Pyrazine-Platinum(II) Nanoparticles as a Potential Anticancer Agent: Synthesis, Binding Mechanisms, and Biological Profiling

Abstract

Abstract Pyrazine, a naturally occurring heterocycle with established safety in food and pharmaceutical applications, is an attractive ligand for the design of platinum-based anticancer agents. In this study, a novel platinum(II) complex, [Pt(Pz) 2 Cl 2 ], was synthesized using pyrazine as a nitrogen-donor ligand. The complex was comprehensively characterized by molar conductivity, elemental analysis, FT-IR, 1 H-NMR, UV–Vis, mass spectrometry, thermal analysis, and magnetic susceptibility. X-ray diffraction confirmed its semicrystalline structure, and TEM revealed irregularly shaped nanoparticles with an average size of 15–20 nm. Biological studies demonstrated strong interaction with DNA, including groove binding and cleavage activity, supported by viscosity measurements and thermal denaturation assays. The complex also exhibited significant binding affinity to bovine serum albumin (BSA), indicating favorable transport and distribution in biological systems. In vitro cytotoxicity assays showed that [Pt(Pz) 2 Cl 2 ] exerted the strongest inhibitory effect on A549 lung cancer cells (IC 50 = 7.97 ± 0.03 µg/mL), followed by HCT-116 colon (IC 50 = 28.22 µg/mL) and HepG2 liver cancer cells (IC 50 = 53.02 µg/mL), while displaying markedly lower toxicity toward normal WI-38 fibroblasts (IC 50 = 235 µg/mL), reflecting selective cytotoxicity. Morphological and flow cytometric analyses confirmed that the complex effectively induces necrotic cell death in A549 cells at concentrations near its IC 50 . Computational studies, including DFT and molecular docking, provided insights into the electronic structure and protein-binding interactions of the complex, while ADME-Tox predictions indicated favorable pharmacokinetic behavior and compliance with drug-likeness rules. Collectively, these findings highlight [Pt(Pz) 2 Cl 2 ] as a promising platinum-based anticancer candidate and reinforce the potential of pyrazine ligands in developing next-generation anticancer therapeutics.