Structural and solution equilibrium studies of trimethylammonium thiosemicarbazones and their interaction with gold...

A series of three water-soluble methylenetrimethylammonium α-N-heterocyclic thiosemicarbazones (TSCs) was synthesized and characterized, and their proton dissociation and complex formation equilibria with Cu(II), Fe(II), and Fe(III) were studied using UV-visible, NMR, and electron paramagnetic resonance spectroscopic methods. In addition, the structures of one ligand and one Cu(II) complex were determined by single-crystal X-ray diffraction, revealing that the Cu(II) complex adopts coordination of the Schiff base through an (N,N,S) donor set. The interaction of the most active Cu(II) complex with human serum albumin-stabilized gold nanoclusters was also investigated to explore the association of the two systems and the impact of this protein-based matrix on the stability of the complex. The effect of the -CH₂-N(CH₃)₃⁺ substituent in position 6 of the pyridine ring on the solution chemical properties and cytotoxicity was examined. At physiological pH, the positively charged species dominate for all compounds studied, providing excellent aqueous solubility. The -CH₂-N(CH₃)₃⁺ moiety resulted in lower stability of the metal complexes compared to their corresponding non-substituted TSC analogues. Complexation with Cu(II) enhanced the activity against human colon adenocarcinoma (Colo205) and lung adenocarcinoma (A549) cell lines, although only moderate cytotoxicity was observed. Association with the protein-stabilized gold nanoclusters induced partial dissociation of the selected Cu(II) complex. Overall, while the methylenetrimethylammonium group in position 6 of the pyridine ring improves aqueous solubility, it adversely affects both metal ion binding capacity and in vitro cytotoxicity against cancer cell lines.