1-Benzyl-3-[3,5-bis(trifluoromethyl)phenyl]-2,5-bis(4-methylphenyl)pyrrole

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡咯
• 英文名称: 1-Benzyl-3-[3,5-bis(trifluoromethyl)phenyl]-2,5-bis(4-methylphenyl)pyrrole
• 英文别名: 1-benzyl-3-[3,5-bis(trifluoromethyl)phenyl]-2,5-bis(4-methylphenyl)pyrrole
• 化学式: C₁₇H₁₆N₃O₃Pol
• 分子量: 549.5
• InChiKey: JIQUZEHZBOEXMG-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  9.7
• 重原子数：
  40
• 可旋转键数：
  5
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.15
• 拓扑面积：
  4.9
• 氢给体数：
  0
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  1-Benzyl-3-[3,5-bis(trifluoromethyl)phenyl]-2,5-bis(4-methylphenyl)pyrrole 在 三氟乙酸 作用下， 生成 Legumain inhibitor 1
  参考文献：
  名称：

  Development of Near-Infrared Fluorophore (NIRF)-Labeled Activity-Based Probes for in Vivo Imaging of Legumain

  摘要：

  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.

  DOI：

  10.1021/cb900232a
• 作为产物：
  描述：

  在 四(三苯基膦)钯 、 苯硅烷 作用下， 以 二氯甲烷 为溶剂， 生成 1-Benzyl-3-[3,5-bis(trifluoromethyl)phenyl]-2,5-bis(4-methylphenyl)pyrrole
  参考文献：
  名称：

  Development of Near-Infrared Fluorophore (NIRF)-Labeled Activity-Based Probes for in Vivo Imaging of Legumain

  摘要：

  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.

  DOI：

  10.1021/cb900232a

文献信息

• Synthesis and evaluation of aza-peptidyl inhibitors of the lysosomal asparaginyl endopeptidase, legumain
  作者：Jiyoun Lee、Matthew Bogyo

  DOI：10.1016/j.bmcl.2011.12.079

  日期：2012.2

  Highly potent and selective inhibitors of legumain would not only be valuable for studying the functional roles of legumain in these conditions, but may have therapeutic potential as well. We describe here the design, synthesis and in vitro evaluation of selective legumain inhibitors based on the aza-asparaginyl scaffold. We synthesized a library of aza-peptidyl inhibitors with various non-natural amino

  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
• Horner−Wadsworth−Emmons Reagents as Azomethine Ylide Analogues: Pyrrole Synthesis via (3 + 2) Cycloaddition
  作者：Marie S. T. Morin、Daniel J. St-Cyr、Bruce A. Arndtsen

  DOI：10.1021/ol102075y

  日期：2010.11.5

  Amido-substituted Horner-Wadsworth-Emmons reagents can serve as precursors to 1,3-dipoles for use in cycloaddition. These compounds are assembled in one pot via the TMSOTf-catalyzed Arbuzov reaction of imines, acid chlorides, and phosphites. The coupling of this synthesis with alkyne cycloaddition provides a three-component synthesis of pyrroles. The dipoles can be prepared with a diverse range of imines and acid chlorides, and (3 + 2) cycloaddition with unsymmetrical alkynes is highly regiospecific, providing a modular approach to form substituted pyrroles.
• 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.