In these studies, we designed and investigated cyto- and genotoxic potential of five ruthenium cyclopentadienyl complexes bearing different phosphine and phosphite ligands. All of the complexes were characterized with spectroscopic analysis (NMR, FT-IR, ESI-MS, UV-vis, fluorescence and XRD (for two compounds)). For biological studies, we used three types of cells – normal peripheral blood mononuclear (PBM) cells, leukemic HL-60 cells and doxorubicin-resistance HL-60 cells (HL-60/DR). We compared the results obtained with those obtained for the complex with maleimide ligand CpRu(CO)₂(η¹-N-maleimidato) 1, which we had previously reported. We observed that the complexes CpRu(CO)(PPh₃)(η¹-N-maleimidato) 2a and CpRu(CO)(P(OEt)₃)(η¹-N-maleimidato) 3a were the most cytotoxic for HL-60 cells and non-cytotoxic for normal PBM cells. However, complex 1 was more cytotoxic for HL-60 cells than complexes 2a and 3a (IC₅₀ = 6.39 μM vs. IC₅₀ = 21.48 μM and IC₅₀ = 12.25 μM, respectively). The complex CpRu(CO)(P(OPh)₃)(η¹-N-maleimidato) 3b is the most cytotoxic for HL-60/DR cells (IC₅₀ = 104.35 μM). We found the genotoxic potential of complexes 2a and 3a only in HL-60 cells. These complexes also induced apoptosis in HL-60 cells. Docking studies showed that complexes 2a and CpRu(CO)(P(Fu)₃)(η¹-N-maleimidato) 2b have a small ability to degrade DNA, but they may cause a defect in DNA damage repair mechanisms leading to cell death. This hypothesis is corroborated with the results obtained in the plasmid relaxation assay in which ruthenium complexes bearing phosphine and phosphite ligands induce DNA breaks.

In these studies, we investigated the antioxidant activity of three ruthenium cyclopentadienyl complexes bearing different imidato ligands: (η⁵-cyclopentadienyl)Ru(CO)₂-N-methoxysuccinimidato (1), (η⁵-cyclopentadienyl)Ru(CO)₂-N-ethoxysuccinimidato (2), and (η⁵-cyclopentadienyl)Ru(CO)₂-N-phthalimidato (3). We studied the effects of ruthenium complexes 1–3 at a low concentration of 50 µM on the viability and the cell cycle of peripheral blood mononuclear cells (PBMCs) and HL-60 leukemic cells exposed to oxidative stress induced by hydrogen peroxide (H₂O₂). Moreover, we examined the influence of these complexes on DNA oxidative damage, the level of reactive oxygen species (ROS), and superoxide dismutase (SOD) activity. We have observed that ruthenium complexes 1–3 increase the viability of both normal and cancer cells decreased by H₂O₂ and also alter the HL-60 cell cycle arrested by H₂O₂ in the sub-G1 phase. In addition, we have shown that ruthenium complexes reduce the levels of ROS and oxidative DNA damage in both cell types. They also restore SOD activity reduced by H₂O₂. Our results indicate that ruthenium complexes 1–3 bearing succinimidato and phthalimidato ligands have antioxidant activity without cytotoxic effect at low concentrations. For this reason, the ruthenium complexes studied by us should be considered interesting molecules with clinical potential that require further detailed research.

Succinimides are among the most studied compounds due to their wide profile of biological activities. It is well-known that succinimides undergo ring-opening reactions under alkaline conditions. This feature limits the formation of 3-substituted succinimides from maleimides by an oxa-Michael reaction, for which basic conditions are required. Herein, we report the synthesis, characterization, and crystal structure of metallocarbonyl (Fe, Ru) complexes bearing 3-substituted succinimide ligands. These complexes were obtained in oxa-Michael reactions of CpM(CO)₂(η¹-maleimidato) (M = Fe, Ru) with alcohols (MeOH, EtOH) in the presence of K₂CO₃. During the crystallographic studies of an iron complex bearing the 3-methoxysuccinimide ligand, we also identified unexpected crystals of free 3-methoxysuccinimide. We performed some additional experiments and theoretical calculations to determine the mechanism of formation of the obtained N-nonsubstituted succinimide. We demonstrate that 3-methoxysuccinimide resulted from light-induced degradation of CpFe(CO)₂(η¹-3-methoxysuccinimidato). On the basis of these findings, we propose an indirect route leading to 3-substituted succinimides starting from maleimide via the light-induced degradation of iron metallocarbonyl succinimidato complexes. The proposed methodology prevents ring opening of succinimide under alkaline conditions and gives N-nonsubstituted succinimide products. To confirm the effectiveness of the described method, CpFe(CO)₂(η¹-maleimidato) was allowed to react with several aliphatic alcohols and phenol, affording the oxa-Michael reaction products in the case of primary alcohols. The irradiation of the obtained compounds with daylight gave the N-nonsubstituted 3-alkoxysuccinimides.

The quest to find new inhibitors of biologically relevant targets is considered an important strategy to introduce new drug candidates for the treatment of neurodegenerative diseases. A series of (aminomethyl)benzylphosphonates 8a–c and their metallocarbonyl iron 9a–c and ruthenium 10a–c complexes were designed, synthesized, and evaluated for their inhibitory potentials against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) by determination of IC₅₀. Metallocarbonyl derivatives, in general, did not show significant inhibition activity against these enzymes, the most potent inhibitor was the (aminomethyl)benzylphosphonate 8a (IC₅₀ = 1.215 µM against AChE). Molecular docking analysis of AChE and (aminomethyl)benzylphosphonates 8a–c showed the strongest interactions of 8a and AChE compared to isomers 8b and 8c. Cytotoxicity studies of synthesized compounds towards the V79 cell line were also performed and discussed.