In these studies, we investigated a cytotoxic and genotoxic potential of four ruthenium cyclopentadienyl complexes bearing different imidato ligands: (η5‐cyclopentadienyl)Ru (CO)2(η1‐N‐maleimidato) (1), (η5‐cyclopentadienyl)Ru (CO)2‐N‐methoxysuccinimidato (2), (η5‐cyclopentadienyl)Ru (CO)2‐N‐ethoxysuccinimidato (3), and (η5‐cyclopentadienyl)Ru (CO)2‐N‐phthalimidato (4). We used two types of cells—normal peripheral blood mononuclear cells (PBMCs) and leukemic HL‐60 cells. We observed that complex 1 was highly cytotoxic and genotoxic, both for normal and cancer cells at concentrations from 0.5 to 250 μM. Interestingly, complex 1 was 10 times more cytotoxic to HL‐60 cells compared with PBMCs. Complexes 2–4 were cytotoxic only for HL‐60 cells at the highest used concentrations. Furthermore, we observed an increase in the viability of PBMCs after incubation with succinimide complexes 2 and 3. We also showed that complex 1 arrested cell cycle in the sub‐G1 phase and induced apoptosis. We found that different properties of studied ruthenium complexes depend significantly on the type of imide ligand bind to the ruthenium atom. The density functional theory (DFT) calculation of maleimide and succinimide revealed some significant differences of these compounds that would be related to biological activity. Our results indicate that ruthenium complex 1 should be further investigated in detail for its anticancer properties.
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.
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.
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.
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