(1R,2S,5S)-3-[(9H-fluoren-9-ylmethoxy)carbonyl]-3-azabicyclo[3.1.0]hexane-2-carboxylic acid | 886846-30-6

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: (1R,2S,5S)-3-[(9H-fluoren-9-ylmethoxy)carbonyl]-3-azabicyclo[3.1.0]hexane-2-carboxylic acid
• 英文别名: Fmoc-cis-3,4-methanoPro；Fmoc-cis-3,4-methanoproline；Fmoc-trans-3-azabicyclo[3.1.0]hexane-2-carboxylic acid；(1R,2S,5S)-3-(9H-fluoren-9-ylmethoxycarbonyl)-3-azabicyclo[3.1.0]hexane-2-carboxylic acid
• CAS: 886846-30-6
• 化学式: C₂₁H₁₉NO₄
• 分子量: 349.386
• InChiKey: BTOGCFAOJIQONJ-LLSQANQASA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.3
• 重原子数：
  26
• 可旋转键数：
  4
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  66.8
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  (1R,2S,5S)-3-[(9H-fluoren-9-ylmethoxy)carbonyl]-3-azabicyclo[3.1.0]hexane-2-carboxylic acid 、 tert-butyl N-[3-[4-([[(2R,3S)-3-amino-5-carbamoylpentan-2-yl]oxy]methyl)phenyl]propyl]carbamate 在 三乙胺 、 Methanaminium,N-[(dimethylamino)(3H-1,2,3-triazolo[4,5-b]pyridin-3-yloxy)methylene]-N-methyl-, hexafluorophosphate(1-) 作用下， 以 N,N-二甲基乙酰胺 为溶剂， 反应 1.08h， 以76%的产率得到(9H-fluoren-9-yl)methyl (1R,2S,5S)-2-[[(3S,4R)-4-[(4-[3-[(tert-butoxycarbonyl)amino]propyl]phenyl)methoxy]-1-carbamoylpentan-3-yl]carbamoyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate
  参考文献：
  名称：

  [EN] STAT DEGRADERS AND USES THEREOF
  [FR] AGENTS DE DÉGRADATION DE STAT ET LEURS UTILISATIONS

  摘要：

  本发明提供了化合物、其组合物以及使用方法。

  公开号：

  WO2020206424A1

文献信息

• INHIBITORS OF STAT3 AND USES THEREOF
  申请人：McMurray John S.

  公开号：US20120035114A1

  公开（公告）日：2012-02-09

  Compounds which inhibit the activity of signal transducer and activator of transcription 3 (STAT3) are provided together with methods of making and using the same. The compounds are designed to bind to the SH2 domain of STAT3, preventing STAT3 from binding to receptors for interleukin-6 family cytokines, growth factors such as the platelet-derived growth factor, the epidermal growth factor, vascular endothelial growth factor, and other signaling molecules such as leptin. Blocking these interactions prevents STAT3 from being phosphorylated on Tyr705, which is required for the dimerization of STAT3, translocation to the nucleus, binding to STAT3 response elements on promotors, and transcription of genes. In addition to these activities, binding to the SH2 domain of STAT3 breaks up pre-formed dimmers, thereby preventing the transcriptional activity of the inhibitor.

  本发明提供了抑制信号转导与激活转录因子3 (STAT3) 活性的化合物，以及制备和使用这些化合物的方法。这些化合物被设计成结合STAT3的SH2结构域，防止STAT3与白细胞介素6家族细胞因子、血小板源性生长因子、表皮生长因子、血管内皮生长因子等生长因子和瘦素等信号分子的受体结合。阻断这些相互作用可防止STAT3在Tyr705位点磷酸化，这是STAT3二聚化、向细胞核转位、结合启动子上的STAT3响应元件和基因转录所必需的。除了这些作用，结合STAT3的SH2结构域还可以分解已形成的二聚体，从而防止抑制剂的转录活性。
• Potent and Selective Phosphopeptide Mimetic Prodrugs Targeted to the Src Homology 2 (SH2) Domain of Signal Transducer and Activator of Transcription 3
  作者：Pijus K. Mandal、Fengqin Gao、Zhen Lu、Zhiyong Ren、Rajagopal Ramesh、J. Sanderson Birtwistle、Kumaralal K. Kaluarachchi、Xiaomin Chen、Robert C. Bast、Warren S. Liao、John S. McMurray

  DOI：10.1021/jm2000882

  日期：2011.5.26

  Signal transducer and activator of transcription 3 (Stat3), a target for anticancer drug design, is activated by recruitment to phosphotyrosine residues on growth factor and cytokine receptors via its SH2 domain. We report here structure activity relationship studies on phosphopeptide mimics targeted to the SH2 domain of Stat3. Inclusion of a methyl group on the beta-position of the pTyr mimic 4-phosphocinnamide enhanced affinity 2- to 3-fold. Bis-pivaloyloxymethyl prodrugs containing beta-methylcinnamide, dipeptide scaffolds Haic and Nle-cis-3,4-methanoproline, and glutamine surrogates were highly potent, completely inhibiting phosphorylation of Stat3 Tyr705 at 0.5-1,mu M in a variety of cancer cell lines. The inhibitors were selective for Stat3 over Stat1, Stat5, Src, and p85 of PI3K, indicating ability to discriminate individual SH2 domains in intact cells. At concentrations that completely inhibited Stat3 phosphorylation, the prodrugs were not cytotoxic to a panel of tumor cells, thereby showing clear distinction between cytotoxicity and effects downstream of activated Stat3.
• Structure−Affinity Relationships of Glutamine Mimics Incorporated into Phosphopeptides Targeted to the SH2 Domain of Signal Transducer and Activator of Transcription 3
  作者：Pijus K. Mandal、Zhiyong Ren、Xiaomin Chen、Chiyi Xiong、John S. McMurray

  DOI：10.1021/jm901105k

  日期：2009.10.8

  In cancer cells, signal transducer and activator of transcription 3 (Stat3) participates in aberrant growth, survival, angiogenesis, and invasion signals and is a validated target for anticancer drug design. We are targeting its SH2 domain to prevent docking to cytokine and growth factor receptors and subsequent signaling. One of the important elements of the recognition sequence, pTyr-Xxx-Xxx-Gln, is glutamine. We incorporated novel Gin mimics into a lead peptide, pCinn-Leu-Pro-Gln-NHBn, and found that a linear, unconstrained side chain and carboxamide are necessary for high affinity, and the benzamide can be eliminated. Replacement of Gln-NHBn with (R)-4-aminopentanamide or 2-aminoethylurea produced inhibitors with equal or greater potency than that of the lead, as judged by fluorescence polarization (IC50 values were 110 and 130 nM, respectively). When Pro was replaced with cis-3,4-methanoproline, the glutamine mimic, (4R,5S)-4-amino-5-benzyloxyhexanamide resulted in an IC50 of 69 nM, the highest affinity Stat3 inhibitor reported to date.
• STAT DEGRADERS AND USES THEREOF
  申请人：Kymera Therapeutics, Inc.

  公开号：EP3946360A1

  公开（公告）日：2022-02-09
• US8841257B2
  申请人：——

  公开号：US8841257B2

  公开（公告）日：2014-09-23