4-methoxy-3,5-dimethyl-2-((3-(2-(methylthio)phenyl)-1H-pyrazol-1-yl)methyl)pyridine | 960379-14-0

• 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-((3-(2-(methylthio)phenyl)-1H-pyrazol-1-yl)methyl)pyridine
• 英文别名: CH3O(CH3)2C5HNCH2C3H2N2(C6H4SMe)；4-Methoxy-3,5-dimethyl-2-[[3-(2-methylsulfanylphenyl)pyrazol-1-yl]methyl]pyridine；4-methoxy-3,5-dimethyl-2-[[3-(2-methylsulfanylphenyl)pyrazol-1-yl]methyl]pyridine
• CAS: 960379-14-0
• 化学式: C₁₉H₂₁N₃OS
• 分子量: 339.461
• InChiKey: BHZIITSCACMFJZ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.7
• 重原子数：
  24
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.26
• 拓扑面积：
  65.2
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  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
• 作为产物：
  描述：

  2-(氯甲基)-4-甲氧基-3,5-二甲基吡啶 、 3-[(2-methylthio)phenyl]pyrazole 在 四丁基氢氧化铵 、 sodium hydroxide 作用下， 以 水 、 甲苯 为溶剂， 生成 4-methoxy-3,5-dimethyl-2-((3-(2-(methylthio)phenyl)-1H-pyrazol-1-yl)methyl)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

• Mononuclear and Polynuclear Copper(I) Complexes with a New N,N‘,S-Donor Ligand and with Structural Analogies to the Copper Thionein Core
  作者：Marcello Gennari、Maurizio Lanfranchi、Roberto Cammi、Maria Angela Pellinghelli、Luciano Marchiò

  DOI：10.1021/ic701189b

  日期：2007.11.1

  The N,N',S-donor ligand 4-methoxy-3,5-dimethyl-2-((3-(2-(methylthio)phenyl)-1H-pyrazol-1-yl)methyl)pyridi ne (L) was prepared from 2-(chloromethyl)-4-methoxy-3,5-dimethylpyridine hydrochloride and 3-(2-(methylthio)phenyl)-1H-pyrazole. The Cu(I) complexes [Cu2(L)2CH3CN][Cu(L)CH3CN](BF4)3 (1), [Cu(L)PPh3]BF4 (2), and [Cu6(L)2(C6F5S)6] (3) were prepared and characterized by X-ray crystallography (PPh

  N，N'，S供体配体4-甲氧基-3,5-二甲基-2-（（3-（2-（甲硫基）苯基）-1H-吡唑-1-基）甲基）吡啶（L）由2-（氯甲基）-4-甲氧基-3,5-二甲基吡啶盐酸盐和3-（2-（甲硫基）苯基）-1H-吡唑制备。Cu（I）络合物[Cu2（L）2CH3CN] [Cu（L）CH3CN]（BF4）3（1），[Cu（L）PPh3] BF4（2）和[Cu6（L）2（C6F5S） [6]（3）被制备并通过X-射线晶体学表征（PPh 3 ＝三苯基膦，C 6 F 5 S- ＝五氟硫酚盐）。化合物1的晶胞由共结晶的单核和双核实体组成，其中所有铜原子均表现出扭曲的四面体配位。化合物2为单体，L结合在κ3-N，N'，S模式下，并带有一个PPh3分子，可完成配位环境。化合物2由于六元N，N'螯合环的舟状反转（DeltaH = + 43.6（3）kJ mol（-1），DeltaS = -16（1）J mol（
• Copper Binding Agents Acting as Copper Ionophores Lead to Caspase Inhibition and Paraptotic Cell Death in Human Cancer Cells
  作者：Saverio Tardito、Irene Bassanetti、Chiara Bignardi、Lisa Elviri、Matteo Tegoni、Claudio Mucchino、Ovidio Bussolati、Renata Franchi-Gazzola、Luciano Marchiò

  DOI：10.1021/ja109413c

  日期：2011.4.27

  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.