2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-5-(2-(2,4-dinitrophenylamino)ethylamino)-5-oxopentanoic acid | 949026-86-2

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: 2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-5-(2-(2,4-dinitrophenylamino)ethylamino)-5-oxopentanoic acid
• 英文别名: Fmoc-Glu-EDDnp；(2S)-5-[2-(2,4-dinitroanilino)ethylamino]-2-(9H-fluoren-9-ylmethoxycarbonylamino)-5-oxopentanoic acid
• CAS: 949026-86-2
• 化学式: C₂₈H₂₇N₅O₉
• 分子量: 577.55
• InChiKey: JTRVVKLKACTAHZ-DEOSSOPVSA-N

物化性质

• 沸点：
  908.6±65.0 °C(Predicted)
• 密度：
  1.435±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  4.2
• 重原子数：
  42
• 可旋转键数：
  12
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.25
• 拓扑面积：
  208
• 氢给体数：
  4
• 氢受体数：
  10

反应信息

• 作为反应物：
  描述：

  2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-5-(2-(2,4-dinitrophenylamino)ethylamino)-5-oxopentanoic acid 、 Fmoc-L-缬氨酸 、 Fmoc-L-丙氨酸 、 Fmoc-L-酪氨酸 、 N-芴甲氧羰基-D-天冬氨酸-4-叔丁酯 、 Fmoc-L-正缬氨酸 在 O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate 、 N,N-二异丙基乙胺 、 哌啶 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 1.0h， 生成 2-amino-N-[(2S)-1-[[(2S)-1-[[(2S)-1-[[(4S,7R)-8-[[(2S)-1-[[(2S)-1-[[(2S)-5-azaniumyl-1-[2-(2,4-dinitroanilino)ethylamino]-1,5-dioxopentan-2-yl]amino]-3-(4-hydroxyphenyl)-1-oxopropan-2-yl]amino]-3-carboxy-1-oxopropan-2-yl]amino]-7-methyl-5,8-dioxooctan-4-yl]amino]-3-carboxy-1-oxopropan-2-yl]amino]-1-oxopropan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]benzenecarboximidate
  参考文献：
  名称：

  人类中性粒细胞蛋白酶3的可逆酮基的抑制剂。

  摘要：

  中性粒细胞丝氨酸蛋白酶，蛋白酶3（PR3）和人中性粒细胞弹性蛋白酶（HNE）被认为是慢性炎症性疾病的靶标。尽管具有很高的序列相似性，但这两种酶具有不同的底物特异性和功能。尽管存在大量的HNE抑制剂，但PR3特异性抑制剂仍处于起步阶段。我们为PR3设计了基于酮亚甲基的抑制剂，这些抑制剂显示出低的微摩尔IC 50值。通过修改先前报道的酮亚甲基二肽等排体的合成使其合成成为可能，以允许制备适于固相肽合成的衍生物。最佳抑制剂（Abz-VA D nV [Ψ]（COCH 2）A DY发现Q-EDDnp）对PR3的选择性高于HNE，并且显示出竞争性和可逆的抑制机制。分子动力学模拟表明，酶和含酮亚甲基的抑制剂之间的相互作用与相应底物的相互作用相似。我们还证实，N端和C端FRET基团对于确保对PR3的高抑制力很重要。

  DOI：

  10.1021/jm500782s
• 作为产物：
  描述：

  tert-butyl 2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-5-(2-(2,4-dinitrophenylamino)ethylamino)-5-oxopentanoate 在 三氟乙酸 作用下， 以 二氯甲烷 为溶剂， 反应 5.0h， 以87%的产率得到2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-5-(2-(2,4-dinitrophenylamino)ethylamino)-5-oxopentanoic acid
  参考文献：
  名称：

  Development of a FRET Assay for Monitoring of HIV gp41 Core Disruption

  摘要：

  The fusogenic core assembly of human immunodeficiency virus type 1 (HIV-1) fusion protein gp41 is a critical transformation for viral entry. Molecules that are able to intercept this process are of great therapeutic value as HIV-1 fusion inhibitors. In the search for such molecules, assay systems that can be adapted to high-throughput screens are valuable. Given that gp41 fusogenic transformation is characterized by the hexameric association of heptads located at the N and C terminal regions of the protein ectodomain, the corresponding heptad peptides (CHR and NHR), known to form the six-helix bundle core of gp41 fusion active form, are potentially useful in developing a fluorescence resonance energy transfer (FRET) system for identification of HIV fusion inhibitors. We demonstrate that by strategically placing two FRET probes on these two peptides, we are able to monitor the intermolecular co-association by fluorescence quenching between the fluorescence donor and acceptor. The utility of the system is that it should be adaptable to high-throughput screening (HTS) toward peptide or small-molecule HIV fusion inhibitors targeting the gp41 core. Herein, we report the design, synthesis, and development of a N- and C- terminal peptide FRET pair for screening of gp41 six-helix bundle disruption.

  DOI：

  10.1021/jo070836l

文献信息

• Reversible Ketomethylene-Based Inhibitors of Human Neutrophil Proteinase 3
  作者：Adnan Budnjo、Shailesh Narawane、Cédric Grauffel、Anne-Sophie Schillinger、Torgils Fossen、Nathalie Reuter、Bengt Erik Haug

  DOI：10.1021/jm500782s

  日期：2014.11.26

  micromolar IC50 values. Their synthesis was made possible by amending a previously reported synthesis of ketomethylene dipeptide isosteres to allow for the preparation of derivatives suitable for solid phase peptide synthesis. The best inhibitor (Abz-VADnV[Ψ](COCH2)ADYQ-EDDnp) was found to be selective for PR3 over HNE and to display a competitive and reversible inhibition mechanism. Molecular dynamics

  中性粒细胞丝氨酸蛋白酶，蛋白酶3（PR3）和人中性粒细胞弹性蛋白酶（HNE）被认为是慢性炎症性疾病的靶标。尽管具有很高的序列相似性，但这两种酶具有不同的底物特异性和功能。尽管存在大量的HNE抑制剂，但PR3特异性抑制剂仍处于起步阶段。我们为PR3设计了基于酮亚甲基的抑制剂，这些抑制剂显示出低的微摩尔IC 50值。通过修改先前报道的酮亚甲基二肽等排体的合成使其合成成为可能，以允许制备适于固相肽合成的衍生物。最佳抑制剂（Abz-VA D nV [Ψ]（COCH 2）A DY发现Q-EDDnp）对PR3的选择性高于HNE，并且显示出竞争性和可逆的抑制机制。分子动力学模拟表明，酶和含酮亚甲基的抑制剂之间的相互作用与相应底物的相互作用相似。我们还证实，N端和C端FRET基团对于确保对PR3的高抑制力很重要。
• Development of a FRET Assay for Monitoring of HIV gp41 Core Disruption
  作者：Yang Xu、Mark S. Hixon、Philip E. Dawson、Kim D. Janda

  DOI：10.1021/jo070836l

  日期：2007.8.31

  The fusogenic core assembly of human immunodeficiency virus type 1 (HIV-1) fusion protein gp41 is a critical transformation for viral entry. Molecules that are able to intercept this process are of great therapeutic value as HIV-1 fusion inhibitors. In the search for such molecules, assay systems that can be adapted to high-throughput screens are valuable. Given that gp41 fusogenic transformation is characterized by the hexameric association of heptads located at the N and C terminal regions of the protein ectodomain, the corresponding heptad peptides (CHR and NHR), known to form the six-helix bundle core of gp41 fusion active form, are potentially useful in developing a fluorescence resonance energy transfer (FRET) system for identification of HIV fusion inhibitors. We demonstrate that by strategically placing two FRET probes on these two peptides, we are able to monitor the intermolecular co-association by fluorescence quenching between the fluorescence donor and acceptor. The utility of the system is that it should be adaptable to high-throughput screening (HTS) toward peptide or small-molecule HIV fusion inhibitors targeting the gp41 core. Herein, we report the design, synthesis, and development of a N- and C- terminal peptide FRET pair for screening of gp41 six-helix bundle disruption.