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

Abstract

Eight heteroleptic nickel(II) and copper(II) complexes of the type [M(L1–4)(nap)2] (1–8), where L1–4 = 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 (Epc = −0.66 to −1.43 V), and nickel(II) complexes 1–4 displayed an irreversible one-electron oxidation process in the anodic region (Epa = 0.75 to 1.10 V). The obtained magnetic moment values (1.82–1.93 μB) 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.