The largely uncharted complexation chemistry of the veterinary polyether ionophores, monensic and salinomycinic acids (HL) with metal ions of type M⁴⁺ and the known antiproliferative potential of antibiotics has provoked our interest in exploring the coordination processes between MonH/SalH and ions of Ce⁴⁺. (1) Methods: Novel monensinate and salinomycinate cerium(IV)-based complexes were synthesized and structurally characterized by elemental analysis, a plethora of physicochemical methods, density functional theory, molecular dynamics, and biological assays. (2) Results: The formation of coordination species of a general composition [CeL₂(OH)₂] and [CeL(NO₃)₂(OH)], depending on reaction conditions, was proven both experimentally and theoretically. The metal(IV) complexes [CeL(NO₃)₂(OH)] possess promising cytotoxic activity against the human tumor uterine cervix (HeLa) cell line, being highly selective (non-tumor embryo Lep-3 vs. HeLa) compared to cisplatin, oxaliplatin, and epirubicin.

Combining therapeutic with diagnostic agents (theranostics) can revolutionize the course of malignant diseases. Chemotherapy, hyperthermia, or radiation are used together with diagnostic methods such as magnetic resonance imaging (MRI). In contrast to conventional contrast agents (CAs), which only enable non-specific visualization of tissues and organs, the theranostic probe offers targeted diagnostic imaging and therapy simultaneously. Methods: Novel salinomycin (Sal)-based theranostic probes comprising two different paramagnetic metal ions, gadolinium(III) (Gd(III)) or manganese(II) (Mn(II)), as signal emitting motifs for MRI were synthesized and characterized by elemental analysis, infrared spectral analysis (IR), electroparamagnetic resonance (EPR), thermogravimetry (TG) differential scanning calorimetry (DSC) and electrospray ionization mass spectrometry (ESI-MS). To overcome the water insolubility of the two Sal-complexes, they were loaded into empty bacterial ghosts (BGs) cells as transport devices. The potential of the free and BGs-loaded metal complexes as theranostics was evaluated by in vitro relaxivity measurements in a high-field MR scanner and in cell culture studies. Results: Both the free Sal-complexes (Gd(III) salinomycinate (Sal-Gd(III) and Mn(II) salinomycinate (Sal-Mn(II)) and loaded into BGs demonstrated enhanced cytotoxic efficacy against three human tumor cell lines (A549, SW480, CH1/PA-1) relative to the free salinomycinic acid (Sal-H) and its sodium complex (Sal-Na) applied as controls with IC₅₀ in a submicromolar concentration range. Moreover, Sal-H, Sal-Gd(III), and Sal-Mn(II) were able to induce perturbations in the cell cycle of treated colorectal and breast human cancer cell lines (SW480 and MCF-7, respectively). The relaxivity (r₁) values of both complexes as well as of the loaded BGs, were higher or comparable to the relaxivity values of the clinically applied contrast agents gadopentetate dimeglumine and gadoteridol. Conclusion: This research is the first assessment that demonstrates the potential of Gd(III) and Mn(II) complexes of Sal as theranostic agents for MRI. Due to the remarkable selectivity and mode of action of Sal as part of the compounds, they could revolutionize cancer therapy and allow for early diagnosis and monitoring of therapeutic follow-up.

Two trinuclear oxo-centred iron(III) coordination compounds of monensic and salinomycinic acids (HL) were synthesized and their spectral properties were studied using physicochemical/thermal methods (FT–IR, TG–DTA, TG–MS, EPR, Mössbauer spectroscopy, powder XRD) and elemental analysis. The data suggested the formation of [Fe₃(µ₃–O)L₃(OH)₄] and the probable complex structures were modelled using the DFT method. The computed spectral parameters of the optimized constructs were compared to the experimentally measured ones. In each complex, three metal centres were joined together at the axial position by a μ₃–O unit to form a {Fe₃O}⁷⁺ core. The antibiotics monoanions served as bidentate ligands through the carboxylate and hydroxyl groups located at the termini. The carboxylate moieties played a dual role bridging each two metal centres. Hydroxide anions secured the overall neutral character of the coordination species. Mössbauer spectra displayed asymmetric quadrupole doublets that were consistent with the existence of two types of high-spin iron(III) sites with different environments—two Fe[O₅] and one Fe[O₆] centres. The solid-state EPR studies confirmed the +3 oxidation state of iron with a total spin S_t = 5/2 per trinuclear cluster. The studied complexes are the first iron(III) coordination compounds of monensin and salinomycin reported so far.

Lead (Pb) exposure induces severe nephrotoxic effects in humans and animals. Herein, we compare the effects of two chelating agents, salinomycin and deferiprone, on Pb-induced renal alterations in mice and in the homeostasis of essential elements. Adult male mice (Institute of Cancer Research (ICR)) were randomized into four groups: control (Ctrl)—untreated mice administered distilled water for 28 days; Pb-exposed group (Pb)—mice administered orally an average daily dose of 80 mg/kg body weight (BW) lead (II) nitrate (Pb(NO₃)₂) during the first two weeks of the experimental protocol followed by the administration of distilled water for another two weeks; salinomycin-treated (Pb + Sal) group—Pb-exposed mice, administered an average daily dose of 16 mg/kg BW salinomycin for two weeks; deferiprone-treated (Pb + Def) group—Pb-exposed mice, administered an average daily dose of 20 mg/kg BW deferiprone for 14 days. The exposure of mice to Pb induced significant accumulation of the toxic metal in the kidneys and elicited inflammation with leukocyte infiltrations near the glomerulus. Biochemical analysis of the sera revealed that Pb significantly altered the renal function markers. Pb-induced renal toxicity was accompanied by a significant decrease in the endogenous renal concentrations of phosphorous (P), calcium (Ca), copper (Cu) and selenium (Se). In contrast to deferiprone, salinomycin significantly improved renal morphology in Pb-treated mice and decreased the Pb content by 13.62% compared to the Pb-exposed group. There was also a mild decrease in the renal endogenous concentration of magnesium (Mg) and elevation of the renal concentration of iron (Fe) in the salinomycin-treated group compared to controls. Overall, the results demonstrated that salinomycin is a more effective chelating agent for the treatment of Pb-induced alterations in renal morphology compared to deferiprone.

The veterinary 16-membered macrolide antibiotics tylosin (HTyl, 1a) and tilmicosin (HTilm, 1b) react with copper(II) ions in acetone at metal-to-ligand molar ratio of 1:2 to form blue (2) or green (3) metal(II) coordination species, containing nitrate or chloride anions, respectively. The complexation processes and the properties of 2–3 were studied by an assortment of physicochemical techniques (UV-Vis, EPR, NMR, FTIR, elemental analysis). The experimental data revealed that the main portion of copper(II) ions are bound as neutral EPR-silent dinuclear complexes of composition [Cu₂(µ-NO₃)₂L₂] (2a–b) and [Cu₂(µ-Cl)₂Cl₂(HL)₂] (3a–b), containing impurities of EPR-active mono-species [Cu(NO₃)L] (2a’–b’) and [CuCl₂(HL)] (3a’–b’). The possible structural variants of the dinuclear- and mono-complexes were modeled by the DFT method, and the computed spectroscopic parameters of the optimized constructs were compared to those measured experimentally. Using such a combined approach, the main coordination unit of the macrolides, involved in the complex formation, was defined to be their mycaminosyl substituent, which acts as a terminal ligand in a bidentate mode through the tertiary nitrogen atom and the oxygen from a deprotonated (2) or non-dissociated (3) hydroxyl group, respectively.