orthotopic HCC mouse model through the modulation of phospho-STAT3, Ki-67, and cleaved caspase-3 in tumor tissues. Thus, CIMO represents a chemically novel and biologically in vitro and in vivo validated compound, which targets the JAK-STAT pathway as a potential cancer treatment.

  DOI：

  10.1074/jbc.m114.601104

文献信息

• METHODS OF TREATING OCULAR DISORDERS
  申请人：Beta Therapeutics Pty. Ltd.

  公开号：EP3554505A1

  公开（公告）日：2019-10-23
• Methods of Treating Ocular Disorders
  申请人：NELMS Keats

  公开号：US20200093852A1

  公开（公告）日：2020-03-26

  This invention relates to the use of a heparanase inhibitor for treating, or inhibiting the progression or development of, an ocular inflammatory disorder, such as age-related macular degeneration, diabetic retinopathy, retinitis pigmentosa, retinal 5 vein occlusion, retinoblastoma, uveitis, macular edema, dry eye, ocular inflammation associated with an infection or keratoconus.
• [EN] METHODS OF TREATING OCULAR DISORDERS<br/>[FR] MÉTHODES DE TRAITEMENT DE TROUBLES OCULAIRES
  申请人：BETA THERAPEUTICS PTY LTD

  公开号：WO2018107226A1

  公开（公告）日：2018-06-21

  This invention relates to the use of a heparanase inhibitor for treating, or inhibiting the progression or development of, an ocular inflammatory disorder, such as age- related macular degeneration, diabetic retinopathy, retinitis pigmentosa, retinal 5 vein occlusion, retinoblastoma, uveitis, macular edema, dry eye, ocular inflammation associated with an infection or keratoconus.