Biocompatibility, in Vitro Antiproliferative, and in Silico EGFR/VEGFR2 Studies of Heteroleptic Metal(II) Complexes of Thiosemicarbazones and Naproxen

Eight heteroleptic nickel(II) and copper(II) complexes of the type [M(L^1-4)(nap)₂] (1-8), where L^1-4 = 2-(1-(4-substitutedphenyl)ethylidene)hydrazinecarbothioamide, nap = naproxen, and M = Ni(II) or Cu(II), have been synthesized and characterized. UV-vis and EPR spectral studies showed distorted octahedral geometry around metal(II) ions. The cyclic voltammogram of complexes 1-8 displayed an irreversible one-electron transfer process in the cathodic region (E_pc = -0.66 to -1.43 V), and nickel(II) complexes 1-4 displayed an irreversible one-electron oxidation process in the anodic region (E_pa = 0.75 to 1.10 V). The obtained magnetic moment values (1.82-1.93 μ_B) for copper(II) complexes 5-8 indicate distortion from octahedral geometry, which is further supported by EPR studies. The geometry of the complexes is retained in both solid and solution phases as evidenced from UV-vis and EPR studies. All the complexes showed stability for almost 72 h in biologically relevant solutions. The reducing ability of the copper(II) complexes in the presence of ascorbic acid was analyzed by UV-vis and cyclic voltammetry techniques, which indicates the reduction of the copper(II) to a copper(I) center, and possible interaction within the cells. An in vitro antiproliferative study revealed the nontoxic nature of complexes to normal human dermal fibroblast (NHDF) up to a concentration of 100 ng/mL. The antiproliferative activity of the complexes was tested against three cancerous (human breast adenocarcinoma (MCF-7), hepatoma (HepG2), and lung (A549)) cell lines using MTT reduction assay, which showed enhanced activity for complexes 4 and 8 containing the hydrophobic substituent. Apoptotic and cellular uptake studies showed that complex 8 is readily taken up by HepG2 cell lines and induces ROS-mediated mitochondrial and caspase-dependent apoptosis. In silico studies indicated hydrogen bonding, hydrophobic, and π-pair (π-π, π-σ, and π-cation) interactions between the complexes and EGFR/VEGFR2 kinase receptors.