(R)-4-FMOC氨基-Γ-戊酸 | 1189357-66-1

• 分子结构分类: 有机化合物 - 苯类化合物 - 芴
• 中文名称: (R)-4-FMOC氨基-Γ-戊酸
• 英文名称: (R)-4-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-2-pentanoic acid
• 英文别名: (R)-4-(9-fluorenylmethoxycarbonlyamino)-pentanoic acid；4-(9-fluorenylmethyloxycarbonylamino)pentanoic acid；Fmoc-(R)-4-Ava-OH；(4R)-4-(9H-fluoren-9-ylmethoxycarbonylamino)pentanoic acid
• CAS: 1189357-66-1
• 化学式: C₂₀H₂₁NO₄
• 分子量: 339.391
• InChiKey: ASUWOMDZJCFFDR-CYBMUJFWSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.3
• 重原子数：
  25
• 可旋转键数：
  7
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.3
• 拓扑面积：
  75.6
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  (R)-4-FMOC氨基-Γ-戊酸 在 N-甲基吗啉 、 4-二甲氨基吡啶 、 1-羟基苯并三唑 、 N,N'-二异丙基碳二亚胺 作用下， 以 N-甲基吡咯烷酮 、 二氯甲烷 、 N,N-二甲基甲酰胺 、 乙腈 为溶剂， 反应 2.08h， 生成 PM-273G
  参考文献：
  名称：

  靶向信号转导器和转录激活剂 3 (Stat3) 的 Src 同源 2 (SH2) 域的拟磷酸肽前药的构效研究。

  摘要：

  信号转导和转录激活因子 3 (Stat3) 通过其 Src 同源 2 (SH2) 结构域与其受体结合，从而传输来自生长因子和白细胞介素 6 家族细胞因子的信号。这导致 Tyr705 磷酸化、二聚化、易位到细胞核和下游基因转录的调节。Stat3 在几种人类癌症中被组成型激活，并且是抗癌药物设计的目标。我们之前已经表明，靶向 SH2 结构域的磷酸肽模拟物前药可以抑制完整癌细胞中 Tyr705 的磷酸化。在由 4'-膦酰二氟甲基肉桂酰-Haic-Gln-NHBn 的双-新戊酰氧基甲酯组成的一系列前药中，将甲基附加到肉桂酸酯的 β 位可增加效力约。双重，这与相应磷酸肽模型的亲和力增加平行。然而，当 Gln-NHBn 的 C 末端 C(O)NHBn 被简单的甲基取代时，观察到效力的显着增加。在本文中，我们继续探索前药结构修饰对其抑制 Tyr705 磷酸化能力的影响。通过荧光偏振（Pro IC 在本文中，我们继续探索前药结构修饰对其抑制

  DOI：

  10.1007/s10989-012-9313-0
• 作为产物：
  描述：

  benzyl (R)-4-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-(E)-2-pentenoate 在 三乙基硅烷 、 palladium 10% on activated carbon 作用下， 以 四氢呋喃 、 甲醇 为溶剂， 以88%的产率得到(R)-4-FMOC氨基-Γ-戊酸
  参考文献：
  名称：

  Structure−Affinity Relationships of Glutamine Mimics Incorporated into Phosphopeptides Targeted to the SH2 Domain of Signal Transducer and Activator of Transcription 3

  摘要：

  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.

  DOI：

  10.1021/jm901105k

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.
• US8841257B2
  申请人：——

  公开号：US8841257B2

  公开（公告）日：2014-09-23
• 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.
• Structure–Activity Studies of Phosphopeptidomimetic Prodrugs Targeting the Src Homology 2 (SH2) Domain of Signal Transducer and Activator of Transcription 3 (Stat3)
  作者：Pijus K. Mandal、Zhiyong Ren、Xiaomin Chen、Kumar Kaluarachchi、Warren S.-L. Liao、John S. McMurray

  DOI：10.1007/s10989-012-9313-0

  日期：2013.3

  4′-phosphonodifluoromethyl cinnamoyl-Haic-Gln-NHBn, appending methyl group to the β-position of the cinnamate increased potency ca. twofold, which paralleled the increase in affinity of the corresponding phosphopeptide models. However, dramatic increases in potency were observed when the C-terminal C(O)NHBn of Gln-NHBn was replaced with a simple methyl group. In this communication we continue to explore the

  信号转导和转录激活因子 3 (Stat3) 通过其 Src 同源 2 (SH2) 结构域与其受体结合，从而传输来自生长因子和白细胞介素 6 家族细胞因子的信号。这导致 Tyr705 磷酸化、二聚化、易位到细胞核和下游基因转录的调节。Stat3 在几种人类癌症中被组成型激活，并且是抗癌药物设计的目标。我们之前已经表明，靶向 SH2 结构域的磷酸肽模拟物前药可以抑制完整癌细胞中 Tyr705 的磷酸化。在由 4'-膦酰二氟甲基肉桂酰-Haic-Gln-NHBn 的双-新戊酰氧基甲酯组成的一系列前药中，将甲基附加到肉桂酸酯的 β 位可增加效力约。双重，这与相应磷酸肽模型的亲和力增加平行。然而，当 Gln-NHBn 的 C 末端 C(O)NHBn 被简单的甲基取代时，观察到效力的显着增加。在本文中，我们继续探索前药结构修饰对其抑制 Tyr705 磷酸化能力的影响。通过荧光偏振（Pro IC 在本文中，我们继续探索前药结构修饰对其抑制