(S,E)-tert-butyl 4-(4-(methylsulfonyl)-2-aminobut-3-en-1-yl)benzylcarbamate | 1394025-05-8

• 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: (S,E)-tert-butyl 4-(4-(methylsulfonyl)-2-aminobut-3-en-1-yl)benzylcarbamate
• 英文别名: (S,E)-tert-butyl 4-[2-amino-4-(methylsulfonyl)but-3-enyl]benzylcarbamate；tert-butyl N-[[4-[(E,2S)-2-amino-4-methylsulfonylbut-3-enyl]phenyl]methyl]carbamate
• CAS: 1394025-05-8
• 化学式: C₁₇H₂₆N₂O₄S
• 分子量: 354.47
• InChiKey: VTBYQMZHXWDLLW-BOLDSZDNSA-N

物化性质

• 沸点：
  576.9±50.0 °C(Predicted)
• 密度：
  1.175±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.3
• 重原子数：
  24
• 可旋转键数：
  8
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.47
• 拓扑面积：
  107
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  (S,E)-tert-butyl 4-(4-(methylsulfonyl)-2-aminobut-3-en-1-yl)benzylcarbamate 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]-N-[(E,2S)-1-[4-(aminomethyl)phenyl]-4-methylsulfonylbut-3-en-2-yl]-4-methylpentanamide
  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：

  (S,E)-tert-butyl 4-(4-(methylsulfonyl)-2-(tritylamino)but-3-en-1-yl)benzylcarbamate 在 水 、 三氟乙酸 作用下， 以 二氯甲烷 为溶剂， 反应 0.5h， 生成 (S,E)-tert-butyl 4-(4-(methylsulfonyl)-2-aminobut-3-en-1-yl)benzylcarbamate
  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

• Incorporation of the Constrained Peptidomimetic, 5-Methylpyridin-2-one into Peptide Vinyl Sulfones and Peptide Epoxy Ketones is Detrimental for Proteasome Inhibition
  作者：Bo-Tao Xin、Gerjan de Bruin、Jan-Willem Plomp、Bogdan I. Florea、Gijsbert A. van der Marel、Herman S. Overkleeft

  DOI：10.1002/ejoc.201501401

  日期：2016.2

  in peptide vinyl sulfone and peptide epoxy ketone-based proteasome inhibitors. Pyridin-2-ones have previously been used as constrained peptide isosteres capable to act as a hydrogen-bond acceptor. Our results demonstrate that 5-methylpyridin-2-one can be introduced into proteasome inhibitors, but that the activity of the resulting compounds is compromised compared to their parent peptide vinyl sulfones

  人类蛋白酶体是肿瘤学中经过验证的靶标，并且是免疫相关疾病的有希望的靶标。许多基于肽的蛋白酶体抑制剂已进入临床，其他几种目前正在临床试验中进行研究。尽管取得了这些成就，但基于肽的抑制剂可能容易受到蛋白酶介导的降解。在本文中，我们报告了在肽乙烯基砜和基于肽环氧酮的蛋白酶体抑制剂中引入 5-methylpyridin-2-one 部分的结果。Pyridin-2-ones 以前曾被用作能够作为氢键受体的受限肽等排体。我们的结果表明 5-methylpyridin-2-one 可以被引入蛋白酶体抑制剂中，
• 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。
• Inhibitors of the trypsin-like site of the proteasome and methods of use thereof
  申请人：Kisselev Alexei

  公开号：US08455431B2

  公开（公告）日：2013-06-04

  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.

  本发明是一种抑制蛋白酶体中类胰蛋白酶β2/β2i位点的抑制剂。该抑制剂的特点是一种基于肽的环氧酮或乙烯基磺酰，其在C末端（即P1位置）含有精氨酸或4-氨基甲基-L-苯丙氨酸。还描述了使用该抑制剂来抑制蛋白酶体中β2/β2i位点的活性并治疗蛋白酶体介导的疾病或病状的方法。
• INHIBITORS OF THE TRYPSIN-LIKE SITE OF THE PROTEASOME AND METHODS OF USE THEREOF
  申请人：Trustees Of Dartmouth College

  公开号：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