Three Pt(ii) complexes based on thiosemicarbazone: synthesis, HSA interaction, cytotoxicity, apoptosis and cell cycle arrest

Abstract

Three thiosemicarbazone-based platinum(II) complexes [Pt(MH-TSC)Cl] (1), [Pt(ME-TSC)Cl] (2) and [Pt(NH-TSC)₂]Cl (3) (MH-TSC = (E)-2-(1-(pyridin-2-yl)ethylidene)hydrazinecarbothioamide, ME-TSC = (E)-N-ethyl-2-(1-(pyridin-2-yl)ethylidene) hydrazinecarbothioamide, NH-TSC = (Z)-2-(amino(pyridin-2-yl)methylene)hydrazinecarbothioamide) were synthesized and structurally characterized. X-ray analyses revealed that 1 and 2 possessed similar a neutral mononuclear unit in which one tridentate TSC ligand and one leaving group (Cl⁻) coordinated to Pt(II) ion, while 3 was cationic and formed by two NH-TSC ligands surrounding one Pt atom in a meridional arrangement. UV-visible and fluorescence spectra of human serum albumin (HSA) with the complexes displayed that the quenching mechanism of HSA by 1–3 might be a static binding mode. Moreover, synchronous fluorescence experiments proved that 1–3 affected the microenvironment of tryptophan residues of HSA. In addition, the antiproliferative activities against MCF-7 (human breast cancer lines), HepG-2 (human liver hepatocellular carcinoma cell line), NCI-H460 (non-small cell lung cancer lines) and HeLa (human epithelial cervical cancer cell line) were screened for 1–3. Inspiringly, their cytotoxic activity (IC₅₀ = 1.7–9.6 μM) appeared much better than that of cisplatin (IC₅₀ = 5.2–13.5 μM) against different cell lines, respectively. Among them, complex 3 exhibited the strongest inhibition on the viability of all tested cell lines with IC₅₀ values of 1.7–2.2 μM. Inductively-coupled plasma mass spectrometry (ICP-MS) showed that 3 accumulated rapidly in cells and reached intracellular levels of up to 10-fold higher than those determined for 1 and 2. Furthermore, fluorescence microscopic observation and flow cytometric analysis revealed that 1–3 could effectively induce apoptosis of HeLa cells, which were arrested in the S phase after treatment with 1 (30.31%) and 3 (46.96%), and in G2 phase with 2 (20.2%). All the results mentioned above suggest that complexes 1–3 might be efficient antitumor agents.