(3S,E)-3-(tert-butoxycarbonylamino)-5-phenyl-1-methylsulfonyl-1-pentene | 170111-71-4

• 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: (3S,E)-3-(tert-butoxycarbonylamino)-5-phenyl-1-methylsulfonyl-1-pentene
• 英文别名: tert-butyl N-[(E,3S)-1-methylsulfonyl-5-phenylpent-1-en-3-yl]carbamate
• CAS: 170111-71-4
• 化学式: C₁₇H₂₅NO₄S
• 分子量: 339.456
• InChiKey: SRRUTWKPPZGPEW-LHNRBYRGSA-N

物化性质

• 熔点：
  118-120 °C
• 沸点：
  536.8±50.0 °C(Predicted)
• 密度：
  1.138±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.8
• 重原子数：
  23
• 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：
  80.8
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  (3S,E)-3-(tert-butoxycarbonylamino)-5-phenyl-1-methylsulfonyl-1-pentene 在 1-羟基苯并三唑 、 O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate 作用下， 以 二氯甲烷 为溶剂， 反应 0.5h， 生成 (S)-N-((S)-3-methoxy-1-(((S,E)-1-(methylsulfonyl)-5-phenylpent-1-en-3-yl)amino)-1-oxopropan-2-yl)-2-(2-morpholinoacetamido)-4-phenylbutanamide
  参考文献：
  名称：

  Defining the Determinants of Specificity of Plasmodium Proteasome Inhibitors

  摘要：

  The Plasmodium proteasome is an emerging antimalarial target due to its essential role in all the major life cycle stages of the parasite and its contribution to the establishment of resistance to artemisinin (ART)-based therapies. However, because of a similarly essential role for the host proteasome, the key property of any antiproteasome therapeutic is selectivity. Several parasite-specific proteasome inhibitors have recently been reported, however, their selectivity must be improved to enable clinical development. Here we describe screening of diverse libraries of non-natural synthetic fluorogenic substrates to identify determinants at multiple positions on the substrate that produce enhanced selectivity. We find that selection of an optimal electrophilic "warhead" is essential to enable high selectivity that is driven by the peptide binding elements on the inhibitor. We also find that host cell toxicity is dictated by the extent of coinhibition of the human beta\2 and beta 5 subunits. Using this information, we identify compounds with over 3 orders of magnitude selectivity for the parasite enzyme. Optimization of the pharmacological properties resulted in molecules that retained high potency and selectivity, were soluble, sufficiently metabolically stable and orally bioavailable. These molecules are highly synergistic with ART and can clear parasites in a mouse model of infection, making them promising leads as antimalarial drugs.

  DOI：

  10.1021/jacs.8b06656
• 作为产物：
  描述：

  氨甲酸,[(1S)-1-[(甲氧基甲基氨基)羰基]-3-苯基丙基]-,1,1-二甲基乙基酯 在 lithium aluminium tetrahydride 、 sodium hydride 作用下， 以 四氢呋喃 为溶剂， 生成 (3S,E)-3-(tert-butoxycarbonylamino)-5-phenyl-1-methylsulfonyl-1-pentene
  参考文献：
  名称：

  乙烯基砜是基于机理的半胱氨酸蛋白酶抑制剂。

  摘要：

  DOI：

  10.1021/jm00017a002

文献信息

• Enantiodivergent, Catalytic Asymmetric Synthesis of γ-Amino Vinyl Sulfones
  作者：Anna Picó、Albert Moyano、Miquel A. Pericàs

  DOI：10.1021/jo0268456

  日期：2003.6.1

  A set of diversely substituted N-Boc-gamma-amino vinyl sulfones has been prepared by a four-step procedure from readily available, highly enantiopure anti-N-Boc-3-amino-1,2-alkanediols. This new route, which does not depend on the accessibility of alpha-amino acids as starting materials, is noteworthy for its efficiency, for its generality, and for the fact that both enantiomers of a given gamma-amino vinyl sulfone can be obtained with equal ease.
• Vinyl Sulfones as Mechanism-Based Cysteine Protease Inhibitors
  作者：James T. Palmer、David Rasnick、Jeffrey L. Klaus、Dieter Bromme

  DOI：10.1021/jm00017a002

  日期：1995.8
• Defining the Determinants of Specificity of <i>Plasmodium</i> Proteasome Inhibitors
  作者：Euna Yoo、Barbara H. Stokes、Hanna de Jong、Manu Vanaerschot、TRS Kumar、Nina Lawrence、Mathew Njoroge、Arnold Garcia、Renier Van der Westhuyzen、Jeremiah D. Momper、Caroline L. Ng、David A. Fidock、Matthew Bogyo

  DOI：10.1021/jacs.8b06656

  日期：2018.9.12

  The Plasmodium proteasome is an emerging antimalarial target due to its essential role in all the major life cycle stages of the parasite and its contribution to the establishment of resistance to artemisinin (ART)-based therapies. However, because of a similarly essential role for the host proteasome, the key property of any antiproteasome therapeutic is selectivity. Several parasite-specific proteasome inhibitors have recently been reported, however, their selectivity must be improved to enable clinical development. Here we describe screening of diverse libraries of non-natural synthetic fluorogenic substrates to identify determinants at multiple positions on the substrate that produce enhanced selectivity. We find that selection of an optimal electrophilic "warhead" is essential to enable high selectivity that is driven by the peptide binding elements on the inhibitor. We also find that host cell toxicity is dictated by the extent of coinhibition of the human beta\2 and beta 5 subunits. Using this information, we identify compounds with over 3 orders of magnitude selectivity for the parasite enzyme. Optimization of the pharmacological properties resulted in molecules that retained high potency and selectivity, were soluble, sufficiently metabolically stable and orally bioavailable. These molecules are highly synergistic with ART and can clear parasites in a mouse model of infection, making them promising leads as antimalarial drugs.