L-glutamine 7-amido-4-methylcoumarin | 105888-45-7

• 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: L-glutamine 7-amido-4-methylcoumarin
• 英文别名: H-Gln-AMC；Q-AMC；H-Gln-amc HBr；(2S)-2-amino-N-(4-methyl-2-oxochromen-7-yl)pentanediamide
• CAS: 105888-45-7
• 化学式: C₁₅H₁₇N₃O₄
• 分子量: 303.318
• InChiKey: VEPDWBJBPXVCEN-NSHDSACASA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -0.2
• 重原子数：
  22
• 可旋转键数：
  5
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.27
• 拓扑面积：
  125
• 氢给体数：
  3
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  L-glutamine 7-amido-4-methylcoumarin 在 四丁基氟化铵 、 O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate 、 N,N-二异丙基乙胺 作用下， 以 N-甲基吡咯烷酮 、 二氯甲烷 为溶剂， 反应 51.0h， 生成
  参考文献：
  名称：

  Improving the Specificity of the Prostate-Specific Antigen Substrate Glutaryl-Hyp-Ala-Ser-Chg-Gln as a Promoiety

  摘要：

  To develop PSA peptide substrates with improved specificity and plasma stability from the known substrate sequence glutaryl‐Hyp‐Ala‐Ser‐Chg‐Gln, systematic replacements of the N‐terminal segment with D‐retro‐inverso‐peptides were performed with the incorporation of 7‐amino‐4‐methylcoumarin (7‐AMC) after Gln for convenient fluorometric determination and ranking of the PSA substrate activity. The D‐retro‐inverso‐peptide conjugates with P2‐P5 D‐amino acid substitutions were moderate but poorer PSA substrates as compared to the original peptide, suggesting that inversion of the amide bonds and/or incorporation of the additional atom as in the urea linker adversely affected PSA binding. However, P5 substitution of Hyp with Ser showed significant improvements in PSA cleavage rate; the resulting AMC conjugate, glutaryl‐Ser‐Ala‐Ser‐Chg‐Gln‐AMC (11), exhibited the fastest PSA cleavage rate of 351 pmol/min/100 nmol PSA. In addition, GABA←mGly‐Ala‐Ser‐Chg‐Gln‐AMC (conjugate 6) was the second best PSA substrate and released 7‐AMC at a rate of 225 pmol/min/100 nmol PSA as compared to 171 pmol/min/100 nmol PSA for the control conjugate glutaryl‐Hyp‐Ala‐Ser‐Chg‐Gln‐AMC. Incubations of selected AMC conjugates with mouse and human plasma revealed that GABA←D‐Ser‐ψ[NH‐CO‐NH]‐Ala‐Ser‐Chg‐Gln‐AMC (5) and GABA←mGly‐Ala‐Ser‐Chg‐Gln‐AMC (6) were most stable to non‐PSA‐mediated proteolysis. Our results suggest that the PSA specificity of glutaryl‐Hyp‐Ala‐Ser‐Chg‐Gln is improved with Ser and mGly substitutions of Hyp at the P5.

  DOI：

  10.1111/cbdd.12559
• 作为产物：
  描述：

  7-氨基-4-甲基香豆素 在 吡啶 、 三氟乙酸 、 三氯氧磷 作用下， 以 二氯甲烷 为溶剂， 反应 2.5h， 生成 L-glutamine 7-amido-4-methylcoumarin
  参考文献：
  名称：

  针对 SARS-CoV-2 的主要蛋白酶：从高通量筛选的建立到定制抑制剂的设计

  摘要：

  SARS-CoV-2 (M pro ) 的主要蛋白酶是 COVID-19 的病原体，是一个重要的药物靶点。一种新的荧光底物与内部淬灭的荧光肽进行了动力学比较，结果表明它非常适合用重组表达的 M pro进行高通量筛选。两类蛋白酶抑制剂，氮腈和吡啶酯，经过鉴定、优化并进行了深入的生化表征。配备独特氮腈弹头的定制肽同时抑制 M pro和组织蛋白酶 L（一种与病毒细胞进入相关的蛋白酶）。通过位置扫描分析吡啶基吲哚酯。事实证明，我们针对 M pro抑制剂的重点方法优于虚拟筛选。使用两种不可逆抑制剂，氮腈8 (k inac /K=37 500 m -1 s -1 , K=24.0 nm ) 和吡啶酯17 (k inac /K=29 100 m -1 s -1 , K=10.0 nm ），已经发现了有希望进一步开发的候选药物。

  DOI：

  10.1002/anie.202016961

文献信息

• Synthesis and Initial Evaluation of a Novel Fluorophore for Selective FMDV 3C Protease Detection
  作者：Samerah Malik、Alex Sinclair、Ali Ryan、Adam Le Gresley

  DOI：10.3390/molecules25163599

  日期：——

  The development and evaluation of a Boc-AL(Boc)Q(Trt)-AMC fluorophore to detect 3C Protease, produced by Foot and Mouth Disease Virus (FMDV) is reported, with a view to a potential use as a rapid screen for FMDV infected livestock The peptide-linked conjugate fluorophore is evaluated in vitro for sensitivity, specificity, stability and rapidity and shows statistically significant increases in fluorescence when exposed to physiologically relevant concentrations of 3C Protease and selectivity when compared with other common proteases likely to be located, typically in the absence of FMDV. The stability of deprotected Boc-AL(Boc)Q(Trt)-AMC is reported as a limitation of this probe.

  报道了一种Boc-AL（Boc）Q（Trt）-AMC荧光探针的开发和评价，用于检测口蹄疫病毒（FMDV）产生的3C蛋白酶，旨在作为快速筛选FMDV感染牲畜的潜在用途。该肽偶联荧光探针在体外进行了敏感性、特异性、稳定性和快速性的评估，并在与其他常见蛋白酶的比较中显示出在生理相关浓度下暴露于3C蛋白酶时荧光显着增加的选择性，通常在FMDV缺失的情况下。报道了去保护的Boc-AL（Boc）Q（Trt）-AMC的稳定性作为该探针的局限性。
• 10.1021/acs.jmedchem.4c00049
  作者：Mou, Jun、Ning, Xiang-Li、Wang, Xin-Yue、Hou, Shu-Yan、Meng, Fan-Bo、Zhou, Cong、Wu, Jing-Wei、Li, Chunyan、Jia, Tao、Wu, Xiaoai、Wu, Yong、Chen, Yongping、Li, Guo-Bo

  DOI：10.1021/acs.jmedchem.4c00049

  日期：——

  The secretory glutaminyl cyclase (sQC) and Golgi-resident glutaminyl cyclase (gQC) are responsible for N-terminal protein pyroglutamation and associated with various human diseases. Although several sQC/gQC inhibitors have been reported, only one inhibitor, PQ912, is currently undergoing clinic trials for the treatment of Alzheimer’s disease. We report an X-ray crystal structure of sQC complexed with

  分泌型谷氨酰胺酰环化酶 (sQC) 和高尔基体谷氨酰胺酰环化酶 (gQC) 负责 N 末端蛋白质焦谷氨酸化，并与多种人类疾病相关。尽管已报道了多种 sQC/gQC 抑制剂，但目前只有一种抑制剂 PQ912 正在进行治疗阿尔茨海默病的临床试验。我们报道了 sQC 与 PQ912 复合的 X 射线晶体结构，揭示了苯并咪唑与活性位点锌离子和催化三联体产生“锚定”相互作用。结构引导设计和优化产生了一系列新的苯并咪唑衍生物，对 sQC 和 gQC 均表现出纳摩尔级抑制作用。在 MPTP 诱导的帕金森病 (PD) 小鼠模型中， BI-43通过逆转多巴胺能神经元损失、减少小胶质细胞以及降低 sQC/gQC 底物、α-突触核蛋白和 CCL2 的水平，显示出缓解运动缺陷的功效。这项研究不仅为针对 sQC/gQC 的药物发现提供了结构基础和新线索，而且还提供了支持 sQC/gQC 作为 PD 治疗潜在靶点的证据。
• [DE] SULFOLIPIDE ALS NEUE GLUTAMINYLCYCLASE-INHIBITOREN<br/>[EN] SULFOLIPIDS AS NEW GLUTAMINYL CYCLASE INHIBITORS<br/>[FR] SULFOLIPIDES UTILISÉS COMME NOUVEAUX INHIBITEURS DE LA GLUTAMINYL CYCLASE
  申请人：HOCHSCHULE ANHALT

  公开号：WO2017046256A1

  公开（公告）日：2017-03-23

  Die Erfindung betrifft die Verwendung einer Verbindung der Formel (I) oder einer die Verbindung enthaltenden Zusammensetzung als Glutaminylcyclase (QC) -Inhibitor sowie Herstellungsverfahren.
• Improving the Specificity of the Prostate-Specific Antigen Substrate Glutaryl-Hyp-Ala-Ser-Chg-Gln as a Promoiety
  作者：Herve Aloysius、Longqin Hu

  DOI：10.1111/cbdd.12559

  日期：2015.10

  To develop PSA peptide substrates with improved specificity and plasma stability from the known substrate sequence glutaryl‐Hyp‐Ala‐Ser‐Chg‐Gln, systematic replacements of the N‐terminal segment with D‐retro‐inverso‐peptides were performed with the incorporation of 7‐amino‐4‐methylcoumarin (7‐AMC) after Gln for convenient fluorometric determination and ranking of the PSA substrate activity. The D‐retro‐inverso‐peptide conjugates with P2‐P5 D‐amino acid substitutions were moderate but poorer PSA substrates as compared to the original peptide, suggesting that inversion of the amide bonds and/or incorporation of the additional atom as in the urea linker adversely affected PSA binding. However, P5 substitution of Hyp with Ser showed significant improvements in PSA cleavage rate; the resulting AMC conjugate, glutaryl‐Ser‐Ala‐Ser‐Chg‐Gln‐AMC (11), exhibited the fastest PSA cleavage rate of 351 pmol/min/100 nmol PSA. In addition, GABA←mGly‐Ala‐Ser‐Chg‐Gln‐AMC (conjugate 6) was the second best PSA substrate and released 7‐AMC at a rate of 225 pmol/min/100 nmol PSA as compared to 171 pmol/min/100 nmol PSA for the control conjugate glutaryl‐Hyp‐Ala‐Ser‐Chg‐Gln‐AMC. Incubations of selected AMC conjugates with mouse and human plasma revealed that GABA←D‐Ser‐ψ[NH‐CO‐NH]‐Ala‐Ser‐Chg‐Gln‐AMC (5) and GABA←mGly‐Ala‐Ser‐Chg‐Gln‐AMC (6) were most stable to non‐PSA‐mediated proteolysis. Our results suggest that the PSA specificity of glutaryl‐Hyp‐Ala‐Ser‐Chg‐Gln is improved with Ser and mGly substitutions of Hyp at the P5.
• Targeting the Main Protease of SARS‐CoV‐2: From the Establishment of High Throughput Screening to the Design of Tailored Inhibitors
  作者：Julian Breidenbach、Carina Lemke、Thanigaimalai Pillaiyar、Laura Schäkel、Ghazl Al Hamwi、Miriam Diett、Robin Gedschold、Nina Geiger、Vittoria Lopez、Salahuddin Mirza、Vigneshwaran Namasivayam、Anke C. Schiedel、Katharina Sylvester、Dominik Thimm、Christin Vielmuth、Lan Phuong Vu、Maria Zyulina、Jochen Bodem、Michael Gütschow、Christa E. Müller

  DOI：10.1002/anie.202016961

  日期：2021.4.26

  The main protease of SARS‐CoV‐2 (Mpro), the causative agent of COVID‐19, constitutes a significant drug target. A new fluorogenic substrate was kinetically compared to an internally quenched fluorescent peptide and shown to be ideally suitable for high throughput screening with recombinantly expressed Mpro. Two classes of protease inhibitors, azanitriles and pyridyl esters, were identified, optimized

  SARS-CoV-2 (M pro ) 的主要蛋白酶是 COVID-19 的病原体，是一个重要的药物靶点。一种新的荧光底物与内部淬灭的荧光肽进行了动力学比较，结果表明它非常适合用重组表达的 M pro进行高通量筛选。两类蛋白酶抑制剂，氮腈和吡啶酯，经过鉴定、优化并进行了深入的生化表征。配备独特氮腈弹头的定制肽同时抑制 M pro和组织蛋白酶 L（一种与病毒细胞进入相关的蛋白酶）。通过位置扫描分析吡啶基吲哚酯。事实证明，我们针对 M pro抑制剂的重点方法优于虚拟筛选。使用两种不可逆抑制剂，氮腈8 (k inac /K=37 500 m -1 s -1 , K=24.0 nm ) 和吡啶酯17 (k inac /K=29 100 m -1 s -1 , K=10.0 nm ），已经发现了有希望进一步开发的候选药物。