Antiproliferative Activity of Gold(I) N‐Heterocyclic Carbene and Triphenylphosphine Complexes with Ibuprofen Derivatives as Effective Enzyme Inhibitors

Abstract

A series of gold(I) complexes of ligand ibuprofen‐alkynyl (but‐3‐yn‐1‐yl 2‐(4‐isobutylphenyl)propanoate, LE) with N‐heterocyclic carbene (LC: 1,3‐dimethylimidazol‐2‐ylidene) and triphenylphosphine (PPh3) ligands with formula (LE)Au (LC) (complex 1) and (LE)Au (PPh3) (complex 2) were synthesized and fully characterized by spectroscopic methods. In order to reveal the cytotoxicity mechanism, the interaction of complex 1 or 2 with cysteine (HCys) has been studied by experimental and density functional theory (DFT) methods. The compounds were investigated for their anticancer activity against MCF‐7, MDAMB 231 breast cancer cells, HT‐29 colon cancer cells and MCF‐10A non‐tumor breast cell line. The results were compared with cisplatin and auranofin as reference drugs. The complex 2 showed more cytotoxic activity than complex 1. The complex 2 was 4.2, 3.7, and 1.7 fold more active than cisplatin against HT‐29, MDA‐MB‐231, MCF‐7 cancer cell lines, respectively. The inhibition of thioredoxin reductase of complexes 1 and 2 including cytosolic (TrxR1) and mitochondrial (TrxR2) thioredoxin reductase and also the inhibition of glutathione reductase (GR) were studied in detail. Moreover, the cellular uptake and reactive oxygen species (ROS) generation of compounds were investigated. Based on the DFT calculations a relationship between the σ‐donor ability of the isolated ligands and cytotoxicity is suggested.