Thioamido coordination in a thioxo-1,2,4-triazole copper(II) complex enhances nonapoptotic programmed cell death associated with copper accumulation and oxidative stress in human cancer cells
Thioamido coordination in a thioxo-1,2,4-triazole copper(II) complex enhances nonapoptotic programmed cell death associated with copper accumulation and oxidative stress in human cancer cells
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DOI：
10.1021/jm061174f
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发表时间：
2007-04-19
影响因子：
7.3
通讯作者：
Marchio, Luciano
中科院分区：
文献类型：
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作者：
Tardito, Saverio;Bussolati, Ovidio;Marchio, Luciano
将细胞毒性铜络合物[CuCl2(1H)]Cl2(2)(1=4-amino-1，4-dihydro-3-(2-pyridyl)-5-thioxo-1，2，4-triazole)，)的硫代酰胺基官能团转化为硫醚基团，合成了[CuCl2(3)](2)(4)和[CuCl2(5)](6)(3=6-methyl-3-pyridin-2-yl-7H-[1，2，4]triazolo[3，4-b][1，3，4]thiadiazine；5=4-amino-5-ethylthio-3-(2-pyridyl)-1，2，4-triazole).对这些配合物进行了结构表征，测定了它们的稳定常数和生物活性。4和6的稳定性略低于2，活性显著低于2。然而，AS 2两种配合物均可诱导非凋亡性空泡细胞死亡。在敏感和不敏感的细胞类型中，铜的摄取都被研究，在敏感的细胞中，铜的摄取明显更高，这与氧化谷胱甘肽的增加有关。这些数据表明，硫代酰胺功能增强了铜配合物在癌细胞中的细胞毒性，促进了金属的积累及其与细胞硫醇的相互作用。
The thioamido function of [CuCl2(1H)]Cl (2) (1 = 4-amino-1,4-dihydro-3-(2-pyridyl)-5-thioxo-1,2,4-triazole), a cytotoxic copper complex, was converted into thioether moieties, leading to the synthesis of [CuCl2(3)](2) (4) and [CuCl2(5)] (6) (3 = 6-methyl-3-pyridin-2-yl-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine; 5 = 4-amino-5-ethylthio-3-(2-pyridyl)-1,2,4-triazole). These complexes were structurally characterized, and their stability constants, along with their biological activity, were determined. 4 and 6 were slightly less stable and significantly less active than 2. However, as 2, both complexes induced nonapoptotic vacuolar cell death. Copper uptake, investigated in both 2-sensitive and -insensitive cell types, was markedly higher in sensitive cells where it was associated with an increase in oxidized glutathione. These data suggest that the thioamido function enhances the cytotoxicity of copper complexes in cancer cells promoting the accumulation of the metal and its interaction with cell thiols.