Imine‐N‐Heterocyclic Carbenes as Versatile Ligands in Ruthenium(II) p‐Cymene Anticancer Complexes: A Structure–Activity Relationship Study

Abstract

A family of novel imine-N-heterocyclic carbene ruthenium(II) complexes of the general formula [(η -p-cymene)Ru(C^N)Cl]PF (where C^N is an imine-N-heterocyclic carbene chelating ligand with varying substituents) have been prepared and characterized. In this imine-N-heterocyclic carbene chelating ligand framework, there are three potential sites that can be modified, which distinguishes this class of ligand and provides a body of flexibilities and opportunities to tune the cytotoxicity of these ruthenium(II) complexes. The influence of substituent effects of three tunable domains on the anticancer activity and catalytic ability in converting coenzyme NADH to NAD is investigated. This family of complexes displays an exceedingly distinct anticancer activity against A549 cancer cells, despite their close structural similarity. Complex 9 shows the highest anticancer activity in this series against A549 cancer cells (IC =14.36 μm), with an approximately 1.5-fold better activity than the clinical platinum drug cisplatin (IC =21.30 μm) in A549 cancer cells. Mechanistic studies reveal that complex 9 mediates cell death mainly through cell stress, including cell cycle arrest, inducing apoptosis, increasing intracellular reactive oxygen species (ROS) levels, and depolarization of the mitochondrial membrane potential (MMP). Furthermore, lysosomal damage is also detected by confocal microscopy.

Evaluation of Ruthenium(II) N-Heterocyclic Carbene Complexes as Antibacterial Agents and Inhibitors of Bacterial Thioredoxin Reductase

“…We and others have recently reported on ruthenium(II) NHC complexes of the general type ( p -cymene)(NHC)Ru(II)X 2 (where X = halide) and structurally related complexes as novel anticancer drug candidates [ 14 , 15 , 16 , 17 , 18 , 19 , 20 ]. For complexes with the general structure ( p -cymene)(NHC)Ru(II)Cl 2 with different substituents on the NHC nitrogen atoms, the antiproliferative activity was dependent on the lipophilicity of the nitrogen side chains and on cellular uptake.…”

New Organometallic Tetraphenylethylene⋅Iridium(III) Complexes with Antineoplastic Activity

“…In vivo, the transformation from NADH to NAD + was able to induce the accumulation of the reactive oxygen species (ROS) H 2 O 2 and lead to apoptosis, thus providing an antineoplastic mechanism of oxidation . As shown in Figures A and S3, the absorbance at 339 nm (the maximum UV/Vis absorbance of NADH) significantly decreased and that at 259 nm (the maximum absorbance of NAD + ) increased with the addition of the half‐sandwich Ir III complexes 1 and 2 , especially in the case of complex 1 . However, almost no changes occurred in the cases of the cycloiridium complexes 3 and 4 .…”

Theranostic Lysosomal Targeting Anticancer and Antimetastatic Agents: Half-Sandwich Iridium(III) Rhodamine Complexes

“…To investigate the anticancer mechanism of complex entry into cells, analysis of whether complex 1 with good antiproliferative capacity can disrupt or prevent cell cycle to affect apoptosis by using flow cytometry. 55 A549 cells were treated with complex 1 at the IC 50 concentrations of 0.25, 0.5, 1.0, and 2.0 for 24 h (Figure 4, Table S1). By flow cytometry analysis, the cells in the S phase increased by 8.58% compared to the control treatment at a complex’s concentration of 2 × IC 50 .…”