Olga Semenova

Reversion of Structure-Activity Relationships of Antitumor Platinum Complexes by Acetoxime but Not Hydroxylamine Ligands

The presence of cis-configured exchangeable ligands has long been considered a prerequisite for antitumor activity of platinum complexes, but over the past few years, several examples violating this structure-activity relationship have been recognized. We report here on studies with the geometric isomers of [PtCl2(acetoxime)2], cis-[dichlorobis(acetoxime)platinum(II)] [1 (cis)] and trans-[dichlorobis(acetoxime)platinum(II)] [2 (trans)], as well as those of [PtCl2(hydroxylamine)2], cis-[dichlorobis(hydroxylamine)platinum(II)] [3 (cis)] and trans-[dichlorobis(hydroxylamine)platinum(II)] [4 (trans)]. We found that 2 (trans)is 16 times more cytotoxic than 1 (cis) and as cytotoxic as cisplatin in cisplatin-sensitive ovarian carcinoma cells (CH1). Moreover, 2 (trans) is 15 times more cytotoxic than either cisplatin or 1 (cis) in intrinsically cisplatin-resistant colon carcinoma cells (SW480). Thus, compound 2 (trans) represents a novel type of active platinum(II) complexes of the trans geometry, whereas the hydroxylamine-containing complexes conform to the classic structure-activity relationships. The reactivity of the compounds toward dGMP and DNA and their capacity to alter the structure of double-stranded DNA and form interstrand cross-links were studied by capillary electrophoresis and gel electrophoresis. The slow binding of 2 (trans) to dGMP (τ½ = 50 h versus 8.9 h in the case of cisplatin), the low reactivity toward DNA, the comparatively small impact on DNA secondary structure, and the lack of detectable interstrand cross-linking suggest a mode of action fundamentally different from that of cisplatin. Implications of our findings for the minimal structural requirements (e.g., planarity around the nitrogen donor atom and/or ramified aliphatic moiety attached to the latter) of active trans-configured platinum complexes are discussed.

Capillary zone electrophoresis of lanthanoid elements after complexation with aminopolycarboxylic acids

Capillary zone electrophoresis was applied to the separation of the lanthanoid elements chelated with aminopolycarboxylic acids. Several aminopolycarboxylic reagents (ethylenediaminetetraacetic acid and chemically similar analogues) were varied in an effort to optimize the separation resolution. By varying the pH and concentration of the electrophoretic buffer, it was also possible to manipulate the migration times, efficiency and detectability. Optimum resolution and analysis time (within 12 min) for lanthanoids(III), and also scandium(III) and yttrium(III), was achieved with cyclohexane-1,2-diaminetetraacetic acid (CDTA) and simple electrolytes such as a borate buffer (20 mmol l–1, pH 11.0) containing 1 mmol l–1 CDTA. Determination of the lanthanoid complexes was performed by direct UV detection at 214 nm. The calibration graphs were linear (r > 0.99) over at least two orders of magnitude of concentration. The detection limits were at the mid-ppb level and the relative standard deviation was about 2.8% at the mid-calibration range. The method appeared to be feasible to determining the lanthanoid elements in nuclear fuel waste, and may be also recommended for assessing lanthanoid impurities in nuclear fuel.

Energetics of point defect formation in Ni3Al

Abstract Vacancy and anti-site defect formation energies in L1 2 -ordered Ni 3 Al are calculated by ab initio approaches. Based on a statistical-thermodynamic model the thermodynamic activities of both components are derived as a function of temperature and composition. Comparison with measured activities demonstrates the high reliability of the ab initio approach to defect formation.

A Statistical-Thermodynamic Model for Intermetallic Phases with L12-Structure and Its Application to the Compound Ni3Al

A statistical-thermodynamic model for binary nonstoichiometric L1 2 -phases has been developed based on a mean-field approximation. Vacancies and anti-structure atoms are allowed on both sublattices as possible point defects, and the expressions for the defect concentrations as functions of composition and temperature have been derived. From these the compositional variation of the thermodynamic activities of the two components can be calculated using energies of formation of the four types of point defects as parameters. The model equations are applied to the intermetallic compound Ni 3 Al using defect formation energies from the literature, and the corresponding curves are compared with experimental aluminum activities at 1400 and 1600 K. As it turns out, one particular set of energy parameters (Debiaggi et al., 1996) gives clearly the best agreement, resulting in very low vacancy concentrations (of the order of 10- to 10 -9 ). Thus the thermal disorder and the deviation from stoichiometry in Ni 3 Al is in principle caused entirely by anti-structure atoms. Their concentrations (referred to the total number of lattice sites) at the exactly stoichiometric composition are found to be 0.0075 at 1400 K, i.e. 3% of the At-sites are occupied by Ni-atoms and 1% of the Ni-sites by At-atoms. It is argued that this combination of statistical thermodynamics and experimental activity data permits an assessment of the reliability of the theoretically derived values of the defect formation energies in non-stoichiometric phases.

Improved photometric detection of metal ions by capillary zone electrophoresis after precapillary complexation

Abstract Precapillary reactions using complexing reagents are increasingly being used to carry out separations of metal ions by capillary zone electrophoresis. To compensate for the sensitivity limitations of on-column photometric detection, several approaches were evaluated. Parameters affecting the sensitivity response of a direct detection system, such as the detection wavelength, sample size, applied voltage, and electrolyte concentration, were examined to produce the best possible sensitivity for metal ions complexed with cyclohexane-1,2-diaminetetraacetic acid. Using injection in the electrokinetic mode, a 2-fold increase in detectability over hydrodynamic (gravity) injection was obtained for certain metal analytes that corresponds to the detection limits in the sub-μg/l range. A characterization and optimization of photometric detection in an indirect format have been conducted. An organic dye, combined with the carrier electrolyte to impart an absorbance background in the visible range and selected with due account for its spectral and electrophoretic characteristics, was found to provide micromolar-level sensitivities. Feasibility of on-line (stacking) sample concentration for metal complexes has also been demonstrated.

Migration behavior of metal complexes in capillary zone electrophoresis: Interpretation in terms of quantitative structure–mobility relationships

Significant advances in metal ion analysis by capillary zone electrophoresis (CZE) have occurred as a consequence of using metal complexes with various organic and inorganic ligands. Metal-ligand complexes that contribute to metal speciation in solution have also gained the attention of researchers. An understanding of the molecular properties that control the separation and further insight into the migration mechanism call for a systematic analysis of relationships between migration parameters and charge and size characteristics of metal complexes. To perform such an investigation, a number multiparametric migration models derived from a generally valid equation for electrophoretic mobility as a function of charge density were developed. The models operating with tabular or readily calculated structural descriptors (in particular, metal atom electronegativity or effective charge) as well as with the formal charge and ligand number were evaluated using numerous sets of experimental migration data for inorganic and organic ligand complexes. Consistent--in a great many instances--approximation results confirm the separation mechanism for metal complexes in CZE as governed basically by differences in charge-to-size parameters, present a valuable and convincing selection of such parameters, possessing a definite physical meaning, and owing to the general validity of the multivariate regression approach, open new possibilities in its application to more complex (i.e., electrokinetic chromatographic) systems.

Estimation of point defect formation energies in the D019-type intermetallic compound Ti3Al

Abstract A statistical-thermodynamic model for binary nonstoichiometric intermetallic A 3 B compounds with D0 19 -structure was developed based on a mean-field approximation. Vacancies and anti-structure atoms are allowed on the two sublattices as possible point defects. Due to the identical stoichiometry and the analogous coordination around A and B atoms it turned out that the same approach is valid as for A 3 B compounds with L1 2 -structure, and identical expressions were obtained, both for the concentrations of the different point defects and for the thermodynamic activities. The energies of formation of the four types of point defects were used as parameters. The model equations were applied to the intermetallic compound Ti 3 Al using experimental aluminum activities from the literature. By a simple curve fitting procedure the following defect formation energies were obtained: E f (V Ti )= E f (V Al )=1.5 eV, and E f (Ti Al )= E f (Al Ti )=0.6 eV. This results in very low vacancy concentrations which means that the thermal disorder and the deviation from stoichiometry in Ti 3 Al is caused almost entirely by anti-structure atoms. Their concentrations (referred to the total number of lattice sites) are found to be about 0.0009 at 1123 K, i.e., 0.12% of the Ti sites are occupied by Al atoms and 0.36% of the Al sites by Ti atoms.

Intermetallic phases with D03-structure: a statistical-thermodynamic model☆

Abstract A statistical-thermodynamic model for binary non-stoichiometric D0 3 -phases has been developed based on a mean-field approximation. The corresponding D0 3 crystal lattice is divided into three sublattices, the α-, β- and γ-sublattices, where A-atoms occupy the α- and γ-sublattices, and B-atoms occupy the β-sublattice in the perfectly ordered case. Neglecting interstitial defects, all other possible point defects, i.e. anti-structure atoms and vacancies on all three sublattices are considered. Based on a grand-canonical approach the expressions for the defect concentrations are derived as functions of composition and temperature, and from these the thermodynamic activities of the two components can be calculated using energies of formation of the six types of point defects as parameters. The model equations are applied to the two intermetallic phases Fe 3 Al (at 500 K) and Ni 3 Sb (at 1200 K).

Quantitative structure-mobility relationship modelling of electrokinetic chromatography of metal complexes: approaches and limitations.

A charged surfactant or an ionic polymer added to the capillary electrolyte introduces micellar solubilization and ion‐exchange interactions, respectively, as a supplementary separation principle for metal complexes among a great many other analytes. Acting as a pseudostationary phase, such electrolyte additives make the separation mechanism fairly different from that based only on differences in electrophoretic mobility. A range of quantitative structure‐mobility relationships were developed to explain the migration behavior of metal complexes in micellar and ion‐exchange electrokinetic chromatographic systems as a function of their primary structural parameters. The validity of migration models tested using a comprehensive selection of experimental data available in the literature was shown to depend significantly on the judicious choosing of the analyte structural descriptors and on the dominance of either of the electrophoretic mobility of the analyte, partitioning into the micelle, and the ion‐exchange interaction with the polymer. In the systems where the separation mechanism is dominated by neither chromatography nor electrophoresis, their relative contributions were accounted for by the degree of correlation between experimental and calculated mobilities and by variations in the absolute value and sign of regression coefficients at the most influencing parameters.

Quasi chemical and defect correlation models for intermetallic compounds with B2-structure: new applications

A generalized, quantitative, and predictive statistical-thermodynamic model is proposed employing a quasi-chemical argument for description of thermodynamic behavior and ordering phenomena in B2 ordered binary intermetallic materials. A modified procedure is given for the application of the Bethe-Guggenheim QC method which takes into account the presence of all possible defects in the structure, both vacancies and anti-structure atoms. Interactions between nearest-neighbor atoms result in correlations between their arrangements in the crystal lattice. The QC method which can be regarded as the simplest form of the cluster variation method takes these correlations into consideration by describing the formation of point defect pairs and assuming random distribution of these point defect pairs. The results are compared with those obtained by the defect correlation model, a simple Ising-type model which is, however, able to describe defect clusters formed by two, three or even more atoms or vacancies in non-frustrated crystal lattices like the B2 structure. Both modeling approaches were applied for description of thermodynamic activities and vacancy concentrations over composition range and temperature in non-stoichiometric B2 ordered intermetallic compounds with triple-defect mechanism (PdIn, NiGa, and CoGa), as well as with substitutional (anti-structure) defect mechanism (FeCo, NiZn, AgMg). The (hypothetical) critical temperatures of the order–disorder transformations were derived from the model calculations. Comparison with a wealth of experimental data provided in the literature confirms the viability of these simple models.