5-(2-nitrobenzyl)-2-(4-fluorophenyl)-dihydrobenzo-1,5-thiazepin-4(5H)-one | 1448990-66-6

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并硫氮卓类
• 英文名称: 5-(2-nitrobenzyl)-2-(4-fluorophenyl)-dihydrobenzo-1,5-thiazepin-4(5H)-one
• 英文别名: 2-(4-Fluorophenyl)-5-[(2-nitrophenyl)methyl]-2,3-dihydro-1,5-benzothiazepin-4-one；2-(4-fluorophenyl)-5-[(2-nitrophenyl)methyl]-2,3-dihydro-1,5-benzothiazepin-4-one
• CAS: 1448990-66-6
• 化学式: C₂₂H₁₇FN₂O₃S
• 分子量: 408.453
• InChiKey: CUGGXUDATWGDNO-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.5
• 重原子数：
  29
• 可旋转键数：
  3
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.14
• 拓扑面积：
  91.4
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  对氟肉桂酸 在 sodium hydride 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 6.5h， 生成 5-(2-nitrobenzyl)-2-(4-fluorophenyl)-dihydrobenzo-1,5-thiazepin-4(5H)-one
  参考文献：
  名称：

  Design, synthesis and biological evaluation of benzothiazepinones (BTZs) as novel non-ATP competitive inhibitors of glycogen synthase kinase-3β (GSK-3β)

  摘要：

  Glycogen synthase kinase-3 beta (GSK-3 beta) plays a key role in type II diabetes and Alzheimer's diseases, to which non-ATP competitive inhibitors represent an effectively therapeutical approach due to their good specificity. Herein, a series of small molecules benzothiazepinones (BTZs) as novel non-ATP competitive inhibitors of GSK-3 beta have been designed and synthesized. The in vitro evaluation performed by luminescent assay showed most BTZ derivatives have inhibitory effects in micromolar scale. Among them compounds 61, 6t and 6v have the IC50 values of 25.0 mu M, 27.8 mu M and 23.0 mu M, respectively. Moreover 6v is devoid of any inhibitory activity in the assays to other thirteen protein kinases. Besides, SAR is analyzed and a hypothetical enzymatic binding mode is proposed by molecular docking study, which would be useful for new candidates design. (C) 2012 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2012.09.021

文献信息

• Discovery and anti-inflammatory evaluation of benzothiazepinones (BTZs) as novel non-ATP competitive inhibitors of glycogen synthase kinase-3β (GSK-3β)
  作者：Yang Gao、Peng Zhang、Anfeng Cui、De-Yong Ye、Meng Xiang、Yong Chu

  DOI：10.1016/j.bmc.2018.09.027

  日期：2018.11

  Glycogen synthase kinase-3β (GSK-3β) has been identified to promote inflammation and its inhibitors have also been proven to treat some inflammatory mediated diseases in animal models. Non-ATP competitive inhibitors inherently have better therapeutical value due to their higher specificity than ATP competitive ones. In this paper, we designed and synthesized a series of new BTZ derivatives as non-ATP

  糖原合酶激酶3β（GSK-3β）已被证实可促进炎症，并且其抑制剂也已被证明可治疗动物模型中的某些炎症介导的疾病。非ATP竞争性抑制剂由于其特异性高于ATP竞争性抑制剂，因此固有地具有更好的治疗价值。在本文中，我们设计并合成了一系列新型BTZ衍生物作为非ATP竞争性GSK-3β抑制剂。动力学分析表明，两种典型化合物6j和3j分别显示了底物竞争或对GSK-3β的变构调节的不同非ATP竞争机制。不出所料，这两种化合物在16种蛋白激酶的面板测试中显示出良好的特异性，甚至对最接近的酶（如CDK-1 / cyclin B和CK-II）也是如此。这体内结果证明，这两种化合物均可通过抑制IL-1β和IL-6的mRNA表达而大大减轻LPS诱导的急性肺损伤（ALI），并减轻小鼠的炎症反应。蛋白质印迹分析表明，它们对GSK-3β负调控，并且所观察到的抑制剂有益作用的机制可能涉及到GSK-3β上Ser9残基的磷酸化增加以及Sirtuin