caboxybenzyl-Phe-Lys-acyloxymethylketone | 956479-18-8

• 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: caboxybenzyl-Phe-Lys-acyloxymethylketone
• 英文别名: GB111-NH2；Z-Phe-Lys-methyl (2,6-dimethyl)benzoate；(S)-7-amino-3-((S)-2-(benzyloxycarbonylamino)-3-phenylpropanamido)-2-oxoheptyl 2,6-dimethylbenzoate；[(3S)-7-amino-2-oxo-3-[[(2S)-3-phenyl-2-(phenylmethoxycarbonylamino)propanoyl]amino]heptyl] 2,6-dimethylbenzoate
• CAS: 956479-18-8
• 化学式: C₃₃H₃₉N₃O₆
• 分子量: 573.689
• InChiKey: SRXNAWHDCFMFNI-NSOVKSMOSA-N

物化性质

• 熔点：
  136-139 °C
• 沸点：
  801.1±65.0 °C(Predicted)
• 密度：
  1.188±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  5
• 重原子数：
  42
• 可旋转键数：
  17
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  137
• 氢给体数：
  3
• 氢受体数：
  7

制备方法与用途

一种新型半胱氨酸组织蛋白酶抑制剂可以阻断组织蛋白酶B、L和S的活性，同时抑制自噬并增加氧化应激，尤其是促使巨噬细胞死亡。

反应信息

• 作为反应物：
  描述：

  caboxybenzyl-Phe-Lys-acyloxymethylketone 在 1H-咪唑-1-磺酰叠氮盐酸盐 、 copper(ll) sulfate pentahydrate 、 potassium carbonate 作用下， 以 甲醇 为溶剂， 以77%的产率得到caboxybenzyl-Phe-Lys(Az)-acyloxymethylketone
  参考文献：
  名称：

  Disruption of glycolytic flux is a signal for inflammasome signaling and pyroptotic cell death

  摘要：

  当巨噬细胞等先天性免疫细胞受到环境压力或病原体感染的挑战时，它们会触发被称为炎性体的多蛋白复合物的快速组装，这种复合物负责启动促炎反应和一种被称为脓毒症的细胞死亡形式。我们在本文中描述了一种细胞内触发 NLRP3 介导的炎症信号传导、IL-1β 生成和小鼠骨髓巨噬细胞热噬的机制，这种机制是由糖酵解通量的破坏介导的。这一信号是由 NADH 水平下降和诱导线粒体 ROS 生成引起的，加入能恢复 NADH 生成的产品后即可缓解。这种信号对于宿主细胞对胞内病原体鼠伤寒沙门氏菌的反应也很重要，鼠伤寒沙门氏菌可通过摄取宿主细胞的葡萄糖来破坏新陈代谢。这些结果揭示了免疫细胞用于感知代谢功能障碍或细胞内病原体感染的重要炎症信号网络。

  DOI：

  10.7554/elife.13663
• 作为产物：
  描述：

  Fmoc-Lys(Boc)-AOMK 在 N,N-二异丙基乙胺 、 三氟乙酸 作用下， 以 二氯甲烷 为溶剂， 反应 2.08h， 生成 caboxybenzyl-Phe-Lys-acyloxymethylketone
  参考文献：
  名称：

  [EN] PHOTODYNAMIC QUENCHED ACTIVITY BASED PROBES AND USES THEREOF IN IMAGING AND TARGETED THERAPY
  [FR] SONDES BASÉES SUR L'ACTIVITÉ PHOTODYNAMIQUE ATTÉNUÉE ET LEURS UTILISATIONS EN IMAGERIE ET EN THÉRAPIE CIBLÉE

  摘要：

  公开号：

  WO2016157198A9

文献信息

• CT Imaging of Enzymatic Activity in Cancer Using Covalent Probes Reveal a Size-Dependent Pattern
  作者：Darya Tsvirkun、Yael Ben-Nun、Emmanuelle Merquiol、Ivan Zlotver、Karen Meir、Tommy Weiss-Sadan、Ilan Matok、Rachela Popovtzer、Galia Blum

  DOI：10.1021/jacs.8b05817

  日期：2018.9.26

  targets in an activity-dependent manner. Using a CT instrument, these novel probes enable detection of the elevated cathepsin activity within cancerous tissue, thus creating a direct link between biological processes and imaging signals. We present the generation and biochemical evaluation of a library of ABPs tagged with different sized gold nanoparticles (GNPs), with various ratios of cathepsin-targeting

  X 射线 CT 仪器是医院中最可用、最高效且最具成本效益的成像方式之一。CT 分子成像领域正在兴起，主要依赖于检测金纳米粒子和含碘化合物，以标记各种丰富的生物分子。这是我们第一次尝试检测酶活性，而 CT 扫描仪对造影剂的低灵敏度使这项任务成为一项具有挑战性的任务。因此，我们开发了一类新的纳米级组织蛋白酶靶向活性探针（ABP），用于癌症的功能性 CT 成像。ABP 是设计用于以活性依赖方式共价修饰酶靶标的小分子。使用 CT 仪器，这些新型探针能够检测癌组织内升高的组织蛋白酶活性，从而在生物过程和成像信号之间建立直接联系。我们展示了用不同尺寸的金纳米粒子 (GNP) 标记的 ABP 库的生成和生化评估，具有不同比例的组织蛋白酶靶向部分和不同聚乙二醇 (PEG) 保护层的组合。最有效和最稳定的 GNP-ABP 被应用于小鼠的非侵入性癌症成像。令人惊讶的是，从肿瘤中检测到的 CT 对比与 GNP
• Modulation of the inhibitor properties of dipeptidyl (acyloxy)methyl ketones toward the CaaX proteases
  作者：Anne-Marie R. Dechert、James P. MacNamara、Sarah R. Breevoort、Emily R. Hildebrandt、Ned W. Hembree、Adam C. Rea、Duncan E. McLain、Stephen B. Porter、Walter K. Schmidt、Timothy M. Dore

  DOI：10.1016/j.bmc.2010.07.041

  日期：2010.9

  Dipeptidyl (acyloxy) methyl ketones (AOMKs) have been identified as mechanism-based inhibitors of certain cysteine proteases. These compounds are also inhibitors of the integral membrane proteins Rce1p and Ste24p, which are proteases that independently mediate a cleavage step associated with the maturation of certain isoprenylated proteins. The enzymatic mechanism of Rce1p is ill-defined, whereas Ste24p is a zinc metalloprotease. Rce1p is required for the proper processing of the oncoprotein Ras and is viewed as a potential target for cancer therapy. In this study, we synthesized a small library of dipeptidyl AOMKs to investigate the structural elements that contribute to the inhibitor properties of this class of molecules toward Rce1p and Ste24p. The compounds were evaluated using a fluorescence-based in vitro proteolysis assay. The most potent dipeptidyl AOMKs contained an arginine residue and the identity of the benzoate group strongly influenced potency. A 'warhead' free AOMK inhibited Rce1p and Ste24p. The data suggest that the dipeptidyl AOMKs are not mechanism-based inhibitors of Rce1p and Ste24p and corroborate the hypothesis that Rce1p is not a cysteine protease. (C) 2010 Elsevier Ltd. All rights reserved.
• Identification of new peptide amides as selective cathepsin L inhibitors: The first step towards selective irreversible inhibitors?
  作者：Ana Torkar、Brigita Lenarčič、Tamara Lah、Vincent Dive、Laurent Devel

  DOI：10.1016/j.bmcl.2013.03.041

  日期：2013.5

  A small library of peptide amides was designed to profile the cathepsin L active site. Within the cathepsin family of cysteine proteases, the first round of selection was on cathepsin L and cathepsin B, and then selected hits were further evaluated for binding to cathepsin K and cathepsin S. Five highly selective sequences with submicromolar affinities towards cathepsin L were identified. An acyloxymethyl ketone warhead was then attached to these sequences. Although these original irreversible inhibitors inactivate cathepsin L, it appears that the nature of the warhead drastically impact the selectivity profile of the resulting covalent inhibitors. (C) 2013 Elsevier Ltd. All rights reserved.
• Disruption of glycolytic flux is a signal for inflammasome signaling and pyroptotic cell death
  作者：Laura E Sanman、Yu Qian、Nicholas A Eisele、Tessie M Ng、Wouter A van der Linden、Denise M Monack、Eranthie Weerapana、Matthew Bogyo

  DOI：10.7554/elife.13663

  日期：——

  When innate immune cells such as macrophages are challenged with environmental stresses or infection by pathogens, they trigger the rapid assembly of multi-protein complexes called inflammasomes that are responsible for initiating pro-inflammatory responses and a form of cell death termed pyroptosis. We describe here the identification of an intracellular trigger of NLRP3-mediated inflammatory signaling, IL-1β production and pyroptosis in primed murine bone marrow-derived macrophages that is mediated by the disruption of glycolytic flux. This signal results from a drop of NADH levels and induction of mitochondrial ROS production and can be rescued by addition of products that restore NADH production. This signal is also important for host-cell response to the intracellular pathogen Salmonella typhimurium, which can disrupt metabolism by uptake of host-cell glucose. These results reveal an important inflammatory signaling network used by immune cells to sense metabolic dysfunction or infection by intracellular pathogens.

  当巨噬细胞等先天性免疫细胞受到环境压力或病原体感染的挑战时，它们会触发被称为炎性体的多蛋白复合物的快速组装，这种复合物负责启动促炎反应和一种被称为脓毒症的细胞死亡形式。我们在本文中描述了一种细胞内触发 NLRP3 介导的炎症信号传导、IL-1β 生成和小鼠骨髓巨噬细胞热噬的机制，这种机制是由糖酵解通量的破坏介导的。这一信号是由 NADH 水平下降和诱导线粒体 ROS 生成引起的，加入能恢复 NADH 生成的产品后即可缓解。这种信号对于宿主细胞对胞内病原体鼠伤寒沙门氏菌的反应也很重要，鼠伤寒沙门氏菌可通过摄取宿主细胞的葡萄糖来破坏新陈代谢。这些结果揭示了免疫细胞用于感知代谢功能障碍或细胞内病原体感染的重要炎症信号网络。
• [EN] PHOTODYNAMIC QUENCHED ACTIVITY BASED PROBES AND USES THEREOF IN IMAGING AND TARGETED THERAPY<br/>[FR] SONDES BASÉES SUR L'ACTIVITÉ PHOTODYNAMIQUE ATTÉNUÉE ET LEURS UTILISATIONS EN IMAGERIE ET EN THÉRAPIE CIBLÉE
  申请人：BLUM GALIA

  公开号：WO2016157198A9

  公开（公告）日：2016-11-17