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

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.