methyl γ-aminocrotonate trifluoroacetate | 99281-88-6

• 分子结构分类: 有机化合物 - 脂质和类脂质分子 - 脂肪酰基
• 英文名称: methyl γ-aminocrotonate trifluoroacetate
• 英文别名: methyl 4-amino-2-butenoate trifluoroacetate；trifluoroacetic acid methyl (2E)-4-aminobut-2-enoate；(E)-methyl 4-aminobut-2-enoate trifluoroacetic acid salt；(E)-methyl 4-aminobut-2-enoate 2,2,2-trifluoroacetate；(E)-4-amino-2-butenoic acid methyl ester trifluoroacetate；2-Butenoic acid, 4-amino-, methyl ester, (E)-, trifluoroacetate；methyl (E)-4-aminobut-2-enoate;2,2,2-trifluoroacetic acid
• CAS: 99281-88-6
• 化学式: C₂HF₃O₂*C₅H₉NO₂
• 分子量: 229.156
• InChiKey: QOPUSJRSVLGGIR-SQQVDAMQSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.31
• 重原子数：
  15
• 可旋转键数：
  3
• 环数：
  0.0
• sp3杂化的碳原子比例：
  0.43
• 拓扑面积：
  89.6
• 氢给体数：
  2
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  methyl γ-aminocrotonate trifluoroacetate 在 N-甲基吗啉 、 盐酸 、 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， 以 1,4-二氧六环 、 N,N-二甲基甲酰胺 为溶剂， 反应 9.0h， 生成 C₇H₁₂N₂O₃*ClH
  参考文献：
  名称：

  通过病毒蛋白酶 Lbpro 催化的化学酶连接法快速合成泛素样蛋白 ISG15 工具

  摘要：

  来自口蹄疫病毒的蛋白酶 (Lb pro ) 可以将合成的甘氨酰化合物与 ISG15（干扰素刺激基因 15）连接，生成各种 ISG15 蛋白工具，用于细胞蛋白质组学研究，以及筛选和评估抗 SARS 的小分子-CoV-2 类木瓜蛋白酶 (PLpro)。该策略还可以合成ISG15修饰肽和Ub（泛素）/NEDD8（泛素样蛋白Nedd8）蛋白工具。

  DOI：

  10.1002/anie.202206205
• 作为产物：
  描述：

  methyl (E)-4-((tert-butoxycarbonyl)amino)but-2-enoate 、 三氟乙酸 反应 0.33h， 以94%的产率得到methyl γ-aminocrotonate trifluoroacetate
  参考文献：
  名称：

  羧基修饰的氨基酸和肽作为蛋白酶抑制剂。

  摘要：

  制备几种类型的羧基修饰的氨基酸和肽，它们具有适合于几种代表性蛋白酶之一的N末端修饰（载体片段），并评估了它们对这些酶的抑制作用。羧基修饰（抑制单元）包括（b）CONH 2，（c）CSNH 2，（d）CN，（e）反式-CH ＝ CHCO 2 Me和（f）反式-CH ＝ CHSO 2 Me。载体片段包括NH2（PhCH2）CHX（1），AcNH（PhCH2）CHX（2），H2NCH2CONH（PhCH2）CHX（3）和AcNH（PhCH2）CHCONHCH2X（4）。化合物1b，1d，1e和1f是微粒体和胞质亮氨酸氨基肽酶的竞争性抑制剂（前者的Ki分别为14.8、67、61和3.7 mM，后者分别为14.1、26.4、27.3和8.8 mM） 。化合物1c和亮氨酸硫代酰胺均对这两种酶均无任何可检测的作用。化合物2b-f还是胰凝乳蛋白酶的竞争性抑制剂（Ki分别为13.9、23.0、5.3、30.8和29

  DOI：

  10.1021/jm00151a018

文献信息

• [EN] HETEROARYL INHIBITORS OF PAD4<br/>[FR] INHIBITEURS HÉTÉROARYLES DE PAD4
  申请人：PADLOCK THERAPEUTICS INC

  公开号：WO2018049296A1

  公开（公告）日：2018-03-15

  The present invention provides compounds useful as inhibitors of PAD4, compositions thereof, and methods of treating PAD4-related disorders.

  本发明提供了作为PAD4抑制剂有用的化合物，其组合物以及治疗与PAD4相关疾病的方法。
• Fragment-Based Covalent Ligand Screening Enables Rapid Discovery of Inhibitors for the RBR E3 Ubiquitin Ligase HOIP
  作者：Henrik Johansson、Yi-Chun Isabella Tsai、Ken Fantom、Chun-Wa Chung、Sandra Kümper、Luigi Martino、Daniel A. Thomas、H. Christian Eberl、Marcel Muelbaier、David House、Katrin Rittinger

  DOI：10.1021/jacs.8b13193

  日期：2019.2.13

  of 3 subunits, HOIP, HOIL-1L, and SHARPIN. Herein, we describe the discovery of inhibitors targeting the active site cysteine of the catalytic subunit HOIP using fragment-based covalent ligand screening. We report the synthesis of a diverse library of electrophilic fragments and demonstrate an integrated use of protein LC–MS, biochemical ubiquitination assays, chemical synthesis, and protein crystallography

  用多聚泛素链修饰蛋白质是控制细胞行为的关键调节机制，泛素系统的改变与许多疾病有关。线性（M1 连接）多聚泛素链在介导免疫和炎症反应以及细胞凋亡的多种细胞信号通路中发挥关键作用。这些链由线性泛素链组装复合物 (LUBAC) 形成，LUBAC 是一种多蛋白 E3 连接酶，由 3 个亚基 HOIP、HOIL-1L 和 SHARPIN 组成。在此，我们描述了使用基于片段的共价配体筛选靶向催化亚基 HOIP 的活性位点半胱氨酸的抑制剂的发现。我们报告了多种亲电片段库的合成，并展示了蛋白质 LC-MS、生化泛素化分析、化学合成、和蛋白质晶体学，使 RBR E3 连接酶的共价抑制剂的第一个基于结构的开发成为可能。此外，使用基于细胞的测定和化学蛋白质组学，我们证明这些化合物有效地渗透哺乳动物细胞以标记和抑制 HOIP 和 NF-κB 激活，使其成为开发选择性探针以研究 LUBAC 生物学的合适选择。我们的
• A Small Molecule That Switches a Ubiquitin Ligase From a Processive to a Distributive Enzymatic Mechanism
  作者：Stefan G. Kathman、Ingrid Span、Aaron T. Smith、Ziyang Xu、Jennifer Zhan、Amy C. Rosenzweig、Alexander V. Statsyuk

  DOI：10.1021/jacs.5b06839

  日期：2015.10.7

  E3 ligases are genetically implicated in many human diseases, yet E3 enzyme mechanisms are not fully understood, and there is a strong need for pharmacological probes of E3s. We report the discovery that the HECT E3 Nedd4-1 is a processive enzyme and that disruption of its processivity by biochemical mutations or small molecules switches Nedd4-1 from a processive to a distributive mechanism of polyubiquitin chain synthesis. Furthermore, we discovered and structurally characterized the first covalent inhibitor of Nedd4-1, which switches Nedd4-1 from a processive to a distributive mechanism. To visualize the binding mode of the Nedd4-1 inhibitor, we used X-ray crystallography and solved the first structure of a Nedd4-1 family ligase bound to an inhibitor. Importantly, our study shows that processive Nedd4-1, but not the distributive Nedd4-1:inhibitor complex, is able to synthesize polyubiquitin chains on the substrate in the presence of the deubiquitinating enzyme USP8. Therefore, inhibition of E3 ligase processivity is a viable strategy to design E3 inhibitors. Our study provides fundamental insights into the HECT E3 mechanism and uncovers a novel class of HECT E3 inhibitors.
• Structure-activity relationships for inhibition of papain by peptide Michael acceptors
  作者：Siming Liu、Robert P. Hanzlik

  DOI：10.1021/jm00084a012

  日期：1992.3

  Two series of peptidyl Michael acceptors, N-Ac-L-Phe-NHCH2CH = CH-E with different electron withdrawing groups (E = CO2CH3, 1a; SO2CH3, 1b; CO2H, 1c; CN, 1d; CONH2, 1e; and C6H4-p-NO2, 1f) and R-NHCH2CH = CHCOOCH3 with different recognition and binding groups (R = N-Ac-D-Phe, 2a; N-Ac-L-Leu, 3a; N-Ac-L-Met, 4a; PhCH2CH2CO, 5a; PhCO, 6a), were synthesized and evaluated as inactivators against papain. It was found that the inhibition of papain by peptidyl Michael acceptors is a general phenomenon and that the intrinsic chemical reactivity of the E group in the Michael acceptors has a direct effect on the kinetics of the inactivation process as reflected in k2/K(i). At pH 6.2, the reactivity of papain toward the Michael acceptors is about 283 000-fold higher than the reactivity of the model thiol 3-mercaptopropionate. This large increase in reactivity is attributable to at least 2 factors; one is the low apparent pK(a) of Cys-25 of papain, and the other is the recruitment of catalytic power by specific enzyme-substrate interactions. The unexpectedly high reactivity of 1c (E = COOH) was rationalized by proposing a direct interaction of the acid group with His-159 in the active site of papain. The unexpected inactivity of 1f (E = C6H4-p-NO2) as a Michael acceptor and its very powerful competitive inhibition of papain were rationalized by molecular graphics which showed the nitrophenyl moiety rotated out of conjugation with the olefin and interacting instead with the hydrophobic S1' region of papain. A plot of log (k2/K(i)) for 1a-6a vs log (k(cat)/K(m)) for analogous R-Gly-p-NA substrates was linear (r = 0.98) with slope of 0.83, suggesting that binding energy from specific enzyme-ligand interactions can be used to drive the self-inactivation reaction to almost the same extent as it is used to drive catalysis.
• [EN] PLPRO INHIBITORS<br/>[FR] INHIBITEURS DE PLPRO
  申请人：[en]HUAHAI US INC.

  公开号：WO2023114379A1

  公开（公告）日：2023-06-22

  Provided herein are novel compounds (e.g., Formula X or Y), pharmaceutical compositions, and methods of using the same. The compounds herein can typically inhibit PLpro activities. The compounds herein can also be used for treating a variety of diseases or disorders, such as viral infection caused by a coronavirus such as SARS-CoV- 2.