Designing anticancer copper(II) complexes by optimizing 2-pyridine-thiosemicarbazone ligands

Abstract

To develop potential next-generation metal anticancer agents, we designed and synthesised five Cu(II) 2-pyridine-thiosemicarbazone complexes by modifying the hydrogen atom at the N-4 position of ligands, and then investigated their structure-activity relationships and anticancer mechanisms. Modification of the N-4 position with different groups caused significant differences in cellular uptake and produced superior antitumor activity. Cu complexes arrested the cell cycle at S phase, leading to down-regulation of levels of cyclin and cyclin-dependent kinases and up-regulation of expression of cyclin-dependent kinase inhibitors. Cu complexes exerted chemotherapeutic effects via activating p53 and inducing production of reactive oxygen species to regulate expression of the B-cell lymphoma-2 family of proteins, causing a change in the mitochondrial membrane potential and release of cytochrome c to form a dimer with apoptosis protease activating factor-1, resulting in activation of caspase-9/3 to induce apoptosis. In addition, Cu complexes inhibited telomerase by down-regulating the c-myc regulator gene and expression of the human telomerase reverse transcriptase.

Cu(II) and Ni(II) Complexes with New Tridentate NNS Thiosemicarbazones: Synthesis, Characterisation, DNA Interaction, and Antibacterial Activity

“…The IR spectra of complexes 1 – 4 and the three bands (1434–1540 cm −1 , 1306–1316 cm −1 , and 1005–1023 cm −1 ) due to vibrational modes ν4, ν1, and ν2 of the nitrate group confirmed that this anion occupies the fourth coordination site in the monodentate mode [33]. The monodentate nature of the nitrate group in metal complexes with thiosemicarbazone ligands has been described through X-ray diffraction studies [34].…”

Therapeutic strategies for targeting telomerase in cancer

“…Metal‐organic complexes have gradually become the mainstream G4 ligands. In the last 2 years, a large number of metal complexes have been reported to have superior biological activity as G4 binders . Metal complexes have a very broad range of structural and electronic properties that can be successfully utilized in design of G4 binders.…”

Synthesis, structure elucidation, DNA binding and molecular docking studies of novel copper(II) complexes of two 1,3,4‐thiadiazolethiosemicarbazone derivatives

“…Coordination chemistry considers as a good generator for several marketing drugs that are known to be effective in treating many serious diseases such as cancer. [ 1,2 ] The utility of metal complexes was also reported as efficient catalysts in several valuable organic synthesis. [ 3,4 ] Sometimes the high price of mineral salts is one of the obstacles in producing effective complexes such as platinum and palladium salts.…”