1,1'-(2-(phenylthio)ethane-1,1-diyl)-bis(3,5-diisopropyl-1H-pyrazole) | 1292840-77-7

• 分子结构分类: 有机化合物 - 有机硫化合物 - 硫醚类
• 英文名称: 1,1'-(2-(phenylthio)ethane-1,1-diyl)-bis(3,5-diisopropyl-1H-pyrazole)
• 英文别名: 1'-(2-(phenylthio)ethane-1,1-diyl)bis(3,5-diisopropyl-1H-pyrazole)；PhSCH2CH(C3HN2(iPr)2)2；1-[1-[3,5-Di(propan-2-yl)pyrazol-1-yl]-2-phenylsulfanylethyl]-3,5-di(propan-2-yl)pyrazole；1-[1-[3,5-di(propan-2-yl)pyrazol-1-yl]-2-phenylsulfanylethyl]-3,5-di(propan-2-yl)pyrazole
• CAS: 1292840-77-7
• 化学式: C₂₆H₃₈N₄S
• 分子量: 438.681
• InChiKey: AOSORMZGTDNTOB-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  7.3
• 重原子数：
  31
• 可旋转键数：
  9
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.54
• 拓扑面积：
  60.9
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  copper(II) choride dihydrate 、 1,1'-(2-(phenylthio)ethane-1,1-diyl)-bis(3,5-diisopropyl-1H-pyrazole) 以 甲醇 为溶剂， 生成 [CuCl2(PhSCH2CH(C3HN2(iPr)2)2-N,N')]
  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-(苯硫基)乙醛 、 bis(3,5-diisopropyl-1H-pyrazol-1-yl)ketone 在 cobalt(II) chloride hexahydrate 作用下， 以29%的产率得到1,1'-(2-(phenylthio)ethane-1,1-diyl)-bis(3,5-diisopropyl-1H-pyrazole)
  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

• Structural Variability in Ag(I) and Cu(I) Coordination Polymers with Thioether-Functionalized Bis(pyrazolyl)methane Ligands
  作者：Irene Bassanetti、Luciano Marchiò

  DOI：10.1021/ic201338w

  日期：2011.11.7

  We present here two ligand classes based on a bis(pyrazolyl)methane scaffold functionalized with a rigid (-Ph-S-Ph) or flexible (-CH(2)-S-Ph) thioether function: L(R)PhS (R = H, Me) and L(R)CH(2)S (R = H, Me, iPr). The X-ray molecular structures of Ag(I) and Cu(I) binary complexes with L(R)PhS or L(R)CH(2)S using different types of counterions (BF(4)(-), PF(6)(-), and CF(3)SO(3)(-)) are reported. In these complexes, the ligands are N(2) bound on a metal center and bridge on a second metal with the thioether group. In contrast, when using triphenylphosphine (PPh(3)) as an ancillary ligand, mononuclear ternary complexes [M(L)PPh3] (M = Cu(I), Ag(I); L = L(R)PhS, L(R)CH(2)S) are formed. In these complexes, the more flexible ligand type, L(R)CH(2)S, is able to provide the N(2)S chelation, whereas the more rigid L(R)PhS ligand class is capable of chelating only N(2) because the thioether function preorganized, as it did in the coordination polymers, to point away from the metal center. Rigid potential-energy surface scans were performed by means of density functional theory (DFT) calculations (B3LYP/6-31+G) on the two representative ligands, L(H)PhS and L(H)CH(2)S. The surface scans proved that the thioether function is preferably oriented on the opposite side of the bispyrazole N(2) chelate system. These results confirm that both ligand classes are suitable components for the construction of coordination polymers. Nevertheless, the methylene group that acts as a spacer in L(H)CH(2)S imparts an inherent flexibility to this ligand class so that the conformation responsible for the N(2)S chelation is energetically accessible.
• 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.