(E)-2-methylsulfonyl-3-[1-(2,3,4,5,6-pentafluorophenyl)sulfonylpyrrol-2-yl]prop-2-enenitrile

• 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: (E)-2-methylsulfonyl-3-[1-(2,3,4,5,6-pentafluorophenyl)sulfonylpyrrol-2-yl]prop-2-enenitrile
• 化学式: C₅₇H₆₁N₄O₉Pol
• 分子量: 426.3
• InChiKey: FVYLRPUXYFEPFL-VMPITWQZSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2
• 重原子数：
  27
• 可旋转键数：
  4
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.07
• 拓扑面积：
  114
• 氢给体数：
  0
• 氢受体数：
  10

反应信息

• 作为反应物：
  描述：

  (E)-2-methylsulfonyl-3-[1-(2,3,4,5,6-pentafluorophenyl)sulfonylpyrrol-2-yl]prop-2-enenitrile 在 哌啶 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 生成 (Difluoromethyl-oxo-phenyl-lambda6-sulfanylidene)-dimethylazanium
  参考文献：
  名称：

  Discovery and Optimization of Sulfonyl Acrylonitriles as Selective, Covalent Inhibitors of Protein Phosphatase Methylesterase-1

  摘要：

  The serine hydrolase protein phosphatase methylesterase-1 (PME-1) regulates the methylesterification state of protein phosphatase 2A (PP2A) and has been implicated in cancer and Alzheimer's disease. We recently reported a fluorescence polarization-activity-based protein profiling (fluopol-ABPP) high-throughput screen for PME-1 that uncovered a remarkably potent and selective class of aza-beta-lactam (ABL) PME-1 inhibitors. Here, we describe a distinct set of sulfonyl acrylonitrile inhibitors that also emerged from this screen. The optimized compound, 28 (AMZ30), selectively inactivates PME-1 and reduces the demethylated form of PP2A in living cells. Considering that 28 is structurally unrelated to ABL inhibitors of PME-1, these agents, together, provide a valuable set of pharmacological probes to study the role of methylation in regulating PP2A function. We furthermore observed that several serine hydrolases were sensitive to analogues of 28, suggesting that more extensive structural exploration of the sulfonyl acrylonitrile chemotype may result in useful inhibitors for other members of this large enzyme class.

  DOI：

  10.1021/jm200502u
• 作为产物：
  描述：

  2-吡咯甲醛 在 三乙胺 作用下， 以 乙醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 4.0h， 生成 (E)-2-methylsulfonyl-3-[1-(2,3,4,5,6-pentafluorophenyl)sulfonylpyrrol-2-yl]prop-2-enenitrile
  参考文献：
  名称：

  Discovery and Optimization of Sulfonyl Acrylonitriles as Selective, Covalent Inhibitors of Protein Phosphatase Methylesterase-1

  摘要：

  The serine hydrolase protein phosphatase methylesterase-1 (PME-1) regulates the methylesterification state of protein phosphatase 2A (PP2A) and has been implicated in cancer and Alzheimer's disease. We recently reported a fluorescence polarization-activity-based protein profiling (fluopol-ABPP) high-throughput screen for PME-1 that uncovered a remarkably potent and selective class of aza-beta-lactam (ABL) PME-1 inhibitors. Here, we describe a distinct set of sulfonyl acrylonitrile inhibitors that also emerged from this screen. The optimized compound, 28 (AMZ30), selectively inactivates PME-1 and reduces the demethylated form of PP2A in living cells. Considering that 28 is structurally unrelated to ABL inhibitors of PME-1, these agents, together, provide a valuable set of pharmacological probes to study the role of methylation in regulating PP2A function. We furthermore observed that several serine hydrolases were sensitive to analogues of 28, suggesting that more extensive structural exploration of the sulfonyl acrylonitrile chemotype may result in useful inhibitors for other members of this large enzyme class.

  DOI：

  10.1021/jm200502u

文献信息

• Synthesis and radiobiological evaluation of a new 99mTc-labeled small peptide: 99mTc-YGGSLAK as imaging agent
  作者：Kakali De、Susmita Chandra、Santanu Ganguly、Bhart Sarkar、Mridula Misra

  DOI：10.1002/jlcr.1883

  日期：2011.6.15

  Peptides are known as receptor-specific molecules that play an important role not only in diagnosis and therapy of neoplastic diseases, but also in the pathogenesis of other diseases. In an effort to develop a peptide-based radiopharmaceutical for scintigraphic studies, a small peptide Tyr-Gly-Gly-Ser-Leu-Ala-Lys (YGGSLAK) was synthesized by Fmoc solid-phase peptide synthesis using an automated synthesizer. This peptide was analyzed by TLC, HPLC and mass spectroscopy. Then, we investigated its analytical and pharmacokinetic study after radiolabeling with technetium-99 m (99mTc) using SnCl2. The radiochemical purity of the complex was over 95% and log p value was 1.46. In vivo biodistribution studies in rat showed that most activity of this injected radiolabeled peptide (99mTc-YGGSLAK) was accumulated in the liver and followed by gallbladder, intestines and kidney. Scintigraphy studies on rabbits also showed very high uptake and retention in the liver and gallbladder, and after 1 h slowly excreted through the hepatobiliary system and a little amount was also excreted through the renal system. The radiochemical and in vitro and in vivo characterization indicates that 99mTc-YGGSLAK has certain favorable properties and it might be used as a new radiopharmaceutical for hepatobiliary scintigraphy. Copyright © 2011 John Wiley & Sons, Ltd.

  肽是众所周知的受体特异性分子，不仅在肿瘤疾病的诊断和治疗中发挥着重要作用，而且在其他疾病的发病机制中也发挥着重要作用。为了开发一种基于肽的放射性药物用于闪烁成像研究，我们使用自动合成器通过 Fmoc 固相肽合成法合成了一种小肽 Tyr-Gly-Gly-Ser-Leu-Ala-Lys (YGGSLAK)。对该肽进行了 TLC、HPLC 和质谱分析。然后，我们用 SnCl2 对其进行了锝-99 m (99mTc) 放射性标记后的分析和药代动力学研究。该复合物的放射化学纯度超过 95%，对数 p 值为 1.46。大鼠体内生物分布研究表明，注射的放射性标记肽（99mTc-YGGSLAK）大部分在肝脏积累，其次是胆囊、肠道和肾脏。对兔子进行的闪烁照相研究也显示，肝脏和胆囊的摄取和潴留率非常高，1 小时后通过肝胆系统缓慢排出体外，也有少量通过肾脏系统排出体外。放射化学和体内外表征表明，99m锝-YGGSLAK具有一定的良好特性，可作为一种新的放射性药物用于肝胆闪烁成像。Copyright © 2011 John Wiley & Sons, Ltd. All Rights Reserved.
• Discovery and Optimization of Sulfonyl Acrylonitriles as Selective, Covalent Inhibitors of Protein Phosphatase Methylesterase-1
  作者：Daniel A. Bachovchin、Andrea M. Zuhl、Anna E. Speers、Monique R. Wolfe、Eranthie Weerapana、Steven J. Brown、Hugh Rosen、Benjamin F. Cravatt

  DOI：10.1021/jm200502u

  日期：2011.7.28

  The serine hydrolase protein phosphatase methylesterase-1 (PME-1) regulates the methylesterification state of protein phosphatase 2A (PP2A) and has been implicated in cancer and Alzheimer's disease. We recently reported a fluorescence polarization-activity-based protein profiling (fluopol-ABPP) high-throughput screen for PME-1 that uncovered a remarkably potent and selective class of aza-beta-lactam (ABL) PME-1 inhibitors. Here, we describe a distinct set of sulfonyl acrylonitrile inhibitors that also emerged from this screen. The optimized compound, 28 (AMZ30), selectively inactivates PME-1 and reduces the demethylated form of PP2A in living cells. Considering that 28 is structurally unrelated to ABL inhibitors of PME-1, these agents, together, provide a valuable set of pharmacological probes to study the role of methylation in regulating PP2A function. We furthermore observed that several serine hydrolases were sensitive to analogues of 28, suggesting that more extensive structural exploration of the sulfonyl acrylonitrile chemotype may result in useful inhibitors for other members of this large enzyme class.