Legumain inhibitor 1 | 1207092-99-6

• 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: Legumain inhibitor 1
• 英文别名: LI-1；(2S,3S)-Ethyl 3-(2-((S)-1-acetylpyrrolidine-2-carbonyl)-1-(2-amino-2-oxoethyl)hydrazinecarbonyl)oxirane-2-carboxylate；ethyl (2S,3S)-3-[[[(2S)-1-acetylpyrrolidine-2-carbonyl]amino]-(2-amino-2-oxoethyl)carbamoyl]oxirane-2-carboxylate
• CAS: 1207092-99-6
• 化学式: C₁₅H₂₂N₄O₇
• 分子量: 370.362
• InChiKey: TZKVALJHLJILLI-DLOVCJGASA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -1.8
• 重原子数：
  26
• 可旋转键数：
  7
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.67
• 拓扑面积：
  152
• 氢给体数：
  2
• 氢受体数：
  7

反应信息

• 作为产物：
  描述：

  N-乙酰-L-脯氨酸 在 氯化亚砜 、 N,N-二异丙基乙胺 作用下， 以 二氯甲烷 、 苯 为溶剂， 反应 1.0h， 生成 Legumain inhibitor 1
  参考文献：
  名称：

  溶酶体天冬酰胺内肽酶的氮杂肽抑制剂的合成和评价，legumain

  摘要：

  Legumain 或天冬酰胺内肽酶 (AEP) 是一种溶酶体半胱氨酸蛋白酶，对天冬酰胺残基后的蛋白质底物切割具有高度特异性。当处于溶酶体的酸性环境中时，它也能够在天冬氨酸位点后裂解。Legumain 的表达和活性与许多病理状况有关，包括癌症、动脉粥样硬化和炎症，但其在这些病理中的生物学作用尚不清楚。高效和选择性的legumain抑制剂不仅对研究legumain在这些条件下的功能作用很有价值，而且可能具有治疗潜力。我们在这里描述了基于氮杂天冬酰胺支架的选择性legumain 抑制剂的设计、合成和体外评估。我们合成了具有各种非天然氨基酸和不同亲电子弹头的氮杂肽基抑制剂库，并表征了legumain失活的动力学特性。我们还合成了荧光标记的抑制剂，以研究化合物的细胞渗透性和选择性。抑制剂的二阶速率常数高达 5 × 10针对重组小鼠legumain的4  M -1  s -1和IC 50值低至4 nM。此外，抑制剂对legumain

  DOI：

  10.1016/j.bmcl.2011.12.079

文献信息

• Specific inhibitors and active site probes for legumain
  申请人：Lee Jiyoun

  公开号：US09345789B2

  公开（公告）日：2016-05-24

  Compounds which specifically inhibit legumain, also known as asparaginyl endopeptidase are provided. The compounds have an epoxide or N-Michael acceptor warhead, and have an asparagine side chain attached to a nitrogen atom in the backbone adjacent the warhead. The compounds also preferably comprise a proline residue adjacent the asparagine, and the compound may also contain a third residue and/or a label for cellular or in vivo imaging of active legumain.

  提供了特异抑制腿曼酶（也称为天门冬氨酸内切肽酶）的化合物。这些化合物具有环氧或N-迈克尔受体战斗头，且在与战斗头相邻的骨架中的氮原子上连接有一个天门冬氨酸侧链。这些化合物还最好包括相邻于天门冬氨酸的脯氨酸残基，化合物还可能包含第三个残基和/或用于细胞或体内活性腿曼酶成像的标记。
• Development of Near-Infrared Fluorophore (NIRF)-Labeled Activity-Based Probes for <i>in Vivo</i> Imaging of Legumain
  作者：Jiyoun Lee、Matthew Bogyo

  DOI：10.1021/cb900232a

  日期：2010.2.19

  Asparaginyl endopeptidase, or legumain, is a lysosomal cysteine protease that was originally identified in plants and later found to be involved in antigen presentation in higher eukaryotes. Legumain is also up-regulated in a number of human cancers, and recent studies suggest that it may play important functional roles in the process of tumorigenesis. However, detailed functional studies in relevant animal models of human disease have been hindered by the lack of suitably selective small molecule inhibitors and imaging reagents. Here we present the design, optimization, and in vivo application of fluorescently labeled activity-based probes (ABPs) for legumain. We demonstrate that optimized aza-peptidyl Asn epoxides are highly selective and potent inhibitors that can be readily converted into near-infrared fluorophore-labeled ABPs for whole body, noninvasive imaging applications. We show that these probes specifically label legumain in various normal tissues as welt as in solid tumors when applied in vivo. Interestingly, addition of cell-penetrating peptides to the probes enhanced cellular uptake but resulted in increased cross-reactivity toward other lysosomal proteases as the result of their accumulation in lysosomes. Overall, we find that aza-peptidyl Asn ABPs are valuable new tools for the future study of legumain function in more complex models of human disease.