4-methoxy-3,5-dimethyl-2-(2-methylthio-1-(3-(2-methylthiophenyl)-1H-pyrazol-1-yl)ethyl)pyridine | 1013404-50-6

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: 4-methoxy-3,5-dimethyl-2-(2-methylthio-1-(3-(2-methylthiophenyl)-1H-pyrazol-1-yl)ethyl)pyridine
• 英文别名: CH3O(CH3)2C5HNCH(CH2SMe)C3HN2(C6H4SMe)
• CAS: 1013404-50-6
• 化学式: C₂₁H₂₅N₃OS₂
• 分子量: 399.581
• InChiKey: ZRACTQHVHALYKS-GOSISDBHSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.24
• 重原子数：
  27.0
• 可旋转键数：
  7.0
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  39.94
• 氢给体数：
  0.0
• 氢受体数：
  6.0

反应信息

• 作为反应物：
  描述：

  copper(II) choride dihydrate 、 4-methoxy-3,5-dimethyl-2-(2-methylthio-1-(3-(2-methylthiophenyl)-1H-pyrazol-1-yl)ethyl)pyridine 以 甲醇 为溶剂， 生成 [CuCl2(κ3-N,N',S-4-methoxy-3,5-dimethyl-2-(2-methylthio-1-(3-(2-methylthiophenyl)-1H-pyrazol-1-yl)ethyl)pyridine)]
  参考文献：
  名称：

  Copper Binding Agents Acting as Copper Ionophores Lead to Caspase Inhibition and Paraptotic Cell Death in Human Cancer Cells

  摘要：

  We report a quantitative structure activity relationship study of a new class of pyrazole-pyridine copper complexes that establishes a clear correlation between the ability to promote copper accumulation and cytotoxicity. Intracellular metal accumulation is maximized when ligand lipophilicity allows the complex to rapidly cross the membrane. Copper and ligand follow different uptake kinetics and reach different intracellular equilibrium concentrations. These results support a model in which the ligand acts as an ionophore for the metal ion, cycling between intra- and extracellular compartments as dissociated or complexed entities. When treating cancer cells with structurally unrelated disulfiram and pyrazole-pyridine copper complexes, as well as with inorganic copper, the same morphological and molecular changes were reproduced, indicating that copper overload is responsible for the cytotoxic effects. Copper-based treatments drive sensitive cancer cells toward paraptotic cell death, a process hallmarked by endoplasmic reticulum stress and massive vacuolization in the absence of apoptotic features. A lack of caspase activation, as observed in copper-treated dying cells, is a consequence of metal-mediated inhibition of caspase-3. Thus, copper acts simultaneously as an endoplasmic reticulum (ER) stress inducer and a caspase-3 inhibitor, forcing the cell into caspase-independent paraptotic death. The establishment of a mechanism of action common to different copper binding agents provides a rationale for the exploitation of copper toxicity as an anticancer tool.

  DOI：

  10.1021/ja109413c
• 作为产物：
  描述：

  氯甲基甲硫醚 、 4-methoxy-3,5-dimethyl-2-((3-(2-(methylthio)phenyl)-1H-pyrazol-1-yl)methyl)pyridine 在 正丁基锂 作用下， 以 四氢呋喃 为溶剂， 生成 4-methoxy-3,5-dimethyl-2-(2-methylthio-1-(3-(2-methylthiophenyl)-1H-pyrazol-1-yl)ethyl)pyridine
  参考文献：
  名称：

  Copper Binding Agents Acting as Copper Ionophores Lead to Caspase Inhibition and Paraptotic Cell Death in Human Cancer Cells

  摘要：

  We report a quantitative structure activity relationship study of a new class of pyrazole-pyridine copper complexes that establishes a clear correlation between the ability to promote copper accumulation and cytotoxicity. Intracellular metal accumulation is maximized when ligand lipophilicity allows the complex to rapidly cross the membrane. Copper and ligand follow different uptake kinetics and reach different intracellular equilibrium concentrations. These results support a model in which the ligand acts as an ionophore for the metal ion, cycling between intra- and extracellular compartments as dissociated or complexed entities. When treating cancer cells with structurally unrelated disulfiram and pyrazole-pyridine copper complexes, as well as with inorganic copper, the same morphological and molecular changes were reproduced, indicating that copper overload is responsible for the cytotoxic effects. Copper-based treatments drive sensitive cancer cells toward paraptotic cell death, a process hallmarked by endoplasmic reticulum stress and massive vacuolization in the absence of apoptotic features. A lack of caspase activation, as observed in copper-treated dying cells, is a consequence of metal-mediated inhibition of caspase-3. Thus, copper acts simultaneously as an endoplasmic reticulum (ER) stress inducer and a caspase-3 inhibitor, forcing the cell into caspase-independent paraptotic death. The establishment of a mechanism of action common to different copper binding agents provides a rationale for the exploitation of copper toxicity as an anticancer tool.

  DOI：

  10.1021/ja109413c

文献信息

• Cu^I Complexes with <i>N</i>,<i>N</i>′,<i>S</i>,<i>S</i>′ Scorpionate Ligands: Evidence for Dimer−Monomer Equilibria
  作者：Marcello Gennari、Matteo Tegoni、Maurizio Lanfranchi、Maria Angela Pellinghelli、Marco Giannetto、Luciano Marchiò

  DOI：10.1021/ic702108x

  日期：2008.3.1

  The heteroscorpionate N, N', S, S' donor ligands 4-methoxy-3,5-dimethyl-2-(3-(methylthio)-1-(3-(2-(methylthio)phenyl)-1H-pyrazol-1 -yl)propyl)pyridine (L(a)) and 4-methoxy-3,5-dimethyl-2-(2-(methylthio)-1-(3-(2-(methylthio)phenyl)-1H-pyrazol-1 -yl)ethyl)pyridine (L(b)) were prepared. The Cu(I) complexes [Cu(L(a))]2(BF4)2 (a2(BF4)2) and [Cu(L(b))]2(BF4)2 (b2(BF4)2) were synthesized and characterized

  杂蝎子的N，N'，S，S'供体配体4-甲氧基-3,5-二甲基-2-（3-（甲硫基）-1-（3-（2-（甲硫基）苯基）-1H-吡唑- 1-（基）丙基）吡啶（L（a））和4-甲氧基-3,5-二甲基-2-（2-（甲硫基）-1-（3-（2-（甲硫基）苯基）-1H-吡唑制备-1-基）乙基）吡啶（L（b））。Cu（I）络合物[Cu（L（a））] 2（BF4）2（a2（ ）2）和[Cu（L（b））] 2（ ）2（b2（ ）2）为通过X射线晶体学合成并表征。两种化合物均表现出双核结构，在扭曲的N，N'，S，S'四面体环境中呈现出每个Cu（I）中心。根据核磁共振（NMR）和ESI质谱数据，假设两种配合物均存在与二聚体平衡的单核配合物。进程的二聚化常数2a（+）= a2（2+）和2b（+）= b2（2+），通过（1）1H NMR稀释实验（快速交换机制）在CD 3CN中获得：log K（a2（2+））=