Experimental and DFT Study of Monensinate and Salinomycinate Complexes Containing {Fe3(µ3-O)}7+ Core.

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 St = 5/2 per trinuclear cluster. The studied complexes are the first iron(III) coordination compounds of monensin and salinomycin reported so far.

Novel Cerium(IV) Coordination Compounds of Monensin and Salinomycin.

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.

Novel Salinomycin-Based Paramagnetic Complexes-First Evaluation of Their Potential Theranostic Properties.

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.

Dinuclear vs. Mononuclear Copper(II) Coordination Species of Tylosin and Tilmicosin in Non-Aqueous Solutions.

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.

A DFT/PCM Study on the Affinity of Salinomycin to Bind Monovalent Metal Cations.

The affinity of the polyether ionophore salinomycin to bind IA/IB metal ions was accessed using the Gibbs free energy of the competition reaction between SalNa (taken as a reference) and its rival ions: [M+-solution] + [SalNa] → [SalM] + [Na+-solution] (M = Li, K, Rb, Cs, Cu, Ag, Au). The DFT/PCM computations revealed that the ionic radius, charge density and accepting ability of the competing metal cations, as well as the dielectric properties of the solvent, have an influence upon the selectivity of salinomycin. The optimized structures of the monovalent metal complexes demonstrate the flexibility of the ionophore, allowing the coordination of one or two water ligands in SalM-W1 and SalM-W2, respectively. The metal cations are responsible for the inner coordination sphere geometry, with coordination numbers spread between 2 (Au+), 4 (Li+ and Cu+), 5/6 (Na+, K+, Ag+), 6/7 (Rb+) and 7/8 (Cs+). The metals' affinity to salinomycin in low-polarity media follows the order of Li+ > Cu+ > Na+ > K+ > Au+ > Ag+ > Rb+ > Cs+, whereas some derangement takes place in high-dielectric environment: Li+ ≥ Na+ > K+ > Cu+ > Au+ > Ag+ > Rb+ > Cs+.

Factors governing the competition between group IA and IB cations for monensin A: a DFT/PCM study.

The affinity of monensin A to bind monovalent metal cations was evaluated by means of density functional theory (DFT) combined with polarizable continuum model (PCM) computations. The effect of various factors on complex formation between the monensinate A anion and group IA and IB metal ions was assessed. Competition between Na+ taken as a reference and monovalent metal cations was estimated using the Gibbs free energy for substituting the ligand-bound Na+ with its rival ions in the process [M+-solution] + [Mon-Na+] → [Mon-M+] + [Na+-solution] (M+ = Li+, K+, Rb+, Cs+, Cu+, Ag+ and Au+). The calculations revealed that the decrease in size of the cations accompanied by an increase of their accepting ability enhances the metal selectivity towards ligand donor atoms. In the gas-phase the affinity of monensinate A decreases in the order Cu+ > Li+ > Na+ > Au+ > Ag+ > K+ > Rb+ > Cs+. The complex formation can be manipulated by changing the solvent used. The polyether ionophore selectively binds Na+ ions in polar solvents but could become Li+ or Cu+-selective in low-polarity solvents.

A case of 5F-ADB / FUB-AMB abuse: Drug-induced or drug-related death?

Synthetic cannabinoids (SCs) belong to the group of new psychoactive substances (NPS) which appear sprayed on herbal mixtures on the "street" drug market and are intended for smoking like marijuana. In the present report we discuss a fatal case of 18-years-old boy, who had smoked SCs since several months and an overuse of SCs during last 48 h of his life has been apprised. The autopsy findings revealed acute respiratory distress syndrome (ARDS). Both toxicological analysis of deceased blood and urine samples and chemical analysis of the herbal mixture seized revealed presence of two SCs - 5F-ADB and FUB-AMB. The amount of 5F-ADB in blood was found to be 3.7 ng/mL by standard addition method. Severe and irreversible morphology changes in lung specimen, leading to ischemic damage of all internal organs and tissues, were observed during histological examination. The present case can be discussed as an example of both drug-induced and drug-related death resulting from acute intoxication with 5F-ADB and FUB-AMB as well as from systematic use of both synthetic cannabinoids.

Circular Dichroism is Sensitive to Monovalent Cation Binding in Monensin Complexes.

Monensin is a natural antibiotic that exhibits high affinity to certain metal ions. In order to explore its potential in coordination chemistry, circular dichroism (CD) spectra of monensic acid A (MonH) and its derivatives containing monovalent cations (Li(+) , Na(+) , K(+) , Rb(+) , Ag(+) , and Et4 N(+) ) in methanolic solutions were measured and compared to computational models. Whereas the conventional CD spectroscopy allowed recording of the transitions down to 192 nm, synchrotron radiation circular dichroism (SRCD) revealed other bands in the 178-192 nm wavelength range. CD signs and intensities significantly varied in the studied compounds, in spite of their similar crystal structure. Computational modeling based on the Density Functional Theory (DFT) and continuum solvent model suggests that the solid state monensin structure is largely conserved in the solutions as well. Time-dependent Density Functional Theory (TDDFT) simulations did not allow band-to-band comparison with experimental spectra due to their limited precision, but indicated that the spectral changes were caused by a combination of minor conformational changes upon the monovalent cation binding and a direct involvement of the metal electrons in monensin electronic transitions. Both the experiment and simulations thus show that the CD spectra of monensin complexes are very sensitive to the captured ions and can be used for their discrimination. Chirality 28:420-428, 2016. © 2016 Wiley Periodicals, Inc.

Lowering of cholesterol bioaccessibility and serum concentrations by saponins: in vitro and in vivo studies.

Using an in vitro digestion model, we studied the effect of six saponin extracts on the bioaccessibility of cholesterol and saturated fatty acids (SFAs). In the absence of saponins, around 78% of the available cholesterol was solubilized in the simulated intestinal fluids. The addition of two extracts, Quillaja Dry (QD) and Sapindin (SAP), was found to decrease cholesterol bioaccessibility to 19% and 44%, respectively. For both extracts, the main mechanism of this effect is the displacement of cholesterol molecules from the bile salt micelles, leading to formation of cholesterol precipitates that cannot pass through the mucus layer of the intestine. QD decreased strongly the SFA bioaccessibility as well, from 69 to 9%, due to formation of calcium-SFA precipitates, while SAP had no effect on SFA. We studied the in vivo activity of QD and SAP extracts by measuring serum cholesterol in mice fed with experimental diets within a 7-day period. Both extracts were found to prevent dietary hypercholesterolemia in mice fed on a cholesterol-rich diet. The other saponin extracts did not show any significant effect in vitro and, therefore, were not studied in vivo. The cholesterol lowering ability of Sapindin extract is reported for the first time in the current study.

Pd(II) complexes of acetylcholinesterase reactivator obidoxime.

The ability of the acetylcholinesterase reactivator obidoxime (H2L(2+)) to bind palladium(II) cations was evaluated spectrophotometrically at different reaction conditions (pH, reaction time, metal-to-ligand molar ratio). The results showed that immediately after mixing the reagents, pH 7.4, complex species of composition [PdHL](3+) existed predominantly with a value of conditional stability constant lgß'=6.52. The reaction was completed within 24 hours affording the formation of species [Pd2L](4+) with significantly increased stability (lgß'=9.34). The spectral data suggest that obidoxime coordinates metal(II) ions through the oximate functional groups. The in vitro reactivation assay of paraoxon-inhibited rat brain acetylcholinesterase revealed that the new complex species were much less active than the non-coordinated obidoxime. The lack of reactivation ability could be explained by the considerable stability of complexes in solution as well as by the deprotonation of oxime groups essential for recovery of the enzymatic activity.

Hemolytic activity and platelet aggregation inhibitory effect of vipoxin's basic sPLA2 subunit.

In the present study we evaluated the effect of secreted phospholipase A2 (sPLA2) (the toxic subunit of the heterodimeric neurotoxin vipoxin, isolated from the Bulgarian long-nosed viper Vipera ammodytes meridionalis) on hemolysis, erythrocyte morphology and platelet aggregation. Hemolytic activity of sPLA2 was examined in the presence of saturated (palmitic) and unsaturated (oleic) fatty acids and it was found that oleic acid increased the hemolytic activity of sPLA2 in a concentration-dependent manner, compared to the effect of palmitic acid and controls. The addition of heparin to red blood cells (RBC) suspension containing sPLA2 or mixture of sPLA2 and the corresponding fatty acid led to an inhibition of hemolytic activity. The effect of sPLA2 on RBC morphology resulted in formation of echinocytes (spherocyte subtype), suggesting that RBC could be the possible targets attacked by sPLA2. Vipoxin sPLA2 inhibited (in a dose-dependent manner) platelet aggregation when arachidonic acid and collagen were used as inducers, while in the case of ADP its inhibitory effect was inappreciable.

Cd(II) and Pb(II) complexes of the polyether ionophorous antibiotic salinomycin.

BACKGROUND: The natural polyether ionophorous antibiotics are used for the treatment of coccidiosis in poultry and ruminants. They are effective agents against infections caused by Gram-positive microorganisms. On the other hand, it was found that some of these compounds selectively bind lead(II) ions in in vivo experiments, despite so far no Pb(II)-containing compounds of defined composition have been isolated and characterized. To assess the potential of polyether ionophores as possible antidotes in the agriculture, a detailed study on their in vitro complexation with toxic metal ions is required. In the present paper we report for the first time the preparation and the structure elucidation of salinomycin complexes with ions of cadmium(II) and lead(II). RESULTS: New metal(II) complexes of the polyether ionophorous antibiotic salinomycin with Cd(II) and Pb(II) ions were prepared and structurally characterized by IR, FAB-MS and NMR techniques. The spectroscopic information and elemental analysis data reveal that sodium salinomycin (SalNa) undergoes a reaction with heavy metal(II) ions to form [Cd(Sal)2(H2O)2] (1) and [Pb(Sal)(NO3)] (2), respectively. Abstraction of sodium ions from the cavity of the antibiotic is occurring during the complexation reaction. Salinomycin coordinates with cadmium(II) ions as a bidentate monoanionic ligand through the deprotonated carboxylic moiety and one of the hydroxyl groups to yield 1. Two salinomycin anions occupy the equatorial plane of the Cd(II) center, while two water molecules take the axial positions of the inner coordination sphere of the metal(II) cation. Complex 2 consists of monoanionic salinomycin acting in polydentate coordination mode in a molar ratio of 1: 1 to the metal ion with one nitrate ion for charge compensation. CONCLUSION: The formation of the salinomycin heavy metal(II) complexes indicates a possible antidote activity of the ligand in case of chronic/acute intoxications likely to occur in the stock farming.

First solid state alkaline-earth complexes of monensic acid A (MonH): crystal structure of [M(Mon)2(H (2)O)2] (M = Mg, Ca), spectral properties and cytotoxicity against aerobic Gram-positive bacteria.

Alkaline-earth metal complexes of the monoanionic form of the polyether ionophore monensin A were isolated for the first time in solid state and were structurally characterized using various spectroscopic methods (IR, NMR, FAB-MS). The stoichiometric reaction of monensic acid (MonH) with M(2+) (M = Mg, Ca) in the presence of an organic base leads to the formation of mononuclear complexes of composition [M(Mon)(2)(H(2)O)(2)]. The structures of magnesium (1) and calcium (2) monensin complexes in the solid state were established by single crystal X-ray crystallography. The complexes crystallize as [Mg(Mon)(2)(H(2)O)(2)]x5MeCN (1) and [Ca(Mon)(2)(H(2)O)(2)]xH(2)Ox5MeCN (2) in the monoclinic P21 space group. The alkaline-earth metal ion is placed in a distorted octahedral environment, defined by two monensin anions acting as bidentate ligands in the equatorial plane of the complex as well as by two water molecules occupying the axial positions of the inner coordination sphere. The bactericidal activity of 1 and 2 was evaluated against aerobic Gram-positive microorganisms applying the double layer agar hole diffusion method.

Crystal structure and properties of the copper(II) complex of sodium monensin A.

The preparation and structural characterization of a new copper(II) complex of the polyether ionophorous antibiotic sodium monensin A (MonNa) are described. Sodium monensin A binds Cu(II) to produce a heterometallic complex of composition [Cu(MonNa)(2)Cl(2)].H(2)O, 1. The crystallographic data of 1 show that the complex crystallizes in monoclinic space group C2 with Cu(II) ion adopting a distorted square-planar geometry. Copper(II) coordinates two anionic sodium monensin ligands and two chloride anions producing a neutral compound. The sodium ion remains in the inner cavity of the ligand retaining its sixfold coordination with oxygen atoms. Replacement of crystallization water by acetonitrile is observed in the crystal structure of the complex 1. Copper(I) salt of the methyl ester of MonNa, 2, was identified by X-ray crystallography as a side product of the reaction of MonNa with Cu(II). Compound 2, [Me-MonNa][H-MonNa][CuCl(2)]Cl, crystallizes in monoclinic space group C2 with the same coordination pattern of the sodium cation but contains a chlorocuprate(I) counter [CuCl(2)](-), which is linear and not coordinated by sodium monensin A. The antibacterial and antioxidant properties as two independent activities of 1 were studied. Compound 1 is effective against aerobic Gram(+)-microorganisms Bacillus subtilis, Bacillus mycoides and Sarcina lutea. Complex 1 shows SOD-like activity comparable with that of the copper(II) ion.

First divalent metal complexes of the polyether ionophore Monensin A: X-Ray structures of [Co(Mon)2(H2O)2] and [Mn(Mon)2(H2O)2] and their bactericidal properties.

The complexation of carboxylic acid Monensin A (MonH, 1a) with CoCl2.6H2O and MnCl2.4H2O leads to the formation of mononuclear complexes [Co(Mon)2(H2O)2], 2a and [Mn(Mon)2(H2O)2], 2b, respectively. The unique crystal structures of 2a and 2b were determined by X-ray crystallography. The complexes crystallize in the monoclinic space group P2 1 with an octahedrally coordinated transition metal center forming the crystallographically centrosymmetric chromophore CoO6 or MnO6, respectively. Two molecules of Monensin A act bidentately through their carboxylate moiety and a hydroxyl group, and two water molecules are additionally trans-coordinated. Although the transition metal ions are not bound into the cavity of the ligand, the unusual bidentate coordination mode of the ionophore induces its "pseudo-cyclization" forming 22-membered cycles further stabilized by a number of H-bonds. The complexes are the first example of divalent metal complexes of the monovalent polyether ionophore. The parallel study on the complexation ability of the potassium complex of Monensin A (MonK, 1b) towards Co(II) and Mn(II) showed the formation of the isostructural complexes 2a and 2b accompanied by loss of the potassium ion due to the new coordination mode of the ligand. The biological tests performed with the antibiotic MonH and the corresponding metal(II) complexes show greatly enhanced antimicrobial activity of complexes 2a-b against Gram(+)-bacteria.

Synthesis, structure and antimicrobial activity of manganese(II) and cobalt(II) complexes of the polyether ionophore antibiotic Sodium Monensin A.

Mononuclear neutral manganese(II) and cobalt(II) complexes with the antibiotic Sodium Monensin A (Mon-Na, 1b) were synthesized and characterized. The crystal structures of M(Mon-Na)2Cl2.H2O (M=Mn, 2; M=Co, 3) were determined by X-ray crystallography. The complexes crystallize in monoclinic space group C2 with a tetrahedrally coordinated transition metal attached to oxygen atoms of deprotonated carboxyl groups of two Sodium Monensin molecules and two chloride ions. The sodium ion remains in the cavity of the ligand and cannot be replaced by Mn(II) or Co(II). The complexes were additionally characterized by different spectroscopic techniques (UV-Visible, EPR, FAB-MS). A preferable octahedral environment around the transition metal centers is observed in polar solvents while the complexes retain their tetrahedral structure in non-polar media. The antimicrobial activity of 1b, 2 and 3 was tested against Gram(+) and Gram(-) bacteria.

Copper(II) complexes of the beta-blocker pindolol: properties, structure, biological activity.

The complex formation between copper(II) and the antihypertensive drug pindolol (HPin) was studied both in aqueous and methanolic media. Two complexes are formed at different metal-to-ligand molar ratios. The mononuclear complex Cu(Pin)2(HPin)2 contains two ligands in an anionic bidentate form and two--in a neutral form bound monodentately. The second complex Cu2Pin2Cl2 is dinuclear and its structure was determined by X-ray diffraction. The compound crystallizes in the monoclinic group C2/c with cell components a = 14.4998(13)A, b = 18.511(2)A, c = 14.2982(13)A, alpha = 90 degrees, beta = 109.556(2) degrees, gamma = 90 degrees and Z = 12 at 293K. A pharmacological study on the influence of pindolol and its mononuclear complex on the heart rate of rats was performed. The complex is more active and has a longer effect in comparison with the pure non-coordinated pindolol in equitoxic doses.