(3S,E)-3-(tert-butoxycarbonylamino)-5-methyl-1-methylsulfonyl-1-hexene | 193482-43-8

• 分子结构分类: 有机化合物 - 有机硫化合物 - 磺酰类
• 英文名称: (3S,E)-3-(tert-butoxycarbonylamino)-5-methyl-1-methylsulfonyl-1-hexene
• 英文别名: Boc-Leu-vs；tert-butyl N-[(E,3S)-5-methyl-1-methylsulfonylhex-1-en-3-yl]carbamate
• CAS: 193482-43-8
• 化学式: C₁₃H₂₅NO₄S
• 分子量: 291.412
• InChiKey: OQHQFRGRIOZFPG-WSKFYRRCSA-N

物化性质

• 熔点：
  69-70 °C
• 沸点：
  448.9±38.0 °C(Predicted)
• 密度：
  1.075±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.2
• 重原子数：
  19
• 可旋转键数：
  7
• 环数：
  0.0
• sp3杂化的碳原子比例：
  0.77
• 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-methyl-1-methylsulfonyl-1-hexene 在 盐酸 作用下， 以 1,4-二氧六环 为溶剂， 反应 1.0h， 以4.33 g的产率得到(S)-1-((E)-2-Methanesulfonyl-vinyl)-3-methyl-butylamine; hydrochloride
  参考文献：
  名称：

  Optimization of Subsite Binding to the β5 Subunit of the Human 20S Proteasome Using Vinyl Sulfones and 2-Keto-1,3,4-oxadiazoles:  Syntheses and Cellular Properties of Potent, Selective Proteasome Inhibitors

  摘要：

  Beginning with the peptide sequence Cbz-Ile-Glu(OtBu)-Ala-Leu found in PSI (3), a series of vinyl sulfones (VS) were synthesized for evaluation as inhibitors of the chymotrypsin-like activity of the 20S proteasome. Variations at the key P3 position confirmed the importance of a long side chain capped with a hydrophobic group for optimal potency, consistent with a model of binding to the S3 subsite. The tert-butyl glutamic ester initially used at P3 gave plasma unstable, insoluble compounds and was replaced with the better isostere, N-beta-neopentyl asparagine. The inhibitors were shortened by replacing the N-terminal Cbz-isoleucine with a p-tosyl group without loss of potency. Small L-amino acids were used at P2, where D-substitution was not tolerated. The resulting optimized P4-P3-P2 sequence was grafted onto a novel proteasome inhibitor warhead, 2-keto-1,3,4-oxadiazoles (KOD), to produce reversible, subnanomolar proteasome inhibitors that were 1000-fold selective versus cathepsin B (CatB), cathepsin S (CatS), and trypsin-like as well as PGPH-like proteasome activity. A number of compounds in both the VS and the KOD series exhibited growth inhibitory effects against the human prostate cancer cell line PC3 at submicromolar concentrations.

  DOI：

  10.1021/jm058289o
• 作为产物：
  描述：

  (2R,3R)-2,3-epoxy-5-methyl-1-hexanol 在 palladium on activated charcoal 4-二甲氨基吡啶 、 Ti(N3)2(OiPr)2 、 偶氮二甲酸二异丙酯 、 氢气 、 甲基磺酰氯 、 间氯过氧苯甲酸 、 三苯基膦 作用下， 以 甲醇 、 二氯甲烷 、 氯仿 、 乙酸乙酯 、 苯 为溶剂， 反应 1.0h， 生成 (3S,E)-3-(tert-butoxycarbonylamino)-5-methyl-1-methylsulfonyl-1-hexene
  参考文献：
  名称：

  Enantiodivergent, Catalytic Asymmetric Synthesis of γ-Amino Vinyl Sulfones

  摘要：

  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.

  DOI：

  10.1021/jo0268456

文献信息

• Vinylboronic Acids as Efficient Bioorthogonal Reactants for Tetrazine Labeling in Living Cells
  作者：Selma Eising、Nicole G. A. van der Linden、Fleur Kleinpenning、Kimberly M. Bonger

  DOI：10.1021/acs.bioconjchem.7b00796

  日期：2018.4.18

  Bioorthogonal chemistry can be used for the selective modification of biomolecules without interfering with any other functionality present in the cell. The tetrazine ligation is very suitable as a bioorthogonal reaction because of its selectivity and high reaction rates with several alkenes and alkynes. Recently, we described vinylboronic acids (VBAs) as novel hydrophilic bioorthogonal moieties that

  生物正交化学可用于生物分子的选择性修饰，而不会干扰细胞中存在的任何其他功能。四嗪连接非常适合作为生物正交反应，因为它的选择性和与几种烯烃和炔的高反应速率。最近，我们将乙烯基硼酸（VBA）描述为新型的亲水生物正交基部分，可与二吡啶基s-四嗪有效反应并将其用于细胞裂解物中的蛋白质修饰。但是，尚不清楚VBA是否适合在活细胞中进行标记实验，因为它可能与例如邻位碳水化合物二醇配合使用。这里，我们使用不可逆的蛋白酶体抑制剂评估了VBAs作为生物正交反应物，用于标记活细胞中的蛋白质，并将其反应性与含有降冰片烯的抑制剂的反应性进行了比较，降冰片烯是广泛用于四嗪连接的反应物。在两步标记方法中，可穿透细胞的荧光四嗪标记在VBA和降冰片烯探针之间未观察到较大的差异，这表明VBA与二醇的副反应很少或没有副反应，可有效用于活细胞中的蛋白质标记。
• Mixing of peptides and electrophilic traps gives rise to potent, broad-spectrum proteasome inhibitors
  作者：Martijn Verdoes、Bogdan I. Florea、Wouter A. van der Linden、Didier Renou、Adrianus M. C. H. van den Nieuwendijk、Gijs A. van der Marel、Herman S. Overkleeft

  DOI：10.1039/b702268a

  日期：——

  The synthesis and evaluation of hybrid proteasome inhibitors that contain structural elements of the known inhibitors bortezomib, epoxomicin and peptide vinyl sulfones is described. From the panel of 15 inhibitors some structure activity relationships can be deduced with regard to inhibitory activity in relation to peptide recognition element, inhibitor size and nature of the electrophilic trap. Further

  描述了杂合蛋白酶体抑制剂的合成和评估，这些蛋白酶体抑制剂包含已知的硼替佐米，环己霉素和肽乙烯基砜抑制剂的结构元素。从15种抑制剂的组中，可以推断出与肽识别元件，抑制剂大小和亲电子阱性质有关的抑制活性方面的一些结构活性关系。此外，该组包含迄今为止报道的最有效的基于肽的泛蛋白酶体抑制剂之一。
• NOVEL OPTICAL LABELING MOLECULES FOR PROTEOMICS AND OTHER BIOLOGICAL ANALYSES
  申请人：DRATZ Edward

  公开号：US20100252433A1

  公开（公告）日：2010-10-07

  The invention relates to compositions and methods useful in the labeling and identification of changes in protein levels, changes in enzyme activity, and changes in protein modification. The invention provides for highly soluble optical labeling molecules which are optionally cleavable after separation of mixtures of labeled proteins into components. These optical labeling molecules find utility in a variety of applications, including use in the field of proteomics.

  本发明涉及用于标记和识别蛋白质水平变化、酶活性变化和蛋白质修饰变化的组合物和方法。本发明提供了高度溶解的光学标记分子，这些分子在将标记蛋白质的混合物分离成组分后可选择性地被裂解。这些光学标记分子在各种应用中具有实用性，包括在蛋白质组学领域的应用。
• 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.
• Optimization of Subsite Binding to the β5 Subunit of the Human 20S Proteasome Using Vinyl Sulfones and 2-Keto-1,3,4-oxadiazoles:  Syntheses and Cellular Properties of Potent, Selective Proteasome Inhibitors
  作者：Robert M. Rydzewski、Leland Burrill、Rohan Mendonca、James T. Palmer、Mark Rice、Ram Tahilramani、Kathryn E. Bass、Ling Leung、Erik Gjerstad、James W. Janc、Lin Pan

  DOI：10.1021/jm058289o

  日期：2006.5.1

  Beginning with the peptide sequence Cbz-Ile-Glu(OtBu)-Ala-Leu found in PSI (3), a series of vinyl sulfones (VS) were synthesized for evaluation as inhibitors of the chymotrypsin-like activity of the 20S proteasome. Variations at the key P3 position confirmed the importance of a long side chain capped with a hydrophobic group for optimal potency, consistent with a model of binding to the S3 subsite. The tert-butyl glutamic ester initially used at P3 gave plasma unstable, insoluble compounds and was replaced with the better isostere, N-beta-neopentyl asparagine. The inhibitors were shortened by replacing the N-terminal Cbz-isoleucine with a p-tosyl group without loss of potency. Small L-amino acids were used at P2, where D-substitution was not tolerated. The resulting optimized P4-P3-P2 sequence was grafted onto a novel proteasome inhibitor warhead, 2-keto-1,3,4-oxadiazoles (KOD), to produce reversible, subnanomolar proteasome inhibitors that were 1000-fold selective versus cathepsin B (CatB), cathepsin S (CatS), and trypsin-like as well as PGPH-like proteasome activity. A number of compounds in both the VS and the KOD series exhibited growth inhibitory effects against the human prostate cancer cell line PC3 at submicromolar concentrations.