Structural characterization, thermal, DFT, cytotoxicity, and antimetastatic properties of cocaine complexes with La(III), Er(III), and Yb(III)

Abstract

Reaction of cocaine (Cn) with Ln(III) chloride salts [where Ln = La(III), Er(III), and Yb(III)] afforded complexes of the [Ln(Cn)Cl(OH2)3].2Cl type which were structurally characterized by elemental analysis, conductance measurements, spectroscopic methods, and mass spectrometry. Their thermal properties and kinetic thermodynamic parameters were studied. Theoretical calculations including geometry optimization, thermal energies, and some quantum chemical parameters were carried out at DFT/B3LYP/LANL2DZ level of theory. TD-DFT calculations were also performed to assign their electronic spectra. The in vitro antitumor activity of the newly synthesized complexes was investigated by MTT assay on MCF-7 and HepG-2 cell lines. Er(III) complex exhibited promising cytotoxic activity comparable to that of cisplatin on MCF-7 cell line with high safety on normal human cells. Further molecular mechanistic investigations revealed that Er(III) complex was an apoptotic inducer as it elevated the cellular levels of caspase-3 and caspase-9 in MCF-7 cells. In addition, it displayed an elevating effect on the concentrations of the P21 and P27 tumor suppressor nuclear proteins in MCF-7 cells. Moreover, Er(III) complex hindered the cellular scavenger system of the reactive oxygen species by reducing the cellular level of glutathione peroxidase (GPx) imperiling MCF-7 cells by uncontrolled oxidative stress. Furthermore, Er(III) complex showed antimetastatic properties as it decreased the cellular levels of matrix metalloproteinases MMP-3 and MMP-9. These results concluded that the Er(III) complex is a promising anticancer metal-based agent that exerts its cytotoxic action through various molecular mechanisms with high safety on normal human cells and with additional antimetastatic properties. Er(III)complex of Cn, as a representative example, was synthesized as a promising cytotoxic metal-based agent against human HepG-2 and MCF-7 cancer cells and structurally characterized by different spectral and analytical techniques such as elemental analysis, spectroscopic methods, molar conductivity, thermal analysis, and DFT studies. It exerts its action through various molecular mechanisms such as displaying significant antimetastatic effects by decreasing the secretion of MMP-3 and MMP-9, exhibiting remarkable induction of apoptosis by elevating the levels of caspase-3 and caspase-9proteins, inducing the expression of p21 and p27 tumor suppressor genes, and raising the glutathione peroxidase (GPx) activity.