N-[4-hydroxy-3-(1H-1,2,4-triazol-5-ylsulfanyl)naphthalen-1-yl]octane-1-sulfonamide | 1379000-15-3

• 分子结构分类: 有机化合物 - 苯类化合物 - 萘
• 英文名称: N-[4-hydroxy-3-(1H-1,2,4-triazol-5-ylsulfanyl)naphthalen-1-yl]octane-1-sulfonamide
• CAS: 1379000-15-3
• 化学式: C₂₀H₂₆N₄O₃S₂
• 分子量: 434.583
• InChiKey: YXFRXGMTQARJCO-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.7
• 重原子数：
  29
• 可旋转键数：
  11
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.4
• 拓扑面积：
  142
• 氢给体数：
  3
• 氢受体数：
  7

反应信息

• 作为产物：
  描述：

  1-辛烷磺酰胺 在 sodium dithionite 、 titanium(IV) chloride tetrahydrofuran 、 水 、 三乙胺 作用下， 以 四氢呋喃 、 乙酸乙酯 为溶剂， 生成 N-[4-hydroxy-3-(1H-1,2,4-triazol-5-ylsulfanyl)naphthalen-1-yl]octane-1-sulfonamide
  参考文献：
  名称：

  Identification of a Novel Family of BRAF^V600E Inhibitors

  摘要：

  The BRAF oncoprotein is mutated in about half of malignant melanomas and other cancers, and a kinase activating single valine to glutamate substitution at residue 600 (BRAF(V600E)) accounts for over 90% of BRAF-mediated cancers. Several BRAF(V600E) inhibitors have been developed, although they harbor some liabilities, thus motivating the development of other BRAF(V600E) inhibitor options. We report here the use of an ELISA based high-throughput screen to identify a family of related quinolol/naphthol compounds that preferentially inhibit BRAF(V600E) over BRAF(WT) and other kinases. We also report the X-ray crystal structure of a BRAF/quinolol complex revealing the mode of inhibition, employ structure-based medicinal chemistry efforts to prepare naphthol analogues that inhibit BRAF(V600E) in vitro with IC50 values in the 80-200 nM range under saturating ATP concentrations, and demonstrate that these compounds inhibit MAPK signaling in melanoma cells. Prospects for improving the potency and selectivity of these inhibitors are discussed.

  DOI：

  10.1021/jm3004416

文献信息

• Identification of a Novel Family of BRAF^V600E Inhibitors
  作者：Jie Qin、Peng Xie、Christian Ventocilla、Guoqiang Zhou、Adina Vultur、Quan Chen、Qin Liu、Meenhard Herlyn、Jeffrey Winkler、Ronen Marmorstein

  DOI：10.1021/jm3004416

  日期：2012.6.14

  The BRAF oncoprotein is mutated in about half of malignant melanomas and other cancers, and a kinase activating single valine to glutamate substitution at residue 600 (BRAF(V600E)) accounts for over 90% of BRAF-mediated cancers. Several BRAF(V600E) inhibitors have been developed, although they harbor some liabilities, thus motivating the development of other BRAF(V600E) inhibitor options. We report here the use of an ELISA based high-throughput screen to identify a family of related quinolol/naphthol compounds that preferentially inhibit BRAF(V600E) over BRAF(WT) and other kinases. We also report the X-ray crystal structure of a BRAF/quinolol complex revealing the mode of inhibition, employ structure-based medicinal chemistry efforts to prepare naphthol analogues that inhibit BRAF(V600E) in vitro with IC50 values in the 80-200 nM range under saturating ATP concentrations, and demonstrate that these compounds inhibit MAPK signaling in melanoma cells. Prospects for improving the potency and selectivity of these inhibitors are discussed.