(S,E)-tert-butyl (4-(methylsulfonyl)-1-(pyridin-4-yl)but-3-en-2-yl)carbamate | 1421639-92-0

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡啶及其衍生物
• 英文名称: (S,E)-tert-butyl (4-(methylsulfonyl)-1-(pyridin-4-yl)but-3-en-2-yl)carbamate
• 英文别名: tert-butyl N-[(E,2S)-4-methylsulfonyl-1-pyridin-4-ylbut-3-en-2-yl]carbamate
• CAS: 1421639-92-0
• 化学式: C₁₅H₂₂N₂O₄S
• 分子量: 326.417
• InChiKey: QHTQMBWLGGJUDY-UTSBKAFOSA-N

物化性质

• 沸点：
  549.0±50.0 °C(predicted)
• 密度：
  1.187±0.06 g/cm3(Temp: 20 °C; Press: 760 Torr)(predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.4
• 重原子数：
  22
• 可旋转键数：
  7
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.47
• 拓扑面积：
  93.7
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  、 (S,E)-tert-butyl (4-(methylsulfonyl)-1-(pyridin-4-yl)but-3-en-2-yl)carbamate 在 N,N-二异丙基乙胺 、 三氟乙酸 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 0.5h， 生成 (2S)-2-[[(2S)-3-[4-(aminomethyl)phenyl]-2-[[(2S)-2-azido-3-phenylpropanoyl]amino]propanoyl]amino]-4-methyl-N-[(E,2S)-4-methylsulfonyl-1-pyridin-4-ylbut-3-en-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：

  Boc-3-(4-吡啶基)-L-丙氨酸 在 lithium aluminium tetrahydride 、 6-chloro-3-((dimethylamino)(dimethyliminio)methyl)-1H-benzo[d][1,2,3]triazol-3-ium-1-olatehexafluorophosphate(V) 、 sodium hydride 、 N,N-二异丙基乙胺 作用下， 以 四氢呋喃 、 二氯甲烷 、 mineral oil 为溶剂， 反应 4.5h， 生成 (S,E)-tert-butyl (4-(methylsulfonyl)-1-(pyridin-4-yl)but-3-en-2-yl)carbamate
  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：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。
• Inhibitors of the trypsin-like site of the proteasome and methods of use thereof
  申请人：Trustees of Dartmouth College

  公开号：US08609610B2

  公开（公告）日：2013-12-17

  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.

  本发明是蛋白酶体类似胰蛋白酶的β2/β2i位点的抑制剂。该抑制剂特点是以肽基为基础的环氧酮或乙烯基磺酰基，其在C-末端（即在P1位置）包含精氨酸或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的β2/β2i位点的活性，并治疗蛋白酶体介导的疾病或情况的方法。
• Incorporation of Non-natural Amino Acids Improves Cell Permeability and Potency of Specific Inhibitors of Proteasome Trypsin-like Sites
  作者：Paul P. Geurink、Wouter A. van der Linden、Anne C. Mirabella、Nerea Gallastegui、Gerjan de Bruin、Annet E. M. Blom、Mathias J. Voges、Elliot D. Mock、Bogdan I. Florea、Gijs A. van der Marel、Christoph Driessen、Mario van der Stelt、Michael Groll、Herman S. Overkleeft、Alexei F. Kisselev

  DOI：10.1021/jm3016987

  日期：2013.2.14

  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.