(S)-methyl 2-{(R)-4-[(tert-butoxycarbonyl)-amino]-3-oxoisothiazolidin-2-yl}-3-methylbutanoate

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: (S)-methyl 2-{(R)-4-[(tert-butoxycarbonyl)-amino]-3-oxoisothiazolidin-2-yl}-3-methylbutanoate
• 英文别名: methyl (2S)-3-methyl-2-[(4R)-4-[(2-methylpropan-2-yl)oxycarbonylamino]-3-oxo-1,2-thiazolidin-2-yl]butanoate
• 化学式: C₁₄H₂₄N₂O₅S
• 分子量: 332.421
• InChiKey: GRZBHYUICKFZEJ-UWVGGRQHSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2
• 重原子数：
  22
• 可旋转键数：
  7
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.79
• 拓扑面积：
  110
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  (S)-methyl 2-{(R)-4-[(tert-butoxycarbonyl)-amino]-3-oxoisothiazolidin-2-yl}-3-methylbutanoate 、 curcumin 以 甲醇 为溶剂， 以78%的产率得到methyl S-[(1E,6E)-1,7-bis(4-hydroxy-3-methoxyphenyl)-3,5-dioxohepta-1,6-dien-4-yl]-N-(tert-butoxycarbonyl)-L-cysteinyl-L-valinate
  参考文献：
  名称：

  Reactions of 1,3-Diketones with a Dipeptide Isothiazolidin-3-one: Toward Agents That Covalently Capture Oxidized Protein Tyrosine Phosphatase 1B

  摘要：

  Protein tyrosine phosphatase 1B (PTP1B) is a validated therapeutic target for the treatment of type 2 diabetes; however, the enzyme has been classified by some as an "undruggable target". Here we describe studies directed toward the development of agents that covalently capture the sulfenyl amide "oxoform" of PTP1B generated during insulin signaling events. The sulfenyl amide residue found in oxidized PTP1B presents a unique electrophilic sulfur center that may be exploited in drug and probe design. Covalent capture of oxidized PTP1B could permanently disable the intracellular pool of enzyme involved in regulation of insulin signaling. Here, we employed a dipeptide model of oxidized PTP1B to investigate the nucleophilic capture of the sulfenyl amide residue by structurally diverse 1,3-diketones. All of the 1,3-diketones examined here reacted readily with the electrophilic sulfur center in the sulfenyl amide residue to generate stable covalent attachments. Several different types of products were observed, depending upon the substituents present on the 1,3-diketone. The results provide a chemical foundation for the development of agents that covalently capture the oxidized form of PTP1B generated in cells during insulin signaling events.

  DOI：

  10.1021/acs.joc.5b01949
• 作为产物：
  描述：

  (S)-2-{(R)-2-tert-butoxycarbonylamino-3-[(R)-2-tert-butoxycarbonylamino-2-((S)-1-methoxycarbonyl-2-methyl-propionylcarbamoyl)-ethyldisulfanyl]-propionylamino}-3-methyl-butyric acid methyl ester 在 吡啶 、 溴 作用下， 以 二氯甲烷 为溶剂， 反应 2.0h， 以46%的产率得到(S)-methyl 2-{(R)-4-[(tert-butoxycarbonyl)-amino]-3-oxoisothiazolidin-2-yl}-3-methylbutanoate
  参考文献：
  名称：

  Selective Reduction of Peptide Isothiazolidin-3-ones

  摘要：

  Isothiazolidinones are a rare but potentially important chemical moiety in biochemistry. We report the identification of several thiol, phosphinate, and carbon nucleophiles that form covalent adducts by addition to the sulfenamide sulfur. This reduction is selective for isothiazolidinones over similar peptide disulfides. We synthesized a coumarin-based thioacid nucleophile which shows a marked fluorescence increase after addition to an isothiazolidinone sulfenamide bond.

  DOI：

  10.1021/ol062077j

文献信息

• Sulfone-stabilized carbanions for the reversible covalent capture of a posttranslationally-generated cysteine oxoform found in protein tyrosine phosphatase 1B (PTP1B)
  作者：Zachary D. Parsons、Kasi Viswanatharaju Ruddraraju、Nicholas Santo、Kent S. Gates

  DOI：10.1016/j.bmc.2016.03.054

  日期：2016.6

  active site cysteine thiolate into an electrophilic sulfenyl amide residue. Reduction of the sulfenyl amide by biological thiols regenerates the native cysteine residue. Here we explored fundamental chemical reactions that may enable covalent capture of the sulfenyl amide residue in oxidized PTP1B. Various sulfone-containing carbon acids were found to react readily with a model peptide sulfenyl amide via

  蛋白质酪氨酸磷酸酶1B（PTP1B）的氧化还原调节涉及活性位点半胱氨酸硫醇盐的氧化转化为亲电子的亚磺酰胺残基。生物硫醇对亚磺酰胺的还原可再生天然半胱氨酸残基。在这里，我们探索了基本的化学反应，该化学反应可以共价捕获氧化的PTP1B中的亚磺酰胺残基。发现各种含砜的碳酸通过磺酰氨基在磺酰酰胺中的亲电子硫中心上的攻击而容易地与模型肽磺酰酰胺反应。表征产物和这些反应的速率。结果表明，砜稳定的碳负离子捕获肽亚磺酰胺残基可以减慢但不能完全防止，硫醇介导的相应的含半胱氨酸肽的生成。含砜的碳酸可能是构建药物的有用成分，这些药物可通过瞬时共价捕获胰岛素信号传导过程中产生的亚磺酰胺酰胺羰基来降低细胞中的PTP1B活性。
• Selective Reduction of Peptide Isothiazolidin-3-ones
  作者：Timothy P. Shiau、Daniel A. Erlanson、Eric M. Gordon

  DOI：10.1021/ol062077j

  日期：2006.12.1

  Isothiazolidinones are a rare but potentially important chemical moiety in biochemistry. We report the identification of several thiol, phosphinate, and carbon nucleophiles that form covalent adducts by addition to the sulfenamide sulfur. This reduction is selective for isothiazolidinones over similar peptide disulfides. We synthesized a coumarin-based thioacid nucleophile which shows a marked fluorescence increase after addition to an isothiazolidinone sulfenamide bond.
• Reactions of 1,3-Diketones with a Dipeptide Isothiazolidin-3-one: Toward Agents That Covalently Capture Oxidized Protein Tyrosine Phosphatase 1B
  作者：Kasi Viswanatharaju Ruddraraju、Zachary D. Parsons、Elizabeth M. Llufrio、Natasha L. Frost、Kent S. Gates

  DOI：10.1021/acs.joc.5b01949

  日期：2015.12.18

  Protein tyrosine phosphatase 1B (PTP1B) is a validated therapeutic target for the treatment of type 2 diabetes; however, the enzyme has been classified by some as an "undruggable target". Here we describe studies directed toward the development of agents that covalently capture the sulfenyl amide "oxoform" of PTP1B generated during insulin signaling events. The sulfenyl amide residue found in oxidized PTP1B presents a unique electrophilic sulfur center that may be exploited in drug and probe design. Covalent capture of oxidized PTP1B could permanently disable the intracellular pool of enzyme involved in regulation of insulin signaling. Here, we employed a dipeptide model of oxidized PTP1B to investigate the nucleophilic capture of the sulfenyl amide residue by structurally diverse 1,3-diketones. All of the 1,3-diketones examined here reacted readily with the electrophilic sulfur center in the sulfenyl amide residue to generate stable covalent attachments. Several different types of products were observed, depending upon the substituents present on the 1,3-diketone. The results provide a chemical foundation for the development of agents that covalently capture the oxidized form of PTP1B generated in cells during insulin signaling events.