Activation by Oxidation: Ferrocene-Functionalized Ru(II)-Arene Complexes with Anticancer, Antibacterial, and Antioxidant Properties

Abstract

Organometallic Ru­(II)-cymene complexes linked to ferrocene (Fc) via nitrogen heterocycles have been synthesized and studied as cytotoxic agents. These compounds are analogues of Ru­(II)-arene piano-stool anticancer complexes such as RAPTA-C. The Ru center was coordinated by pyridine, imidazole, and piperidine with 0-, 1-, or 2-carbon bridges to Fc to give six bimetallic, dinuclear compounds, and the properties of these complexes were compared with their non-Fc-functionalized parent compounds. Crystal structures for five of the compounds, their Ru-cymene parent compounds, and an unusual trinuclear compound were determined. Cyclic voltammetry was used to determine the formal MIII/II potentials of each metal center of the Ru-cymene-Fc complexes, with distinct one-electron waves observed in each case. The Fc-functionalized complexes were found to exhibit good cytotoxicity against HT29 human colon adenocarcinoma cells, whereas the parent compounds were inactive. Similarly, antibacterial activity from the Ru-cymene-Fc compounds was observed against Bacillus subtilis, but not from the unfunctionalized complexes. In both cases, the IC50 values correlated quantitatively with the Fc+/0 reduction potentials. This is consistent with more facile oxidation to give ferrocenium, and subsequent generation of toxic reactive oxygen species, leading to greater cytotoxicity. The antioxidant properties of the complexes were quantified by a 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging assay. EC50 values indicate that linking of the Ru and Fc centers promotes antioxidant activity.

Metallodrugs are unique: opportunities and challenges of discovery and development

“…Ru-Fe1 †) show a correlation between the cytotoxicity and the Fc +/0 reduction potentials, consistent with facile oxidation to give ferrocenium, and subsequent ROS generation. 59 2.2.4 Ligand oxidation. The hydrolysis product [Ru II (h 6bip)(en)H 2 O] 2+ of the anticancer complex [Ru II (h 6 -bip)(en)Cl] + (Ru1) reacts initially with GSH to form [Ru II (h 6 -bip)(en)(SG)] + .…”

Biological assays and theoretical density functional theory calculations of Rh(I), Ir(III), and Ru(II) complexes of chiral phosphinite ligand

“…Numerous transition metal‐based compounds are an interesting research area due to their biological activities such as antimicrobial, antioxidant, anticancer, DNA cleavage, and DNA binding. [ 1–5 ] Because of the range of coordination geometries, metal complexes provide more stereochemical variability than is possible in organic molecules and often introduce new elements of chirality which may be important for biological molecule recognition and interaction. The metal complexes can also be highly positively charged: because many biological structures such as DNA and RNA, several types of phospholipids, and some regions of proteins are negatively charged, the positive charge of metal complexes could aid the binding with intracellular targets for electrostatic reasons.…”

Synthesis, Characterization, DNA/HSA Interactions, and Anticancer Activity of Two Novel Copper(II) Complexes with 4-Chloro-3-Nitrobenzoic Acid Ligand

“…Hence, novel non-Pt (II/IV) anticancer complexes with fewer side effects are urgently required [ 9 , 10 ]. Copper(II) complexes have attracted attention in medicinal inorganic chemistry research [ 11 , 12 , 13 , 14 , 15 , 16 ]. Copper(II) is an essential micronutrient and a structural and catalytic cofactor in numerous biochemical pathways.…”