5-{[(1Z)-5,6-dimethyl-3-oxo-1-({[4-(trifluoromethyl)phenyl]sulfonyl}imino)-2,3-dihydro-1H-imidazo[5,1-c][1,4]thiazin-8-yl]thio}pentanoic acid | 476426-45-6

• 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: 5-{[(1Z)-5,6-dimethyl-3-oxo-1-({[4-(trifluoromethyl)phenyl]sulfonyl}imino)-2,3-dihydro-1H-imidazo[5,1-c][1,4]thiazin-8-yl]thio}pentanoic acid
• 英文别名: ITZ-3；5-[5,6-Dimethyl-3-oxo-1-[[4-(trifluoromethyl)phenyl]sulfonylamino]imidazo[5,1-c][1,4]thiazin-8-yl]sulfanylpentanoic acid
• CAS: 476426-45-6
• 化学式: C₂₀H₂₀F₃N₃O₅S₃
• 分子量: 535.589
• InChiKey: XDCYFUYACOUVJF-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.5
• 重原子数：
  34
• 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：
  175
• 氢给体数：
  2
• 氢受体数：
  10

反应信息

• 作为反应物：
  描述：

  正己胺 、 5-{[(1Z)-5,6-dimethyl-3-oxo-1-({[4-(trifluoromethyl)phenyl]sulfonyl}imino)-2,3-dihydro-1H-imidazo[5,1-c][1,4]thiazin-8-yl]thio}pentanoic acid 在 氰基磷酸二乙酯 、 三乙胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 以4.6%的产率得到5-{[(1Z)-5,6-dimethyl-3-oxo-1-({[4-(trifluoromethyl)phenyl]sulfonyl}imino)-2,3-dihydro-1H-imidazo[5,1-c][1,4]thiazin-8-yl]thio}-N-hexylpentanamide
  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：

  ethyl 5-[((1Z)-5,6-dimethyl-1-{[(4-trifluoromethylphenyl)sulfonyl]imino}-3-oxo-2,3-dihydro-1H-imidazo[5,1-c][1,4]thiazin-8-yl)thio]pentanoate 在 水 、 sodium hydroxide 作用下， 以 四氢呋喃 、 乙醇 为溶剂， 以75%的产率得到5-{[(1Z)-5,6-dimethyl-3-oxo-1-({[4-(trifluoromethyl)phenyl]sulfonyl}imino)-2,3-dihydro-1H-imidazo[5,1-c][1,4]thiazin-8-yl]thio}pentanoic acid
  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

• (Arylamidoaryl)squaramide compounds
  申请人：Castelhano L. Arlindo

  公开号：US20060111349A1

  公开（公告）日：2006-05-25

  Compounds represented by Formula (I): or a pharmaceutically acceptable salt or N-oxide thereof, wherein A, Q, Y, R 5 , m and J are defined herein, are useful in the treatment of tumors and cancers such as mastocytosis/mast cell leukemia, gastrointestinal stromal tumors (GIST), germ cell tumors, small cell lung carcinoma (SCLC), sinonasal natural killer/T-cell lymphoma, testicular cancer (seminoma), thyroid carcinoma, malignant melanoma, ovarian carcinoma, adenoid cystic carcinoma, acute myelogenous leukemia (AML), breast carcinoma, pediatric T-cell acute lymphoblastic leukemia, neuroblastoma, mast cell leukemia, angiosarcoma, anaplastic large cell lymphoma, endometrial carcinoma, and prostate carcinoma.

  化合物式（I）所代表的化合物，或其药学上可接受的盐或N-氧化物，其中A，Q，Y，R5，m和J在此定义，可用于治疗肿瘤和癌症，如肥大细胞增多症/肥大细胞白血病，胃肠间质瘤（GIST），生殖细胞瘤，小细胞肺癌（SCLC），鼻窦自然杀伤/ T细胞淋巴瘤，睾丸癌（精原细胞瘤），甲状腺癌，恶性黑色素瘤，卵巢癌，腺样囊性癌，急性髓系白血病（AML），乳腺癌，小儿T细胞急性淋巴细胞白血病，神经母细胞瘤，肥大细胞白血病，血管肉瘤，间变性大细胞淋巴瘤，子宫内膜癌和前列腺癌。
• 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。
• US7829717B2
  申请人：——

  公开号：US7829717B2

  公开（公告）日：2010-11-09
• US8450070B2
  申请人：——

  公开号：US8450070B2

  公开（公告）日：2013-05-28