The Effect of Metal Ions (Fe, Co, Ni, and Cu) on the Molecular-Structural, Protein Binding, and Cytotoxic Properties of Metal Pyridoxal-Thiosemicarbazone Complexes

Abstract

Thiosemicarbazones and their transition metal complexes are biologically active compounds and anticancer agents with versatile structural properties. In this contribution, the structural features and stability of four pyridoxal-thiosemicarbazone (PLTSC) complexes with Fe, Co, Ni, and Cu were investigated using the density functional theory and natural bond orbital approach. Special emphasis was placed on the analysis of the donor atom−metal interactions. The geometry of compounds and crystallographic structures were further examined by Hirshfeld surface analysis, and the main intermolecular interactions were outlined. It has been shown that the geometry and the number of PLTSC units in the structure determine the type and contribution of the specific interactions. The binding of all four complexes to bovine and human serum albumin was investigated through spectrofluorometric titration. The dependency of the thermodynamic parameters on the present metal ion and geometry was explained by the possible interactions through molecular docking simulations. The binding of complexes to DNA, as one of the possible ways the compounds could induce cell death, was examined by molecular docking. The cytotoxicity was measured towards HCT116, A375, MCF-7, A2780, and MCF5 cell lines, with Cu-PLTSC being the most active, as it had the highest affinity towards DNA and proteins.

Effects of changing ions on the crystal design, non-covalent interactions, antimicrobial activity, and molecular docking of Cu(II) complexes with a pyridoxal-hydrazone ligand

“…The band of ν(C=O) shows in the ligand at 1669 cm −1 ; a shift of this band to lower and weak wave number by 70–60 cm −1 suggests the coordination of the carbonyl group to the metal ion ( Jevtovic et al, 2022 ). The same behavior is observed for the strong band of ν(C=N) at 1589 cm −1 ; a shift of this band to lower wave number by 50–40 cm −1 suggests the coordination of the hydrazone to the metal ion through the azomethine nitrogen ( Jevtovic et al, 2023 ). It is possible to find the band of ν(C-N) in the spectra of the complexes between 1,100 and 1,000 cm −1 .…”

“…It is noteworthy that, in all complexes, the ligand is in zwitterionic form with the protonation of the N1 nitrogen pyridine ring and deprotonation of the O2 atom, as reported in the literature for other similar metal complexes with pyridoxal ligands ( Jevtovic et al, 2023 ; Jevtovic et al, 2022 ). The value found between 123.7 (7) and 125.3 (2)° for the bond angle C3–N1–C4 indicates the presence of a proton on the N1 atom, as this angle has been observed for deprotonated forms of similar ligands with the value of about 118° ( Jevtovic et al, 2022 ).…”

“…Their effectiveness is increased when coordinated with specific metals since the charges of the molecules are stabilized due to the binding of the metal ion with the ligand ( Gatto et al, 2019 ; Gan et al, 2024 ). Pyridoxal-based ligands also exhibit antitumor activity, particularly those resulting from the reaction with semicarbazide or thiosemicarbazide ( Qi et al, 2022 ; Jevtovic et al, 2023 ).…”

Crystallographic Structure and Quantum-Chemical Analysis of Biologically Active Co(III)-Pyridoxal–Isothiosemicarbazone Complex

“…The crystallographic structure of 1 was used for the optimization at the B3LYP/6-31 + G (d,p)(H,C,N,O,S)/LanL2DZ(Co) level of theory without any geometrical constraints. This theory level was previously applied to describe similar ligand systems regarding first-row transition metal complexes [18,[40][41][42]. The applicability of this theoretical model was investigated by comparing the experimental and theoretical bond lengths and angles by calculating the correlation coefficient (R) and mean absolute error (MAE).…”

“…CrystalExplorer program [57] was employed to analyze contacts between atoms within the crystallographic structure. This surface analysis is presented in a graph connecting two distances, one between the two nearest nuclei (de) and the other between the nuclei and external surface (di) [41,58,59]. The distances are normalized and colored depending on the van der Waals radii separation.…”