Synthesis, crystal structures and anti-cancer mechanism of Cu(II) complex derived from 2-acetylpyrazine thiosemicarbazone

Abstract

Anti-cancer activity of 2-acetylpyrazinethiourea derivatives against NCI-H460, A549, HepG2 and HeLa cell lines was evaluated, with IC₅₀ values ranging from 2.64 to 19.43 µM, among which N,N-diethyl-2-(1-(pyrazin-2-yl)ethylidene)hydrazinecarbothioamide (L4) showed the highest anti-cancer activity (IC₅₀ = 2.64 ± 0.15 µM). L4 reacted with copper bromide, and consequently, Cu(II)-N,N-diethyl-2-(1-(pyrazin-2-yl)ethylidene)hydrazinecarbothioamide (4a) was formed and isolated. This complex was characterized by single crystal X-ray diffraction, elemental analysis, and infrared spectroscopy. L4 is a tridentate ligand that forms a new mononuclear complex with Cu(II). X-Ray diffraction of single crystals showed that 4a crystallizes in the triclinic crystal system in the P-1 space group. The anti-lung cancer (A549) activity of 4a (IC₅₀ = 0.35 ± 0.02 µM) was increased sevenfold compared with that of L4. The detection of anti-cancer mechanisms suggested that the cytotoxicity of 4a is due to its promotion of apoptosis of A549 cells and inhibition of cell cycle. The mechanism by which 4a promotes apoptosis involves a high level of reactive oxygen species, which causes a decrease in the mitochondrial membrane potential and the cleavage of caspase-7 and caspase-9.

Graphical Abstract

Keywords:

• Cu(II) complex
• mitochondria
• reactive oxygen species
• cell cycle
• apoptotic factors

Disclosure statement

The authors declare that they have no conflict of interests.

Additional information

Funding

This work was supported by Henan Engineering Technology Research Center of Funiu Mountain Medicinal Resource Utilization and Molecular Medicine, Key Science and Technology Research Projects in Henan Provincial (No. 202102310476), Youth Fund of Pingdingshan College (No. PXY-QNJJ-202110) and Pingdingshan College PhD Startup Fund under Grant (No. PXY-BSQD-202003).