N-{(1Z)-5,6-dimethyl-3-oxo-8-[(4,4,5,5,5-pentafluoropentyl)thio]-2,3-dihydro-1H-imidazo[5,1-c][1,4]thiazin-1-ylidene}-4-methylbenzenesulfonamide | 1180532-17-5

• 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: N-{(1Z)-5,6-dimethyl-3-oxo-8-[(4,4,5,5,5-pentafluoropentyl)thio]-2,3-dihydro-1H-imidazo[5,1-c][1,4]thiazin-1-ylidene}-4-methylbenzenesulfonamide
• 英文别名: ITZ-1；(Z)-N-(5,6-Dimethyl-3-oxo-8-((4,4,5,5,5-pentafluoropentyl)thio)-2,3-dihydro-1H-imidazo[5,1-c][1,4]thiazin-1-ylidene)-4-methylbenzenesulfonamide；N-[5,6-dimethyl-3-oxo-8-(4,4,5,5,5-pentafluoropentylsulfanyl)imidazo[5,1-c][1,4]thiazin-1-yl]-4-methylbenzenesulfonamide
• CAS: 1180532-17-5；476416-09-8
• 化学式: C₂₀H₂₀F₅N₃O₃S₃
• 分子量: 541.587
• InChiKey: SCESDQSNIUARQD-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.2
• 重原子数：
  34
• 可旋转键数：
  8
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.4
• 拓扑面积：
  138
• 氢给体数：
  1
• 氢受体数：
  10

反应信息

• 作为反应物：
  描述：

  N-{(1Z)-5,6-dimethyl-3-oxo-8-[(4,4,5,5,5-pentafluoropentyl)thio]-2,3-dihydro-1H-imidazo[5,1-c][1,4]thiazin-1-ylidene}-4-methylbenzenesulfonamide 在 氨 作用下， 以 四氢呋喃 为溶剂， 反应 16.5h， 以94%的产率得到1-amino-5,6-dimethyl-8-[(4,4,5,5,5-pentafluoropentyl)thio]-3H-imidazo[5,1-c][1,4]thiazin-3-one
  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：

  4,4,5,5,5-五氟戊基甲烷磺酸酯 、 N-[(1Z)-8-mercapto-5,6-dimethyl-3-oxo-2,3-dihydro-1H-imidazo[5,1-c][1,4]thiazin-1-ylidene]-4-methylbenzenesulfonamide 在 potassium carbonate 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 以45%的产率得到N-{(1Z)-5,6-dimethyl-3-oxo-8-[(4,4,5,5,5-pentafluoropentyl)thio]-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

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。
• US8450070B2
  申请人：——

  公开号：US8450070B2

  公开（公告）日：2013-05-28
• ITZ-1, a Client-Selective Hsp90 Inhibitor, Efficiently Induces Heat Shock Factor 1 Activation
  作者：Haruhide Kimura、Hiroshi Yukitake、Yasukazu Tajima、Hirobumi Suzuki、Tomoko Chikatsu、Shinji Morimoto、Yasunori Funabashi、Hiroaki Omae、Takashi Ito、Yukio Yoneda、Masayuki Takizawa

  DOI：10.1016/j.chembiol.2009.12.012

  日期：2010.1

  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.