N²-((benzyloxy)carbonyl)-N⁶-ethanethioyl-L-lysine | 1125879-55-1

• 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: N²-((benzyloxy)carbonyl)-N⁶-ethanethioyl-L-lysine
• 英文别名: (S)-2-(benzyloxycarbonylamino)-6-(ethanethioamido)hexanoic acid；(2S)-6-(ethanethioylamino)-2-(phenylmethoxycarbonylamino)hexanoic acid
• CAS: 1125879-55-1
• 化学式: C₁₆H₂₂N₂O₄S
• 分子量: 338.428
• InChiKey: PEUPSLVATBCTJZ-AWEZNQCLSA-N

物化性质

• 密度：
  1.228±0.06 g/cm3(Temp: 20 °C; Press: 760 Torr)(predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.1
• 重原子数：
  23
• 可旋转键数：
  10
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.44
• 拓扑面积：
  120
• 氢给体数：
  3
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  N²-((benzyloxy)carbonyl)-N⁶-ethanethioyl-L-lysine 、 环己胺 在 O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate 作用下， 以 吡啶 、 N,N-二甲基甲酰胺 为溶剂， 以89%的产率得到benzyl (S)-1-(cyclohexylamino)-6-(ethanethioamido)-1-oxohexan-2-ylcarbamate
  参考文献：
  名称：

  Structure-Based Design of Pseudopeptidic Inhibitors for SIRT1 and SIRT2

  摘要：

  The lack of substrate-bound crystal structures of SIRT1 and SIRT2 complicates the drug design for these targets. In this work, we aim to study whether SIRT3 could serve as a target structure in the design of substrate based pseudopeptidic inhibitors of SIRT1 and SIRT2. We created a binding hypothesis for pseudopeptidic inhibitors, synthesized a series of inhibitors, and studied how well the fulfillment of the binding criteria proposed by the hypothesis correlated with the in vitro inhibitory activities. The chosen approach was further validated by studying docking results between 12 different SIRT3, Sir2Tm, SIRT1 and SIRT2 X-ray structures and homology models in different conformational forms. It was concluded that the created binding hypothesis can be used in the design of the substrate based inhibitors of SIRT1 and SIRT2 although there are some reservations, and it is better to use the substrate-bound structure of SIRT3 instead of the available apo-SIRT2 as the target structure.

  DOI：

  10.1021/jm200590k
• 作为产物：
  描述：

  (S)-methyl 2-(benzyloxycarbonylamino)-6-(ethanethioamido)hexanoate 在 lithium hydroxide 、 水 、 盐酸 作用下， 以 四氢呋喃 、 甲醇 、 水 为溶剂， 反应 1.0h， 生成 N²-((benzyloxy)carbonyl)-N⁶-ethanethioyl-L-lysine
  参考文献：
  名称：

  [EN] SIRTUIN INHIBITORS
  [FR] INHIBITEURS DE SIRTUINE

  摘要：

  这项发明涉及化合物和用于抑制sirtuin酶活性的方法。更具体地，该发明提供了式(I)的化合物，Y__L__Z__D，以及其N-氧化物、水合物、溶剂合物、药用可接受盐、前药和复合物，以及它们的外消旋和内消旋混合物、非对映体和对映体，其中Y、L、Z和D如规范中所定义。

  公开号：

  WO2009026701A1

文献信息

• Dethioacylation by Sirtuins 1–3: Considerations for Drug Design Using Mechanism-Based Sirtuin Inhibition
  作者：Nima Rajabi、Alexander L. Nielsen、Christian A. Olsen

  DOI：10.1021/acsmedchemlett.9b00580

  日期：2020.10.8

  The sirtuin enzymes are potential drug targets for intervention in a series of diseases. Efforts to inhibit enzymes of this class with thioamide- and thiourea-containing, substrate-mimicking entities have produced a number of high-affinity binders. However, less attention has been dedicated to the investigation of the stability of these inhibitors under various conditions. Here, we provide evidence

  Sirtuin 酶是干预一系列疾病的潜在药物靶点。用含硫代酰胺和硫脲的底物模拟实体抑制此类酶的努力已经产生了许多高亲和力结合剂。然而，对这些抑制剂在各种条件下的稳定性研究的关注较少。在这里，我们提供了短链 ε- N前所未有的裂解程度的证据-硫代酰基赖氨酸修饰旨在靶向这些沉默调节蛋白，并进一步深入了解含有硫代酰胺和硫脲的化合物的血清稳定性。我们的研究对用于药物开发的基于短链硫代酰胺的 Sirtuins 抑制剂提出质疑，并指出基于单烷基化硫脲的化学型在人血清中更稳定。
• Screen of Pseudopeptidic Inhibitors of Human Sirtuins 1–3: Two Lead Compounds with Antiproliferative Effects in Cancer Cells
  作者：Paolo Mellini、Tarja Kokkola、Tiina Suuronen、Heikki S. Salo、Laura Tolvanen、Antonello Mai、Maija Lahtela-Kakkonen、Elina M. Jarho

  DOI：10.1021/jm400438k

  日期：2013.9.12

  In the past few years sirtuins have gained growing attention for their involvement in many biological processes such as cellular metabolism, apoptosis; aging and inflammation. In this contribution, we report the synthesis of a library of thioacetylated pseudopeptides that were screened against human sirtuins 1-3 to reveal their in vitro inhibition activities. Molecular modeling studies were performed to acquire data about the binding modes of the inhibitors. Three sirtuin inhibitors were subjected to cellular studies, and all of them showed an increase in acetylation of Lys382 of p53 after DNA damage. Furthermore, two of the compounds were able to inhibit both A549 lung carcinoma and MCF-7 breast carcinoma cell growth in micromolar concentration with the ability to arrest cancer cell cycle in the GI phase.