1-(3-methoxy-7-nitro-10H-phenothiazin-10-yl)ethanone | 1393520-03-0

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并噻嗪类
• 英文名称: 1-(3-methoxy-7-nitro-10H-phenothiazin-10-yl)ethanone
• 英文别名: 1-(3-methoxy-7-nitrophenothiazin-10-yl)ethanone；1-(3-methoxy-7-nitro-10H-phenothiazin-10-yl)ethan-1-one
• CAS: 1393520-03-0
• 化学式: C₁₅H₁₂N₂O₄S
• 分子量: 316.337
• InChiKey: RQSQPWIBUGPRKQ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.8
• 重原子数：
  22
• 可旋转键数：
  1
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.13
• 拓扑面积：
  101
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  1-(3-methoxy-7-nitro-10H-phenothiazin-10-yl)ethanone 在 三溴化硼 作用下， 以 二氯甲烷 为溶剂， 反应 2.5h， 以67%的产率得到1-(3-hydroxy-7-nitro-10H-phenothiazin-10-yl)ethanone
  参考文献：
  名称：

  [EN] PROTEOLYSIS TARGETING CHIMERIC (PROTAC) COMPOUND WITH E3 UBIQUITIN LIGASE BINDING ACTIVITY AND TARGETING ALPHA-SYNUCLEIN PROTEIN FOR TREATING NEURODEGENERATIVE DISEASES
  [FR] COMPOSÉ CHIMÈRE CIBLANT LA PROTÉOLYSE (PROTAC) AYANT UNE ACTIVITÉ DE LIAISON À L'UBIQUITINE LIGASE E3 ET CIBLANT UNE PROTÉINE ALPHA-SYNUCLÉINE POUR LE TRAITEMENT DE MALADIES NEURODÉGÉNÉRATIVES

  摘要：

  本公开涉及双功能化合物，其作为α-突触核蛋白（目标蛋白）的调节剂具有实用性。具体而言，本公开涉及包含一端为Von Hippel-Lindau、cereblon、凋亡抑制蛋白或鼠双分子同源物2配体的双功能化合物，该配体与相应的E3泛素连接酶结合，另一端为与目标蛋白结合的基团，使得目标蛋白靠近泛素连接酶以促使目标蛋白的降解（和抑制）。本公开展示了与目标蛋白的降解/抑制相关的广泛药理活性范围。本公开的化合物和组合物用于治疗或预防由目标蛋白聚集或积累导致的疾病或紊乱。这些疾病或紊乱是与α-突触核蛋白积累和聚集相关的α-突触核蛋白病或神经退行性疾病，例如帕金森病、阿尔茨海默病、痴呆症、带有Lewy小体的痴呆症或多系统萎缩，特别是帕金森病。

  公开号：

  WO2020041331A1
• 作为产物：
  描述：

  N-(2-((2,4-dinitrophenyl)thio)-4-methoxyphenyl)acetamide 在 potassium hydroxide 作用下， 以 二氯甲烷 、 丙酮 为溶剂， 反应 2.0h， 生成 1-(3-methoxy-7-nitro-10H-phenothiazin-10-yl)ethanone
  参考文献：
  名称：

  TRICYCLIC HETEROAROMATIC COMPOUNDS AS ALPHA-SYNUCLEIN LIGANDS

  摘要：

  描述了吩噻嗪、苯并恶嗪和苯并嗪化合物的衍生物及其作为α-突触核蛋白配体的用途。还描述了使用这些化合物及其放射性标记类似物用于检测、监测和治疗突触核蛋白病，包括帕金森病的方法。

  公开号：

  US20130315825A1

文献信息

• The Structural Combination of SIL and MODAG Scaffolds Fails to Enhance Binding to α-Synuclein but Reveals Promising Affinity to Amyloid β
  作者：Adriana Di Nanni、Ran Sing Saw、Gregory D. Bowden、Natasha S. R. Bidesi、Kaare Bjerregaard-Andersen、Špela Korat、Matthias M. Herth、Bernd J. Pichler、Kristina Herfert、Andreas Maurer

  DOI：10.3390/molecules28104001

  日期：——

  unmet scientific and clinical need that would represent a transformative tool in the understanding, diagnosis, and treatment of various neurodegenerative diseases. Several classes of compounds have shown promising results as potential PET tracers, but no candidate has yet exhibited the affinity and selectivity required to reach clinical application. We hypothesized that the application of the rational drug

  体内成像 α-突触核蛋白 (αSYN) 原纤维的技术是未满足的科学和临床需求，它将代表理解、诊断和治疗各种神经退行性疾病的变革性工具。几类化合物作为潜在的 PET 示踪剂已显示出有希望的结果，但还没有候选化合物表现出达到临床应用所需的亲和力和选择性。我们假设将分子杂交的合理药物设计技术应用于两个有前途的先导支架可以增强与 αSYN 的结合，直至满足这些要求。通过结合 SIL 和 MODAG 示踪剂的结构，我们开发了一个二芳基吡唑 (DAP) 库。通过针对 [3H]SIL26 和 [3H]MODAG-001 的竞争测定进行的体外评估表明，新型混合支架对淀粉样蛋白 β (Aβ) 的结合亲和力优于对 αSYN 原纤维的结合亲和力。吩噻嗪结构单元的开环修饰以产生具有更高三维灵活性的类似物并没有导致 αSYN 结合的改善，而是竞争的完全丧失，以及 Aβ 亲和力的显着降低。吩噻嗪和 3,5-二苯基吡唑支架结合成
• Synthesis and in vitro evaluation of α-synuclein ligands
  作者：Lihai Yu、Jinquan Cui、Prashanth K. Padakanti、Laura Engel、Devika P. Bagchi、Paul T. Kotzbauer、Zhude Tu

  DOI：10.1016/j.bmc.2012.06.023

  日期：2012.8

  Accumulation of misfolded alpha-synuclein in Lewy bodies and Lewy neurites is the pathological hallmark of Parkinson's disease (PD). To identify ligands having high binding potency toward aggregated alpha-synuclein, we synthesized a series of phenothiazine derivatives and assessed their binding affinity to recombinant alpha-synuclein fibrils using a fluorescent thioflavin T competition assay. Among 16 new analogues, the in vitro data suggest that compound 11b has high affinity to alpha-synuclein fibrils (K-i = 32.10 +/- 1.25 nM) and compounds 11d, 16a and 16b have moderate affinity to alpha-synuclein fibrils (K-i approximate to 50-100 nM). Further optimization of the structure of these analogues may yield compounds with high affinity and selectivity for aggregated alpha-synuclein. (C) 2012 Elsevier Ltd. All rights reserved.
• PROTEOLYSIS TARGETING CHIMERIC (PROTAC) COMPOUND WITH E3 UBIQUITIN LIGASE BINDING ACTIVITY AND TARGETING ALPHA-SYNUCLEIN PROTEIN FOR TREATING NEURODEGENERATIVE DISEASES
  申请人：Arvinas Operations, Inc.

  公开号：EP3841100A1

  公开（公告）日：2021-06-30
• MODULATORS OF ALPHA-SYNUCLEIN PROTEOLYSIS AND ASSOCIATED METHODS OF USE
  申请人：Arvinas Operations, Inc.

  公开号：US20200085793A1

  公开（公告）日：2020-03-19

  The present disclosure relates to bifunctional compounds, which find utility as modulators of α-synuclein (target protein). In particular, the present disclosure is directed to bifunctional compounds, which contain on one end a Von Hippel-Lindau, cereblon. Inhibitors of Apotosis Proteins or mouse double-minute homolog 2 ligand which binds to the respective E3 ubiquitin ligase and on the other end a moiety which binds the target protein, such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of target protein. The present disclosure exhibits a broad range of pharmacological activities associated with degradation/inhibition of target protein. Diseases or disorders that result from aggregation or accumulation of the target protein are treated or prevented with compounds and compositions of the present disclosure.