Mitochondria-mediated anti-proliferation of triple-negative breast cancer cells by Pd(II)-, Pt(II)-, and Au(III)-NHC complexes of NCN pincers

Abstract

Limited curative therapies can effectively prevent the most malignant form of breast cancer, triple-negative breast cancer (TNBC), from growing and multiplying. Metal-NHC complexes offer a robust foundation for designing an innovative anticancer pharmacophore. Herein, we report the synthesis and characterization of Pd^II (2), Pt^II (3), and Au^III (4) complexes containing pincer (N^C^N) N-heterocyclic carbene ligands derived from 1,3-bis-(1-methyl-1H-benzo[d]imidazol-2-yl-methyl)-1H-imidazol-3-ium hexafluorophosphate (1·HPF₆). The square-planar type molecular geometries of complexes 2 and 4 were confirmed by X-ray diffraction studies. The synthesized complexes displayed potent in vitro cytotoxic activity against TNBC cells (MDA-MB-231) with IC₅₀ values ranging from 4.00 to 9.25 μM, significantly lower than that of cisplatin (27 μM); complex 4 was the most active at inducing apoptosis. According to mechanistic investigations, the complexes caused apoptosis in MDA-MB-231 cells in a mitochondria-mediated manner, mostly by overproducing intracellular reactive oxygen species (ROS), depolarizing the mitochondrial membrane potential (ΔΨ_m), activating pro-apoptotic proteins (BAX) and releasing cytochrome c. Additional studies revealed that the complexes were also potentially targeting thioredoxin reductase (TrxR) and possessed significant inhibitory effects. Among all tested compounds, complex 4 exhibited the highest inhibitory potential, which was also evidenced by molecular docking studies. The findings of the present investigation collectively emphasize the encouraging potential of the gold(III)-NHC pincer complex as a viable chemotherapeutic drug candidate for treating TNBC, supporting the need for additional research into its therapeutic potential.