NF-κB活化抑制剂VI | 113760-29-5

• 分子结构分类: 有机化合物 - 有机氧化合物
• 中文名称: NF-κB活化抑制剂VI
• 英文名称: 2-phenylimino-4-oxo-4,5,6,7-tetrahydro-6,6-dimethyl-1,3-benzoxathiole
• 英文别名: BOT-64；6,6-dimethyl-2-(phenylimino)-6,7-dihydro-5H-benzo[1,3]oxathiol-4-one；6,6-dimethyl-2-(phenylimino)-6,7-dihydrobenzo[d][1,3]oxathiol-4(5H)-one；1,3-Benzoxathiol-4(5H)-one, 6,7-dihydro-6,6-dimethyl-2-(phenylimino)-；6,6-dimethyl-2-phenylimino-5,7-dihydro-1,3-benzoxathiol-4-one
• CAS: 113760-29-5
• 化学式: C₁₅H₁₅NO₂S
• 分子量: 273.356
• InChiKey: XFSSJIQCIPSBHJ-UHFFFAOYSA-N

物化性质

• 沸点：
  402.1±48.0 °C(Predicted)
• 密度：
  1.27±0.1 g/cm3(Predicted)
• 溶解度：
  溶于乙醇或DMSO

计算性质

• 辛醇/水分配系数(LogP)：
  3.8
• 重原子数：
  19
• 可旋转键数：
  1
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  64
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  硫代异氰酸苯酯 、 5,5-二甲基-1,3-环己二酮 在 dirhodium tetraacetate 亚碘酰苯 作用下， 以 二氯甲烷 、 苯 为溶剂， 反应 6.0h， 以35%的产率得到NF-κB活化抑制剂VI
  参考文献：
  名称：

  Benzoxathiole Derivative Blocks Lipopolysaccharide-Induced Nuclear Factor-κB Activation and Nuclear Factor-κB-Regulated Gene Transcription through Inactivating Inhibitory κB Kinase β

  摘要：

  苯并氧硫醇衍生物已用于治疗痤疮，并显示出细胞抑制、抗牛皮癣和抗菌特性。然而，尽管核因子 (NF)-κB 激活与炎症和细胞增殖密切相关，但人们对这些药理学特性的分子基础知之甚少。在这里，我们证明了新型小分子苯并氧硫醇 6,6-二甲基-2-(苯基亚氨基)-6,7-二氢-5 H -苯并-[1,3]氧硫醇-4-酮 (BOT-64) 抑制通过阻断抑制性 κB(IκB) 激酶 β (IKKβ) 激活 NF-κB，IC50 值为 1 μM，并抑制脂多糖 (LPS) 激活的 RAW 264.7 巨噬细胞中 NF-κB 调节的炎症基因表达。 BOT-64 抑制 LPS 激活的巨噬细胞中 IKKβ 介导的 IκBα 磷酸化，从而顺序预防下游事件，包括 IκBα 的蛋白水解降解、DNA 结合能力和 NF-κB 的转录活性。 BOT-64 抑制细胞中 LPS 诱导的 IKKβ 活性以及高度纯化的 IKKβ 的催化活性。此外，通过将 IKKβ 激活环中的 Ser-177 和 Ser-181 残基替换为谷氨酸残基，消除了 BOT-64 对无细胞 IKKβ 的影响，表明苯并氧硫醇的直接相互作用位点。 BOT-64 减弱 LPS 激活或表达载体 IKKβ 中 NF-κB 调节的炎症基因的表达，例如诱导型一氧化氮合酶、环氧合酶-2、肿瘤坏死因子-α、白细胞介素 (IL)-1β 和 IL-6 -转染的巨噬细胞。此外，BOT-64 剂量依赖性地增加内毒素 LPS 休克小鼠的存活率。

  DOI：

  10.1124/mol.107.041251

文献信息

• The chemistry of photolytically and thermally generated α-ketocarbenes from iodonium ylides of β-diketones
  作者：Lazaros P. Hadjiarapoglou

  DOI：10.1016/s0040-4039(00)96535-3

  日期：1987.1
• Study on anti-proliferative effect of benzoxathiole derivatives through inactivation of NF-κB in human cancer cells
  作者：Eeda Venkateswararao、Hoang Le Tuan Anh、Vinay K. Sharma、Ki-Cheul Lee、Niti Sharma、Youngsoo Kim、Sang-Hun Jung

  DOI：10.1016/j.bmcl.2012.06.001

  日期：2012.7

  To investigate the anti-proliferative effect of a newly discovered NF-kB inhibitor, 6,6-dimethyl-2-(phenylimino)-6,7-dihydrobenzo[d][1,3]oxathiol-4(5H)-one (1a), a series of its analogs (1b-n) were prepared and evaluated for their NF-kappa B inhibition and anti-proliferative activity against various human cancer cell lines. Slight variation of hydrophobicity by replacement of dimethyl group of 1a at 6-position with bulky isopropyl group and introduction of para-fluoro substitution on 2-phenyl group showed good NF-kappa B inhibitory activity and anti-proliferative activity. However, excessive increase in hydrophobicity with 2,4,6-trichloro substituents on phenyl group resulted in the loss of both the activities. From the SAR results, 2-phenylimino-6,7-dihydrobenzo[d][1,3] oxathiol-4(5H)-one was identified as the lead scaffold for investigating new anticancer agent through inactivation of NF-kappa B. (C) 2012 Elsevier Ltd. All rights reserved.
• Benzoxathiole Derivative Blocks Lipopolysaccharide-Induced Nuclear Factor-κB Activation and Nuclear Factor-κB-Regulated Gene Transcription through Inactivating Inhibitory κB Kinase β
  作者：Byung Hak Kim、Eunmiri Roh、Hwa Young Lee、In-Jeong Lee、Byeongwoo Ahn、Sang-Hun Jung、Heesoon Lee、Sang-Bae Han、Youngsoo Kim

  DOI：10.1124/mol.107.041251

  日期：2008.4

  Benzoxathiole derivatives have been used in the treatment of acne and have shown cytostatic, antipsoriatic, and antibacterial properties. However, little is known about the molecular basis for these pharmacological properties, although nuclear factor (NF)-κB activation is closely linked to inflammation and cell proliferation. Here, we demonstrate that the novel small-molecule benzoxathiole 6,6-dimethyl-2-(phenylimino)-6,7-dihydro-5 H -benzo-[1,3]oxathiol-4-one (BOT-64) inhibits NF-κB activation with an IC50 value of 1 μM by blocking inhibitory κB(IκB) kinase β (IKKβ), and suppresses NF-κB-regulated expression of inflammatory genes in lipopolysaccharide (LPS)-activated RAW 264.7 macrophages. BOT-64 inhibits IKKβ-mediated IκBα phosphorylation in LPS-activated macrophages, resulting in sequential prevention of downstream events, including proteolytic degradation of IκBα, DNA binding ability, and transcriptional activity of NF-κB. BOT-64 inhibits LPS-inducible IKKβ activity in the cells and catalytic activity of highly purified IKKβ. Moreover, the effect of BOT-64 on cell-free IKKβ was abolished by substitution of Ser-177 and Ser-181 residues in the activation loop of IKKβ to glutamic acid residues, indicating a direct interaction site of benzoxathiole. BOT-64 attenuates NF-κB-regulated expression of inflammatory genes such as inducible nitric-oxide synthase, cyclooxygenase-2, tumor necrosis factor-α, interleukin (IL)-1β, and IL-6 in LPS-activated or expression vector IKKβ-transfected macrophages. Furthermore, BOT-64 dose-dependently increases the survival rates of endotoxin LPS-shocked mice.

  苯并氧硫醇衍生物已用于治疗痤疮，并显示出细胞抑制、抗牛皮癣和抗菌特性。然而，尽管核因子 (NF)-κB 激活与炎症和细胞增殖密切相关，但人们对这些药理学特性的分子基础知之甚少。在这里，我们证明了新型小分子苯并氧硫醇 6,6-二甲基-2-(苯基亚氨基)-6,7-二氢-5 H -苯并-[1,3]氧硫醇-4-酮 (BOT-64) 抑制通过阻断抑制性 κB(IκB) 激酶 β (IKKβ) 激活 NF-κB，IC50 值为 1 μM，并抑制脂多糖 (LPS) 激活的 RAW 264.7 巨噬细胞中 NF-κB 调节的炎症基因表达。 BOT-64 抑制 LPS 激活的巨噬细胞中 IKKβ 介导的 IκBα 磷酸化，从而顺序预防下游事件，包括 IκBα 的蛋白水解降解、DNA 结合能力和 NF-κB 的转录活性。 BOT-64 抑制细胞中 LPS 诱导的 IKKβ 活性以及高度纯化的 IKKβ 的催化活性。此外，通过将 IKKβ 激活环中的 Ser-177 和 Ser-181 残基替换为谷氨酸残基，消除了 BOT-64 对无细胞 IKKβ 的影响，表明苯并氧硫醇的直接相互作用位点。 BOT-64 减弱 LPS 激活或表达载体 IKKβ 中 NF-κB 调节的炎症基因的表达，例如诱导型一氧化氮合酶、环氧合酶-2、肿瘤坏死因子-α、白细胞介素 (IL)-1β 和 IL-6 -转染的巨噬细胞。此外，BOT-64 剂量依赖性地增加内毒素 LPS 休克小鼠的存活率。