N_α-carbobenzyloxy-L-2-amino-6-acryloylaminohexanoic acid | 366780-95-2

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: N_α-carbobenzyloxy-L-2-amino-6-acryloylaminohexanoic acid
• 英文别名: (2S)-2-{[(benzyloxy)carbonyl]amino}-6-(prop-2-enamido)hexanoic acid；(S)-6-acrylamido-2-(((benzyloxy)carbonyl)amino)hexanoic acid；alpha-N-Carbobenzyloxy-epsilon-N-acryloyl-L-lysine；(2S)-2-(phenylmethoxycarbonylamino)-6-(prop-2-enoylamino)hexanoic acid
• CAS: 366780-95-2
• 化学式: C₁₇H₂₂N₂O₅
• 分子量: 334.372
• InChiKey: TXGDHOVGNMTCSP-AWEZNQCLSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2
• 重原子数：
  24
• 可旋转键数：
  11
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.35
• 拓扑面积：
  105
• 氢给体数：
  3
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  N_α-carbobenzyloxy-L-2-amino-6-acryloylaminohexanoic acid 在 二甲基二环氧乙烷 作用下， 以 丙酮 为溶剂， 以100%的产率得到N_α-carbobenzyloxy-L-2-amino-6-(oxiranecarbonylamino)hexanoic acid
  参考文献：
  名称：

  Synthesis of dipeptide-bound epoxides and α,β-unsaturated amides as potential irreversible transglutaminase inhibitors

  摘要：

  Herein we report the synthesis of 24 novel peptides Lis potential irreversible inactivators of transglutaminase (TGase). These peptides were designed to resemble Cbz-L-Gln-Gly, known to be a good TGase substrate, and to include either alpha,beta -unsaturated amide groups or the corresponding epoxide groups. The side chain length: of the amino acid residue bearing the inhibitor group was also varied in order to permit investigation of this effect. (C) 2001 Elsevier Science Ltd. All rights reserved.

  DOI：

  10.1016/s0968-0896(01)00292-9
• 作为产物：
  描述：

  N-alpha-叔丁氧羰基-L-赖氨酸 在 盐酸 、 N,N-二异丙基乙胺 、 sodium hydroxide 作用下， 以 四氢呋喃 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 18.5h， 生成 N_α-carbobenzyloxy-L-2-amino-6-acryloylaminohexanoic acid
  参考文献：
  名称：

  SAR Development of Lysine-Based Irreversible Inhibitors of Transglutaminase 2 for Huntington's Disease

  摘要：

  We report a series of irreversible transglutaminase 2 inhibitors starting from a known lysine dipeptide bearing an acrylamide warhead. We established new SARs resulting in compounds demonstrating improved potency and better physical and calculated properties. Transglutaminase selectivity profiling and in vitro ADME properties of selected compounds are also reported.

  DOI：

  10.1021/ml300241m

文献信息

• [EN] TG2 INHIBITOR COMPOUNDS AND USES THEREOF<br/>[FR] COMPOSÉS INHIBITEURS DE TG2 ET UTILISATIONS DE CES DERNIERS
  申请人：UNIV OTTAWA

  公开号：WO2017179018A1

  公开（公告）日：2017-10-19

  There are provided Tissue Transglutaminase (TG2) inhibitor compounds, and compositions and methods of use thereof for the prevention or treatment of a cancer. Compounds of Formula I, and pharmaceutically acceptable salts thereof, are provided: Formula (I).

  提供了组织转谷氨酰胺酶（TG2）抑制剂化合物，以及其用于预防或治疗癌症的组合物和使用方法。提供了化合物I的公式，以及其药用盐：公式（I）。
• TRANSGLUTAMINASE TG2 INHIBITORS, PHARMACEUTICAL COMPOSITIONS, AND METHODS OF USE THEREOF
  申请人：DOMINGUEZ Celia

  公开号：US20150232420A1

  公开（公告）日：2015-08-20

  Certain compounds and pharmaceutically acceptable salts are provided herein. Also provided are pharmaceutical compositions comprising at least one compound or pharmaceutically acceptable salt therein and one or more pharmaceutically acceptable vehicle. Methods of treating patients suffering from certain disease states responsive to the inhibition of transglutaminase TG2 activity are described. These disease states include neurodegenerative disorders such as Huntington's disease. Also described are methods of treatment include administering at least one compound or pharmaceutically acceptable salt thereof as a single active agent or administering at least one compound or pharmaceutically acceptable salt thereof in combination with one or more other therapeutic agents.

  本文提供了某些化合物和药用可接受盐。还提供了包含至少一种化合物或药用可接受盐和一个或多个药用可接受载体的药物组合物。描述了治疗对抑制转谷氨酰胺酶TG2活性有响应的某些疾病状态的方法。这些疾病状态包括亨廷顿病等神经退行性疾病。还描述了治疗方法，包括单独使用至少一种化合物或药用可接受盐作为活性剂或与一个或多个其他治疗剂联合使用至少一种化合物或药用可接受盐。
• Novel irreversible peptidic inhibitors of transglutaminase 2
  作者：Nicholas J. Cundy、Jane Arciszewski、Eric W. J. Gates、Sydney L. Acton、Kyle D. Passley、Ernest Awoonor-Williams、Elizabeth K. Boyd、Nancy Xu、Élise Pierson、Catalina Fernandez-Ansieta、Marie R. Albert、Nicole M. R. McNeil、Gautam Adhikary、Richard L. Eckert、Jeffrey W. Keillor

  DOI：10.1039/d2md00417h

  日期：——

  vivo. Our latest efforts in inhibitor optimization involve the modification of a previous lead compound's scaffold by insertion of various amino acid residues into the peptidomimetic backbone, and derivatization of the N-terminus with substituted phenylacetic acids, resulting in 28 novel irreversible inhibitors. These inhibitors were evaluated for their ability to inhibit TG2 in vitro and their pharmacokinetic

  转谷氨酰胺酶 2 (TG2)，也称为组织转谷氨酰胺酶，在蛋白质交联和细胞信号传导中发挥着至关重要的作用。它既能催化转酰胺基作用，又能充当 G 蛋白，这些活性依赖于构象、相互排斥且受到严格调控。这两种活动的失调与许多病理学有关。 TG2 在人类中普遍表达，并且定位于细胞内和细胞外。靶向 TG2 疗法已经开发出来，但面临着许多障碍，包括体内疗效下降。我们在抑制剂优化方面的最新努力包括通过将各种氨基酸残基插入拟肽主链来修饰先前先导化合物的支架，并用取代的苯乙酸对N末端进行衍生化，从而产生 28 种新型不可逆抑制剂。评估了这些抑制剂在体外抑制 TG2 的能力及其药代动力学特性，并在癌症干细胞模型中测试了最有希望的候选药物35 ( k inact / K I = 760 × 10 3 M -1 min -1 )。尽管这些抑制剂与TG2 相比表现出卓越的效力，其k inact / K I比率比其母体化
• Cell-Impermeable Inhibitors Confirm That Intracellular Human Transglutaminase 2 Is Responsible for the Transglutaminase-Associated Cancer Phenotype
  作者：Eric W. J. Gates、Nicholas D. Calvert、Nicholas J. Cundy、Federica Brugnoli、Pauline Navals、Alexia Kirby、Nicoletta Bianchi、Gautam Adhikary、Adam J. Shuhendler、Richard L. Eckert、Jeffrey W. Keillor

  DOI：10.3390/ijms241612546

  日期：——

  Transglutaminase 2 (TG2) is a multifunctional enzyme primarily responsible for crosslinking proteins. Ubiquitously expressed in humans, TG2 can act either as a transamidase by crosslinking two substrates through formation of an Nε(ɣ-glutaminyl)lysine bond or as an intracellular G-protein. These discrete roles are tightly regulated by both allosteric and environmental stimuli and are associated with dramatic changes in the conformation of the enzyme. The pleiotropic nature of TG2 and multi-faceted activities have resulted in TG2 being implicated in numerous disease pathologies including celiac disease, fibrosis, and cancer. Targeted TG2 therapies have not been selective for subcellular localization, such that currently no tools exist to selectively target extracellular over intracellular TG2. Herein, we have designed novel TG2-selective inhibitors that are not only highly potent and irreversible, but also cell impermeable, targeting only extracellular TG2. We have also further derivatized the scaffold to develop probes that are intrinsically fluorescent or bear an alkyne handle, which target both intra- and extracellular TG2, in order to facilitate cellular labelling and pull-down assays. The fluorescent probes were internalized and imaged in cellulo, and provide the first implicit experimental evidence that by comparison with their cell-impermeable analogues, it is specifically intracellular TG2, and presumably its G-protein activity, that contributes to transglutaminase-associated cancer progression.

  转谷氨酰胺酶 2（TG2）是一种多功能酶，主要负责交联蛋白质。TG2 在人体内无独有偶地表达，它既可以通过形成 Nε(ɣ-谷氨酰胺酰)赖氨酸键交联两个底物而充当转氨基酶，也可以充当细胞内的 G 蛋白。这些不同的作用受到异构和环境刺激的严格调控，并与酶构象的剧烈变化有关。TG2 的多效性和多方面活性导致 TG2 与乳糜泻、纤维化和癌症等多种疾病病理有关。靶向 TG2 的疗法对亚细胞定位没有选择性，因此目前还没有工具可以选择性地靶向细胞外而不是细胞内的 TG2。在此，我们设计出了新型 TG2 选择性抑制剂，不仅药效高、不可逆，而且不渗透细胞，只针对细胞外 TG2。我们还对该支架进行了进一步衍生，开发出了同时针对细胞内和细胞外 TG2 的本征荧光探针或带有炔柄的探针，以方便细胞标记和牵引检测。这些荧光探针在细胞内被内化并成像，首次提供了隐含的实验证据，证明与细胞不渗透的类似物相比，细胞内的 TG2（可能是其 G 蛋白活性）才是导致转谷氨酰胺酶相关癌症进展的原因。
• TG2 inhibitor piperazine compounds and uses thereof
  申请人：UNIVERSITY OF OTTAWA

  公开号：US10894777B2

  公开（公告）日：2021-01-19

  There are provided Tissue Transglutaminase (TG2) inhibitor compounds, and compositions and methods of use thereof for the prevention or treatment of a cancer. Compounds of Formula I, and pharmaceutically acceptable salts thereof, are provided:

  提供了组织转谷氨酰胺酶（TG2）抑制剂化合物及其用于预防或治疗癌症的组合物和使用方法。提供了式 I 的化合物及其药学上可接受的盐类：