N₃-Phe-Leu-Leu-NHNH2 | 1394024-91-9

• 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: N₃-Phe-Leu-Leu-NHNH2
• 英文别名: (2S)-2-[[(2S)-2-azido-3-phenylpropanoyl]amino]-N-[(2S)-1-hydrazinyl-4-methyl-1-oxopentan-2-yl]-4-methylpentanamide
• CAS: 1394024-91-9
• 化学式: C₂₁H₃₃N₇O₃
• 分子量: 431.538
• InChiKey: YCBVFYFMCHQSNC-BZSNNMDCSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4
• 重原子数：
  31
• 可旋转键数：
  12
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.57
• 拓扑面积：
  128
• 氢给体数：
  4
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  N₃-Phe-Leu-Leu-NHNH2 在 盐酸 、 亚硝酸特丁酯 、 N,N-二异丙基乙胺 作用下， 以 1,4-二氧六环 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 3.0h， 生成 (2S)-2-[[(2S)-2-azido-3-phenylpropanoyl]amino]-4-methyl-N-[(2S)-4-methyl-1-[[(E,2S)-4-methylsulfonyl-1-pyridin-4-ylbut-3-en-2-yl]amino]-1-oxopentan-2-yl]pentanamide
  参考文献：
  名称：

  Incorporation of Non-natural Amino Acids Improves Cell Permeability and Potency of Specific Inhibitors of Proteasome Trypsin-like Sites

  摘要：

  Proteasomes degrade the majority of proteins in mammalian cells by a concerted action of three distinct pairs of active sites. The chymotrypsin-like sites are targets of antimyeloma agents bortezomib and carfilzomib. Inhibitors of the trypsin-like site sensitize multiple myeloma cells to these agents. Here we describe systematic effort to develop inhibitors with improved potency and cell permeability, yielding azido-Phe-Leu-Leu-4-aminomethyl-Phe-methyl vinyl sulfone (4a, LU-102), and a fluorescent activity-based probe for this site. X-ray structures of 4a and related inhibitors complexed with yeast proteasomes revealed the structural basis for specificity. Nontoxic to myeloma cells when used as a single agent, 4a sensitized them to bortezomib and carfilzomib. This sensitizing effect was much stronger than the synergistic effects of histone acetylase inhibitors or additive effects of doxorubicin and dexamethasone, raising the possibility that cornbinations of inhibitors of the trypsin-like site with bortezomib or carfilzomib would have stronger antincoplastic activity than combinations currently used clinically.

  DOI：

  10.1021/jm3016987
• 作为产物：
  描述：

  N3-Phe-Leu-Leu-OMe 在 一水合肼 作用下， 以 甲醇 为溶剂， 反应 15.0h， 以1.51 g的产率得到N₃-Phe-Leu-Leu-NHNH2
  参考文献：
  名称：

  Incorporation of Non-natural Amino Acids Improves Cell Permeability and Potency of Specific Inhibitors of Proteasome Trypsin-like Sites

  摘要：

  Proteasomes degrade the majority of proteins in mammalian cells by a concerted action of three distinct pairs of active sites. The chymotrypsin-like sites are targets of antimyeloma agents bortezomib and carfilzomib. Inhibitors of the trypsin-like site sensitize multiple myeloma cells to these agents. Here we describe systematic effort to develop inhibitors with improved potency and cell permeability, yielding azido-Phe-Leu-Leu-4-aminomethyl-Phe-methyl vinyl sulfone (4a, LU-102), and a fluorescent activity-based probe for this site. X-ray structures of 4a and related inhibitors complexed with yeast proteasomes revealed the structural basis for specificity. Nontoxic to myeloma cells when used as a single agent, 4a sensitized them to bortezomib and carfilzomib. This sensitizing effect was much stronger than the synergistic effects of histone acetylase inhibitors or additive effects of doxorubicin and dexamethasone, raising the possibility that cornbinations of inhibitors of the trypsin-like site with bortezomib or carfilzomib would have stronger antincoplastic activity than combinations currently used clinically.

  DOI：

  10.1021/jm3016987

文献信息

• Inhibitors of the Trypsin-Like Site of the Proteasome and Methods of Use Thereof
  申请人：Kisselev Alexei

  公开号：US20120214732A1

  公开（公告）日：2012-08-23

  The present invention is an inhibitor of the trypsin-like β2/β2i sites of the proteasome. The inhibitor is characterized as being a peptide-based epoxyketone or vinyl sulfone that contains an arginine or 4-aminomethylene-L-phenylalanine at the C-terminus (i.e., at the P1 position). Methods for using the inhibitor to inhibit the activity of the β2/β2i site of a proteasome and treat a proteasome-mediated disease or condition are also described.

  本发明是一种蛋白酶体胰蛋白酶样β2/β2i位点的抑制剂。该抑制剂的特点是基于肽的环氧酮或乙烯砜，其C端（即P1位置）含有精氨酸或4-氨基亚甲基-L-苯丙氨酸。还描述了使用该抑制剂抑制蛋白酶体β2/β2i位点活性和治疗蛋白酶体介导的疾病或状况的方法。
• Asymmetric Synthesis of Lysine Analogues with Reduced Basicity, and their Incorporation into Proteasome Inhibitors
  作者：Gerjan de Bruin、Eva J. van Rooden、David Ward、Charlotte Wesseling、Adrianus M. C. H. van den Nieuwendijk、Constant A. A. van Boeckel、Christoph Driessen、Alexei F. Kisselev、Bogdan I. Florea、Mario van der Stelt、Herman S. Overkleeft

  DOI：10.1002/ejoc.201701174

  日期：2017.10.25

  described. These amino acids, as well as histidine and diaminopropionic-acid-glycine, were incorporated at the P1 and/or P3 positions of oligopeptide vinyl sulfones. All inhibitors were found to inhibit proteasome subunit β2, but with a loss of potency compared to our most potent and selective β2 inhibitor, LU-102.

  描述了赖氨酸（4-ene）和赖氨酸（4-yne）的第一次对映选择性合成。这些氨基酸以及组氨酸和二氨基丙酸-甘氨酸被掺入到寡肽乙烯基砜的P1和/或P3位置。发现所有抑制剂均能抑制蛋白酶体亚基β2，但与我们最有效和选择性最强的β2抑制剂LU-102相比，其功效却有所降低。
• INHIBITORS OF THE TRYPSIN-LIKE SITE OF THE PROTEASOME AND METHODS OF USE THEREOF
  申请人：Trustees Of Dartmouth College

  公开号：US20130102527A1

  公开（公告）日：2013-04-25

  The present invention is an inhibitor of the trypsin-like β2/β2i sites of the proteasome. The inhibitor is characterized as being a peptide-based epoxyketone or vinyl sulfone that contains an arginine or 4-aminomethylene-L-phenylalanine at the C-terminus (i.e., at the P1 position). Methods for using the inhibitor to inhibit the activity of the β2/β2i site of a proteasome and treat a proteasome-mediated disease or condition are also described.

  本发明是一种蛋白酶体中类似胰蛋白酶的β2 / β2i位点的抑制剂。该抑制剂的特点是含有C-末端（即P1位置）的精氨酸或4-氨基甲基-L-苯丙氨酸的基于肽的环氧酮或乙烯基磺酰。还描述了使用该抑制剂来抑制蛋白酶体的β2 / β2i位点的活性和治疗蛋白酶体介导的疾病或病症的方法。
• US8455431B2
  申请人：——

  公开号：US8455431B2

  公开（公告）日：2013-06-04