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(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.

Synthesis of Palladium(II) Complexes via Michael Addition: Antiproliferative Effects through ROS-Mediated Mitochondrial Apoptosis and Docking with SARS-CoV-2

“…In contrast, the complexes depicted four bands. In addition to the intraligand transitions appeared around 259–274 and 330–341 nm, two new bands were seen in the regions 370–386 and 384–396 nm, which corresponded to ligand to metal charge transfer transitions (LMCT). , …”

“…In addition to the intraligand transitions appeared around 259−274 and 330−341 nm, two new bands were seen in the regions 370− 386 and 384−396 nm, which corresponded to ligand to metal charge transfer transitions (LMCT). 69,70 FT-IR spectra of the ligands exhibited bands at 3354−3377 and 3230−3249 cm −1 , which were assigned to terminal and thioamide NH groups, respectively. Although the terminal NH stretching frequency (3349−3360 cm −1 ) remained in the spectra of the complexes, thioamide NH stretching frequency disappeared.…”

“…66 Schrodinger Glide 67 was used for MD studies of the complexes with VEGFR2 and EGFR enzymes. 68,69 Antiproliferative Activity. Complexes 1−3 and positive controls (cisplatin, carboplatin, and gemcitabine) were dissolved in DMSO (10 mM) to prepare stock solutions for antiproliferative assay.…”

“…Molecular docking was performed for the Pd­(II) complexes using AutoDock Tools (ADT) version 1.5.6 and AutoDock version 4.2.5 software with the receptor binding sites of DNA hexamer d­(CGATCG) 2 (Protein Data Bank (PDB) ID: 1Z3F), BSA (PDB ID: 3V03), and SARS-CoV-2 main protease (PDB ID: 6Y2F) obtained from the Protein Data Bank () . Schrodinger Glide was used for MD studies of the complexes with VEGFR2 and EGFR enzymes. , …”

Depicting the DNA Binding and Cytotoxicity Studies against Human Colorectal Cancer of Aquabis (1-Formyl-2-Naphtholato-k2O,O′) Copper(II): A Biophysical and Molecular Docking Perspective

“…Recently, a remarkable study on small molecules binding with nucleic acids (DNA and RNA), which displayed significant impression owing to their vital roles in molecular biology, was carried out [9][10][11]. Several other cellular constituents have also been established as potential targets for metal-based drugs [12,13]. In particular, metal-based enzyme and protein inhibition plays a crucial role in metabolic pathways associated with cancer, which present common targets for the design of metal-based drugs [14,15].…”