ethyl 3-[((1Z)-5,6-dimethyl-1-{[(4-methylphenyl)sulfonyl]imino}-3-oxo-2,3-dihydro-1H-imidazo[5,1-c][1,4]thiazin-8-yl)thio]propanoate | 607706-81-0

• 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: ethyl 3-[((1Z)-5,6-dimethyl-1-{[(4-methylphenyl)sulfonyl]imino}-3-oxo-2,3-dihydro-1H-imidazo[5,1-c][1,4]thiazin-8-yl)thio]propanoate
• 英文别名: ethyl 3-[[(1Z)-5,6-dimethyl-1-[[(4-methylphenyl)sulfonyl]imino]-3-oxo-2,3-dihydro-1H-imidazo[5,1-c][1,4]thiazin-8-yl]sulfanyl]propanoate；ethyl 3-[5,6-dimethyl-1-[(4-methylphenyl)sulfonylamino]-3-oxoimidazo[5,1-c][1,4]thiazin-8-yl]sulfanylpropanoate
• CAS: 607706-81-0
• 化学式: C₂₀H₂₃N₃O₅S₃
• 分子量: 481.618
• InChiKey: PAQCTNFEAZSCCZ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.9
• 重原子数：
  31
• 可旋转键数：
  9
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.35
• 拓扑面积：
  164
• 氢给体数：
  1
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  ethyl 3-[((1Z)-5,6-dimethyl-1-{[(4-methylphenyl)sulfonyl]imino}-3-oxo-2,3-dihydro-1H-imidazo[5,1-c][1,4]thiazin-8-yl)thio]propanoate 在 甲醇 、 potassium hydroxide 作用下， 以 四氢呋喃 为溶剂， 以88%的产率得到N-[(1Z)-8-mercapto-5,6-dimethyl-3-oxo-2,3-dihydro-1H-imidazo[5,1-c][1,4]thiazin-1-ylidene]-4-methylbenzenesulfonamide
  参考文献：
  名称：

  ITZ-1, a Client-Selective Hsp90 Inhibitor, Efficiently Induces Heat Shock Factor 1 Activation

  摘要：

  ITZ-1 is a chondroprotective agent that inhibits interleukin-1 beta-induced matrix metalloproteinase-13 (MMP-13) production and suppresses nitric oxide-induced chondrocyte death. Here we describe its mechanisms of action. Heat shock protein 90 (Hsp90) was identified as a specific ITZ-1-binding protein. Almost all known Hsp90 inhibitors have been reported to bind to the Hsp90 N-terminal ATP-binding site and to simultaneously induce degradation and activation of its multiple client proteins. However, within the Hsp90 client proteins, ITZ-1 strongly induces heat shock factor-1 (HSF1) activation and causes mild Raf-1 degradation, but scarcely induces degradation of a broad range of Hsp90 client proteins by binding to the Hsp90 C terminus. These results may explain ITZ-1's inhibition of MMP-13 production, its cytoprotective effect, and its lower cytotoxicity. These results suggest that ITZ-1 is a client-selective Hsp90 inhibitor.

  DOI：

  10.1016/j.chembiol.2009.12.012
• 作为产物：
  描述：

  在 乙酸酐 、 对甲苯磺酸 作用下， 以 甲苯 为溶剂， 反应 2.0h， 以9.68 g的产率得到ethyl 3-[((1Z)-5,6-dimethyl-1-{[(4-methylphenyl)sulfonyl]imino}-3-oxo-2,3-dihydro-1H-imidazo[5,1-c][1,4]thiazin-8-yl)thio]propanoate
  参考文献：
  名称：

  ITZ-1, a Client-Selective Hsp90 Inhibitor, Efficiently Induces Heat Shock Factor 1 Activation

  摘要：

  ITZ-1 is a chondroprotective agent that inhibits interleukin-1 beta-induced matrix metalloproteinase-13 (MMP-13) production and suppresses nitric oxide-induced chondrocyte death. Here we describe its mechanisms of action. Heat shock protein 90 (Hsp90) was identified as a specific ITZ-1-binding protein. Almost all known Hsp90 inhibitors have been reported to bind to the Hsp90 N-terminal ATP-binding site and to simultaneously induce degradation and activation of its multiple client proteins. However, within the Hsp90 client proteins, ITZ-1 strongly induces heat shock factor-1 (HSF1) activation and causes mild Raf-1 degradation, but scarcely induces degradation of a broad range of Hsp90 client proteins by binding to the Hsp90 C terminus. These results may explain ITZ-1's inhibition of MMP-13 production, its cytoprotective effect, and its lower cytotoxicity. These results suggest that ITZ-1 is a client-selective Hsp90 inhibitor.

  DOI：

  10.1016/j.chembiol.2009.12.012

文献信息

• METHOD FOR SCREENING OF CELL-PROTECTING AGENT
  申请人：Kimura Haruhide

  公开号：US20100279311A1

  公开（公告）日：2010-11-04

  The invention provides a screening method and screening kit for a cell protecting agent. Specifically, the invention provides a method for screening a cell protecting agent showing an Hsp90-binding activity and a heat shock protein expression-inducing activity but having no Hsp90 client protein degradation-promoting activity. The method comprises the following steps (1) to (3): (1) measuring the binding property of a test compound to Hsp90; (2) measuring the activity of a test compound to induce the expression of a heat shock protein, or measuring the activity of a test compound to disrupt an Hsp90/HSF-1 complex, by using a cell capable of expressing the heat shock protein; and (3) measuring the activity of a test compound to induce the degradation of an Hsp90 client protein by using a cell capable of expressing the Hsp90 client protein. The invention further provides specifically a kit for screening a cell protecting agent, comprising (1) Hsp90; (2) a reagent for measuring the heat shock protein expression-inducing activity; (3) an imidazothiazine derivative; and (4) a reagent for quantifying an Hsp90 client protein.

  本发明提供了一种细胞保护剂的筛选方法和筛选试剂盒。具体而言，本发明提供了一种筛选细胞保护剂的方法，该方法显示出Hsp90结合活性和热休克蛋白表达诱导活性，但没有Hsp90客户蛋白降解促进活性。该方法包括以下步骤（1）至（3）：（1）测量试验化合物与Hsp90的结合性质；（2）利用能够表达热休克蛋白的细胞，测量试验化合物诱导热休克蛋白表达的活性，或测量试验化合物破坏Hsp90/HSF-1复合物的活性；（3）利用能够表达Hsp90客户蛋白的细胞，测量试验化合物诱导Hsp90客户蛋白降解的活性。本发明进一步具体提供了一种用于筛选细胞保护剂的试剂盒，包括（1）Hsp90；（2）用于测量热休克蛋白表达诱导活性的试剂；（3）咪唑噻唑啉衍生物；以及（4）用于定量Hsp90客户蛋白的试剂。
• Method for screening of cell-protecting agent
  申请人：Kimura Haruhide

  公开号：US08450070B2

  公开（公告）日：2013-05-28

  The invention provides a screening method and screening kit for a cell protecting agent. Specifically, the invention provides a method for screening a cell protecting agent showing an Hsp90-binding activity and a heat shock protein expression-inducing activity but having no Hsp90 client protein degradation-promoting activity. The method comprises the following steps (1) to (3): (1) measuring the binding property of a test compound to Hsp90; (2) measuring the activity of a test compound to induce the expression of a heat shock protein, or measuring the activity of a test compound to disrupt an Hsp90/HSF-1 complex, by using a cell capable of expressing the heat shock protein; and (3) measuring the activity of a test compound to induce the degradation of an Hsp90 client protein by using a cell capable of expressing the Hsp90 client protein. The invention further provides specifically a kit for screening a cell protecting agent, comprising (1) Hsp90; (2) a reagent for measuring the heat shock protein expression-inducing activity; (3) an imidazothiazine derivative; and (4) a reagent for quantifying an Hsp90 client protein.

  本发明提供了一种细胞保护剂的筛选方法和筛选工具包。具体而言，本发明提供了一种筛选细胞保护剂的方法，该方法显示出Hsp90结合活性和热休克蛋白表达诱导活性，但没有Hsp90客户蛋白降解促进活性。该方法包括以下步骤（1）至（3）：（1）测量测试化合物与Hsp90的结合性质；（2）使用能够表达热休克蛋白的细胞测量测试化合物诱导热休克蛋白表达的活性，或测量测试化合物破坏Hsp90 / HSF-1复合物的活性；（3）使用能够表达Hsp90客户蛋白的细胞测量测试化合物诱导Hsp90客户蛋白降解的活性。本发明还特别提供了一种用于筛选细胞保护剂的工具包，包括（1）Hsp90；（2）用于测量热休克蛋白表达诱导活性的试剂；（3）咪唑噻唑衍生物；以及（4）用于定量Hsp90客户蛋白的试剂。
• US8450070B2
  申请人：——

  公开号：US8450070B2

  公开（公告）日：2013-05-28