tert-butyl 2-[[(2S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-3-phenylpropyl]amino]acetate | 1429512-59-3

• 分子结构分类: 有机化合物 - 苯类化合物 - 芴
• 英文名称: tert-butyl 2-[[(2S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-3-phenylpropyl]amino]acetate
• CAS: 1429512-59-3
• 化学式: C₃₀H₃₄N₂O₄
• 分子量: 486.611
• InChiKey: ZGHOFKVZAMCOJC-QFIPXVFZSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.6
• 重原子数：
  36
• 可旋转键数：
  12
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  76.7
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  tert-butyl 2-[[(2S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-3-phenylpropyl]amino]acetate 在 吡啶 、 三氟乙酸 作用下， 以 二氯甲烷 为溶剂， 生成 (S)-N-(2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-phenylpropyl)-N-((4-bromophenyl)sulfonyl)glycine
  参考文献：
  名称：

  Rational Design of Right-Handed Heterogeneous Peptidomimetics as Inhibitors of Protein–Protein Interactions

  摘要：

  Peptidomimetics have gained great attention for their function as protein-protein interaction (PPI) inhibitors. Herein, we report the design and investigation of a series of right-handed helical heterogeneous 1:1 alpha/Sulfono-gamma-AA peptides as unprecedented inhibitors for p53-MDM2 and p53-MDMX. The most potent helical heterogeneous 1:1 alpha/Sulfono-gamma-AA peptides were shown to bind tightly to MDM2 and MDMX, with K-d of 19.3 and 66.8 nM, respectively. Circular dichroism spectra, 2D-NMR spectroscopy, and the computational simulations suggested that these helical sulfono-gamma-AA peptides could mimic the critical side chains of p53 and disrupt p53/MDM2 PPI effectively. It was noted that these 1:1 alpha/Sulfono-gamma-AA peptides were completely resistant to proteolytic degradation, boosting their potential for biomedical applications. Furthermore, effective cellular activity is achieved by the stapled 1:1 alpha/Sulfono-gamma-AA peptides, evidenced by significantly enhanced p53 transcriptional activity and much more induced level of MDM2 and p21. The 1:1 alpha/Sulfono-gamma-AA peptides could be an alternative strategy to antagonize a myriad of PPIs.

  DOI：

  10.1021/acs.jmedchem.0c01638
• 作为产物：
  描述：

  Fmoc-L-苯丙氨酸 在 lithium aluminium tetrahydride 、 sodium cyanoborohydride 、 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 作用下， 生成 tert-butyl 2-[[(2S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-3-phenylpropyl]amino]acetate
  参考文献：
  名称：

  Rational Design of Right-Handed Heterogeneous Peptidomimetics as Inhibitors of Protein–Protein Interactions

  摘要：

  Peptidomimetics have gained great attention for their function as protein-protein interaction (PPI) inhibitors. Herein, we report the design and investigation of a series of right-handed helical heterogeneous 1:1 alpha/Sulfono-gamma-AA peptides as unprecedented inhibitors for p53-MDM2 and p53-MDMX. The most potent helical heterogeneous 1:1 alpha/Sulfono-gamma-AA peptides were shown to bind tightly to MDM2 and MDMX, with K-d of 19.3 and 66.8 nM, respectively. Circular dichroism spectra, 2D-NMR spectroscopy, and the computational simulations suggested that these helical sulfono-gamma-AA peptides could mimic the critical side chains of p53 and disrupt p53/MDM2 PPI effectively. It was noted that these 1:1 alpha/Sulfono-gamma-AA peptides were completely resistant to proteolytic degradation, boosting their potential for biomedical applications. Furthermore, effective cellular activity is achieved by the stapled 1:1 alpha/Sulfono-gamma-AA peptides, evidenced by significantly enhanced p53 transcriptional activity and much more induced level of MDM2 and p21. The 1:1 alpha/Sulfono-gamma-AA peptides could be an alternative strategy to antagonize a myriad of PPIs.

  DOI：

  10.1021/acs.jmedchem.0c01638

文献信息

• α-Helix-Mimicking Sulfono-γ-AApeptide Inhibitors for p53–MDM2/MDMX Protein–Protein Interactions
  作者：Peng Sang、Yan Shi、Junhao Lu、Lihong Chen、Leixiang Yang、Wade Borcherds、Sami Abdulkadir、Qi Li、Gary Daughdrill、Jiandong Chen、Jianfeng Cai

  DOI：10.1021/acs.jmedchem.9b00993

  日期：2020.2.13

  for the inhibition of protein-protein interactions (PPIs). Herein, we demonstrate that sulfono-γ-AApeptides can be rationally designed to mimic the p53 α-helix and inhibit p53-MDM2 PPIs. The best inhibitor, with Kd and IC50 values of 26 nM and 0.891 μM toward MDM2, respectively, is among the most potent unnatural peptidomimetic inhibitors disrupting the p53-MDM2/MDMX interaction. Using fluorescence polarization

  拟肽支架的使用是抑制蛋白相互作用的一种有前途的策略。在本文中，我们证明了可以合理设计磺基-γ-AA肽以模仿p53α-螺旋并抑制p53-MDM2 PPI。最好的抑制剂对MDM2的Kd和IC50值分别为26 nM和0.891μM，是破坏p53-MDM2 / MDMX相互作用的最有效的非天然拟肽抑制剂之一。使用荧光偏振分析，圆二色性，核磁共振波谱和计算模拟，我们证明了磺基-γ-AA肽采用类似于p53的螺旋结构，并通过结合到MDM2的疏水缝隙竞争性抑制p53-MDM2相互作用。有趣的是 通过增强p53转录活性并诱导MDM2和p21的表达，吻合的磺酰基-γ-AA肽显示出有希望的细胞活性。此外，磺基-γ-AA肽对蛋白水解表现出显着的抗性，从而增强了它们的生物学潜力。我们的结果表明，磺基-γ-AA肽是一类新型的破坏PPI的非天然螺旋折叠剂。
• GAMMA-AAPEPTIDES WITH POTENT AND BROAD-SPECTRUM ANTIMICROBIAL ACTIVITY
  申请人：Cai Jianfeng

  公开号：US20150274782A1

  公开（公告）日：2015-10-01

  The present invention is directed to a novel class of antimicrobial agents called γ-AApeptides. The current invention provides various categories of γ-AApeptides, for example, linear γ-AApeptides, cyclic γ-AApeptides, and lipidated γ-AApeptides. γ-AApeptides of the current invention are designed to exert antimicrobial activity while being stable and non-toxic. γ-AApeptides also do not appear to lead to the development of microbial resistance in treated microorganisms. Thus, the disclosed γ-AApeptides can be used for the treatment of various medical conditions associated with pathogenic microorganisms.

  本发明涉及一种新型类别的抗微生物药物，称为γ-AA肽。当前发明提供了各种类别的γ-AA肽，例如线性γ-AA肽、环状γ-AA肽和脂质化γ-AA肽。本发明的γ-AA肽被设计为具有抗微生物活性，同时稳定且无毒。γ-AA肽似乎也不会导致被治疗微生物体内微生物产生抗药性。因此，所披露的γ-AA肽可用于治疗与病原微生物相关的各种医疗状况。
• Rapid Access to Multiple Classes of Peptidomimetics from Common γ-AApeptide Building Blocks
  作者：Haifan Wu、Peng Teng、Jianfeng Cai

  DOI：10.1002/ejoc.201301841

  日期：2014.3

  functionality; the method uses a few common N-alloc γ-AApeptide building blocks. More importantly, using the same approach, new classes of peptidomimetics bearing novel backbone scaffolds can also be readily generated. Our results not only demonstrate the versatility of this new synthetic method, but also highlight the possibility that the resulting novel peptidomimetics may find discrete biomedical/biomaterial

  在此，我们报告了一种高效的新方法，用于制备理论上能够包含任何功能的 γ-AApeptides；该方法使用一些常见的 N-alloc γ-AApeptide 构建模块。更重要的是，使用相同的方法，也可以很容易地生成带有新型骨架支架的新类肽模拟物。我们的结果不仅证明了这种新合成方法的多功能性，而且强调了由此产生的新型肽模拟物在未来可能会发现离散的生物医学/生物材料应用的可能性。
• Design and synthesis of unprecedented cyclic γ-AApeptides for antimicrobial development
  作者：Haifan Wu、Youhong Niu、Shruti Padhee、Rongsheng E. Wang、Yaqiong Li、Qiao Qiao、Ge Bai、Chuanhai Cao、Jianfeng Cai

  DOI：10.1039/c2sc20428b

  日期：——

  Antimicrobial drug resistance is one of the greatest threats facing mankind. Antimicrobial peptides (AMPs) can potentially circumvent drug resistance, probably through a bacterial membrane-disruption mechanism. However, they suffer from low in vivo stability, potential immunogenicity, and difficulty in optimization. The development of antimicrobial peptidomimetics is therefore an emerging research area as they avoid the potential disadvantages of AMPs. Cyclic peptidomimetics are of significant interest since constraints induced by cyclization are expected to further improve their antimicrobial activity. Nonetheless, the report of cyclic oligomeric peptidomimetics for antimicrobial development is rare. Herein, for the first time, we report the design and synthesis of cyclic γ-AApeptides via an on-resin cyclization. These cyclic γ-AApeptides are potent and broad-spectrum active against fungus and multi-drug resistant Gram-positive and Gram-negative bacterial pathogens. Our results demonstrate the potential of cyclic γ-AApeptides as a new class of antibiotics to circumvent drug resistance by mimicking the bactericidal mechanism of AMPs. Meanwhile, the facile synthesis of cyclic γ-AApeptides may further expand the applications of γ-AApeptides in biomedical sciences.

  抗菌药耐药性是人类面临的最大威胁之一。抗菌肽（AMPs）可能通过细菌膜破坏机制来规避耐药性。然而，抗菌肽存在体内稳定性低、潜在免疫原性和难以优化等问题。因此，抗菌多肽模拟物的开发成为一个新兴的研究领域，因为它们避免了 AMPs 的潜在缺点。环状拟肽物引起了人们极大的兴趣，因为环化引起的限制有望进一步提高它们的抗菌活性。然而，有关环状低聚拟肽物用于抗菌开发的报道却很少见。在此，我们首次报告了通过树脂环化设计和合成环状δ³-AA 肽的情况。这些环δ-AA 肽对真菌和具有多重耐药性的革兰氏阳性和革兰氏阴性细菌病原体具有强效和广谱的活性。我们的研究结果证明了环δ-A肽作为一类新型抗生素的潜力，它可以通过模仿AMPs的杀菌机制来规避耐药性。同时，环δ-A肽的简易合成可能会进一步扩大δ-A肽在生物医学科学中的应用。
• Novel Feleucin-K3-Derived Peptides Modified with Sulfono-γ-AA Building Blocks Targeting <i>Pseudomonas aeruginosa</i> and Methicillin-Resistant <i>Staphylococcus aureus</i> Infections
  作者：Xiaomin Guo、Tiantian Yan、Jing Rao、Yingying An、Xin Yue、Xiaokang Miao、Rui Wang、Wangsheng Sun、Jianfeng Cai、Junqiu Xie

  DOI：10.1021/acs.jmedchem.2c01396

  日期：2023.1.26