I. F. Seregina

Inductively coupled plasma mass spectrometry for metallodrug development: albumin binding and serum distribution of cytotoxic cis- and trans-isomeric platinum(II) complexes.

Binding to plasma proteins is one of the major metabolic pathways of metallodrugs. In the case of platinum-based anticancer drugs, it is the interaction with serum albumin that affects most strongly their in vivo behavior. Since both the configuration, i.e. cis-trans-isomerism, and the nature of leaving groups have an effect on the reactivity of Pt(II) coordination compounds toward biomolecules, a set of cis- and trans-configured complexes with halide leaving groups (Cl(-), Br(-), and I(-)) and 2-propanone oxime as carrier ligands was chosen for this study. Binding experiments were performed both with albumin and human serum and the Pt content in ultrafiltrates was quantified using inductively coupled plasma mass spectrometry. In order to shed light on the binding mechanism, the albumin binding constant (KHSA) and the octanol-water partition coefficient (P) were experimentally determined and relationships between log KHSA and log P were explored. The correlation was found significant only for cis-configured platinum complexes (R(2)=0.997 and standard deviation=0.02), indicating a certain contribution of the nonspecific binding which is largely dominated by the lipophilicity of compounds. In contrast, for trans-complexes a specific molecular recognition element plays a significant role. The participation of albumin in drug distribution in blood serum was assessed using an equilibrium distribution model and by comparing the percentage binding in the albumin and serum-protein fractions. Irrespective of the compound polarity, albumin contributes from 85 to 100% to the overall binding in serum.

Investigation of the efficiency of the sample pretreatment stage for the determination of the Rare Earth Elements in rock samples by inductively coupled plasma mass spectrometry technique

Different methods of rock sample digestion for final analysis by ICP-MS technique are investigated. It is shown that only basic rocks can be quantitatively digested in a microwave (MW) field with the mixture of HF and HNO(3) acids at 210°C for 60 min. The addition of HCl and H(3)BO(3) provides complete digestion of andesites and some types of granites. Even at maximal temperature in the used MW oven of 210°C syenites, granodiorites and albitized granites are not digested. These types of rocks are not digested in a closed Teflon autoclave for 16 h and can be digested only by fusion with lithium metaborate. The reason for such behavior is discussed. To avoid problems with the introduction of heavily acidic solutions after fusion in ICP the solutions were diluted. To compensate the loss of sensitivity due to the dilution step the REEs (Rare Earth Elements) pre-concentration using aminocarboxylic Pol-DETATA (diethyltriaminetetraacetate) sorbent was tested. The developed scheme is validated by the analysis of a wide range of reference rock materials.

Determination of rare earth elements in rock samples by inductively coupled plasma mass-spectrometry after sorption preconcentration using Pol-DETATA sorbent.

Sorption preconcentration of rare earth elements prior to introduction in inductively coupled plasma mass spectrometry is developed. For the first time Pol-DETATA sorbent was used for REEs preconcentration after digestion of wide classes of rock samples. The developed technique is based on lithium metaborate fusion, preconcentration on Pol-DETATA sorbent, elution with nitric acid and flow-injection sample introduction to the ICP-MS spectrometer. The efficiency of REEs extraction from the resulting solutions in the presence of high amounts of iron is examined. 5-sulfosalicylic acid was used as a masking reagent. Flow-injection introduction of 50 μL of eluate obtained after desorption was used to avoid corrosion of the parts of the ICP-MS instrument due to high acidity of the eluate. The accuracy of the developed technique is checked by the analysis of the certified reference materials of rock samples. The REEs recoveries within 85-100% interval were attained for most REEs in tested reference materials.

Estimation of contamination of atmosphere of Moscow in winter

To establish the priority pollutants in the atmosphere of Moscow in winter 8 snow samples were collected along the perimeter (109 km) of the Moscow Ring Road. Mass spectrometry was used as an analytical tool to identify individual organic compounds (gas chromatography/mass spectrometry) and the most environmentally relevant chemical elements (inductively coupled plasma with mass spectrometric detection). As a result several hundred organic compounds belonging to various classes, including representatives of the list of priority pollutants of the USA Environmental Protection Agency were identified. Their levels as well as the levels of chemical elements were quantified. The importance of accurate mass measurements for the efficient structural elucidation and reliability of quantitative measurements has been demonstrated. The data obtained allow estimating atmospheric pollution in Moscow in the period between December and March and proposing a list of priority pollutants for the atmosphere of Moscow.

Detata-filters for metal preconcentration and multielement determination in natural waters

Abstract New sorption filters containing conformationally flexible aminc-carboxylic groups were proposed for preconcentration of metals. Quantitative recovery of metals was achieved in a dynamic regime at a solution flow rate up to 4 ml.min−1.cm−2 in a pH range 3–8 from solutions with high salt content and in the presence of natural complexing agents. The dynamic capacity of DETATA-filters of the heavy metals was investigated. XRF and ICP-AES methods of heavy metals determination after preconcentration on the filters were developed.

Selective Ruthenium Labeling of the Tryptophan Residue in the Bee Venom Peptide Melittin

Melittin is a membrane-active peptide from bee venom with promising antimicrobial and anticancer activity. Herein we report on a simple and selective method for labeling of the tryptophan residue in melittin by the organometallic fragment [(C5 H5 )Ru](+) in aqueous solution and in air. Ruthenium coordination does not disturb the secondary structure of the peptide (as verified by 2D NMR spectroscopy), but changes the pattern of its intermolecular interactions resulting in an 11-fold decrease of hemolytic activity. The high stability of the organometallic conjugate allowed the establishment of the biodistribution of the labeled melittin in mice by inductively coupled plasma MS analysis of ruthenium.

Metallomics for drug development: serum protein binding and analysis of an anticancer tris(8-quinolinolato)gallium(III) drug using inductively coupled plasma mass spectrometry.

The application of an inductively coupled plasma mass spectrometry (ICP-MS) assay for quantifying in vitro binding of a gallium-based anticancer drug, tris(8-quinolinolato)gallium(III), to serum albumin and transferrin and in human serum is described. The distribution of the drug between the protein-rich and protein-free fractions was assessed via ICP-MS measurement of total gallium in ultrafiltrates. Comparative kinetic studies revealed that the drug exhibits a different reactivity toward individual proteins. While the maximum possible binding to albumin (~10%) occurs practically immediately, interaction with transferrin has a step-like character and the equilibrium state (with more than 50% binding) is reached for about 48 h. Drug transformation into the bound form in serum, also very fast, results in almost quantitative binding (~95%). The relative affinity of protein-drug binding was characterized in terms of the association constants ranging from 10(3) to 10(4)M(-1). In order to further promote clinical testing of the gallium drug, the ICP-MS method was applied for direct quantification of gallium in human serum spiked with the drug. The detection limit for gallium was found to be as low as 20 ng L(-1). The repeatability was better than 8% (as RSD) and the achieved recoveries were in the range 99-103%.

Determination of gallium in biological fluids using inductively coupled plasma mass spectrometry

A procedure for the determination of gallium in biological fluids by inductively coupled plasma mass spectrometry was developed. The detection limits of gallium calculated from the 3s value were 60 ng/L for urine, 32 ng/L for a model solution of intestinal juice, and 50 ng/L for serum. The accuracy of the procedure was tested using a standard addition method. The nature of a background signal on the masses of gallium isotopes was studied with the use of a high-resolution mass spectrometer, and the background concentration of gallium in biological fluids was evaluated (5–7 ng/L). It was found that a background level in measurements performed on a quadrupole mass spectrometer depends on the interfering influence of polyatomic ions with close m/z ratios rather than on the background concentration of gallium. The procedure makes it possible to study the stability of pharmaceutical preparations based on gallium in biological media, their metabolism, and the excretion of preparations from the body.

Oxidative Dearomatization of 4,5,6,7-Tetrahydro-1H-indoles Obtained by Metal- and Solvent-Free Thermal 5-endo-dig Cyclization: The Route to Erythrina and Lycorine Alkaloids

A facile one-pot approach based on a thermally induced metal- and solvent-free 5-endo-dig cyclization reaction of the amino propargylic alcohols in combination with Dess-Martin periodinane-promoted oxidative dearomatization of 4,5,6,7-tetrahydroindole intermediates provides an efficient and robust access to 5,6-dihydro-1H-indol-2(4H)ones. Green, relatively mild and operationally simple characteristics of the synthetic sequence are the major advantages, which greatly amplify the developed methodology. The utility of obtained indolones as unified key precursors is demonstrated by the application of these products to the formal total syntheses of a whole pleiad of Erythrina- and Lycorine-type alkaloids, namely (±)-erysotramidine, (±)-erysotrine, (±)-erythravine, (±)-γ-lycorane, and abnormal erythrinanes (±)-coccoline and (±)-coccuvinine.

Sorbents with non-covalently immobilized β-diketones for preconcentration of rare earth elements

A comparison of the efficiency of sorbents obtained by different methods of non-covalent immobilization of β-diketones on some low-polar matrices with respect to extraction of rare earth elements (REEs) was carried out. It was shown that sorbents containing reagent amounts of 1-8mmol/g can be obtained by sorption of reagents on low-polar matrices from aqueous and aqueous-organic solutions, and the value for the maximum capacity of the sorbent correlates with the specific surface of the matrix. Similar sorbents were also prepared by impregnating the matrix with reagent. It was found out that, under the chosen conditions, sorbents modified by extracting reagent from the aqueous solutions are more stable and extract lanthanum with higher distribution coefficients than those obtained by impregnation. We have found conditions for quantitative extraction of REEs from seawater in the proposed preconcentration systems (pH 4.0, minicolumn dimensions 2×10mm, v=4ml/min). It was shown that all REE may be quantitatively recovered in both ways: on modified sorbents and as complexes with reagents on unmodified matrices. We have proposed a sorbent for lanthanum preconcentration from large volumes of water samples (500ml). The sorbent is stable in dynamic conditions and is based on hyper cross-linked polystyrene modified with 1-phenyl-3-methyl-4-benzoylpyrazol-5-one (PMBP). Desorption could be carried out with 1-2M HNO3. REEs were determined by ICP-MS, LODs achieved were in ng/l range.