Živadin D. Bugarčić

Mechanistic studies on the reactions of platinum(II) complexes with nitrogen- and sulfur-donor biomolecules

A brief overview of mechanistic studies on the reactions of different Pt(II) complexes with nitrogen- and sulfur-donor biomolecules is presented. The first part describes the results obtained for substitution reactions of mono-functional Pt(II) complexes with different biomolecules, under various experimental conditions (temperature, pH and ionic strength). In addition, an overview of the results obtained for the substitution reactions of bi-functional Pt(II) complexes, analogous to cisplatin, with biomolecules is given. The last part of this report deals with different polynuclear Pt(II) complexes and their substitution behaviour with different biomolecules. The purpose of this perspective is to improve the understanding of the mechanism of action of Pt(II) complexes as potential anti-tumour drugs in the human body.

Kinetic and mechanistic study on the reactions of [Pt(bpma)(H2O)]2+ and [Pd(bpma)(H2O)]2+ with some nucleophiles. Crystal structure of [Pd(bpma)(py)](ClO4)2

Substitution reactions of the complexes [Pd(bpma)(H2O)]2+ and [Pt(bpma)(H2O)]2+, where bpma = bis(2-pyridylmethyl)amine, with TU, DMTU and TMTU for both complexes and Cl-, Br-, I- and SCN- for the platinum complex, were studied in aqueous 0.10 M NaClO4 at pH 2.5 using a variable-temperature stopped-flow spectrophotometer. The pKa value for the coordinated water molecule in [Pd(bpma)(H2O)]2+ (6.67) is a unit higher than that of [Pt(bpma)(H2O)]2+. The observed pseudo-first-order rate constants k(obs) (s(-1)) obeyed the equation k(obs) = k2[Nu] (Nu = nucleophile). The second-order rate constants indicate that the Pd(II) complex is a factor of 10(3) more reactive than Pt(II) complex. The nucleophile reactivity attributed to the steric hindrance in case of TMTU and the inductive effect for DMTU was found to be DMTU > TU > TMTU for [Pt(bpma)(H2O)]2+ and DMTU approximately TU > TMTU for [Pd(bpma)(H2O)]2+. The trend for ionic nucleophile was I- > SCN- > Br- > Cl-, an order linked to their polarizability and the softness or hardness of the metal. Activation parameters were determined for all reactions and the negative entropies of activation (Delta S++) support an associative ligand substitution mechanism. The X-ray crystal structure of [Pd(bpma)(py)](ClO4)2 was determined; it belongs to the triclinic space group P1 and has one formula unit in the unit cell. The unit cell dimensions are a = 8.522(2), b = 8.627(2), c = 16.730(4) A; alpha = 89.20(2), beta = 81.03(2), gamma = 60.61(2) degrees ; V = 1055.7(5) A3. The structure was solved using direct methods in WinGXs implementation of SHELXS-97 and refined to R = 0.054. The coordination geometry of [Pd(bpma)(py)]2+ is distorted square-planar. The Pd-N(central) bond distance, 1.996(3) A, is shorter than the other two Pd-N distances, 2.017(3) and 2.019(3) A. The Pd-N(pyridine) distance is 2.037(3) A.

Kinetics and mechanism of the reactions of Pd(II) complexes with azoles and diazines. Crystal structure of [Pd(bpma)(H2O)](ClO4)2·2H2O

Substitution reactions of the complexes [Pd(bpma)(H2O)]2+, [Pd(bpma)Cl]+, [Pd(dien)(H2O)]2+ and [Pd(dien)Cl]+, where bpma = bis(2-pyridylmethyl)amine and dien = diethylentriamine or 1,5-diamino-3-azapentane, with some nitrogen-donor ligands such as triazole, pyrazole, pyrimidine, pyrazine and pyridazine, were studied in an aqueous 0.10 M NaClO4 at pH 2.8 using variable-temperature and -pressure stopped-flow spectrophotometry. The second-order rate constants indicate that the Pd(II) complexes of bpma, viz. [Pd(bpma)(H2O)]2+ and [Pd(bpma)Cl]+, are more reactive than the complexes of dien, viz. [Pd(dien)(H2O)]2+ and [Pd(dien)Cl]+. Also, the aqua complexes, [Pd(bpma)(H2O)]2+ and [Pd(dien)(H2O)]2+, are much more reactive than the corresponding chloro complexes. The most reactive nucleophile of the five-membered rings is triazole and for the six-membered rings the most reactive one is pyridazine. Activation parameters were determined for all reactions and the negative entropies and volumes of activation (Delta S++, Delta V++) support an associative ligand substitution mechanism. The crystal structure of [Pd(bpma)(H2O)](ClO4)2.2H2O was determined by X-ray diffraction. Crystals are monoclinic with the space group P2(1)/c. The coordination geometry of [Pd(bpma)(H2O)]2+ is distorted square-planar. The Pd-N (central) bond distance, 1.958(5) A, is shorter than the other two Pd-N distances, 2.007(5) and 2.009(5) A. The Pd-O distance is 2.043(5) A.

Platinum, palladium, gold and ruthenium complexes as anticancer agents: Current clinical uses, cytotoxicity studies and future perspectives

Metallodrugs offer potential for unique mechanism of drug action based on the choice of the metal, its oxidation state, the types and number of coordinated ligands and the coordination geometry. This review illustrates notable recent progress in the field of medicinal bioinorganic chemistry as many new approaches to the design of innovative metal-based anticancer drugs are emerging. Current research addressing the problems associated with platinum drugs has focused on other metal-based therapeutics that have different modes of action and on prodrug and targeting strategies in an effort to diminish the side-effects of cisplatin chemotherapy. Examples of metal compounds and chelating agents currently in clinical use, clinical trials or preclinical development are highlighted.

Hydrolysis of [Pt(dien)H2O]2+ and [Pd(dien)H2O]2+ complexes in water

The hydrolysis of the [Pt(dien)H2O]2+ and [Pd(dien)H2O]2+ complexes has been investigated by potentiometry at 298 K, in 0.1 mol dm−3 aqueous NaClO4. Least-squares treatment of the data obtained indicates the formation of mononuclear and μ-hydroxo-bridged dinuclear complexes with stability constants: log β11 = −6.94 for [Pt(dien)OH]+, log β11 = −7.16 for [Pd(dien)OH]+, and also log β22 = −9.37 for [Pt2(dien)2(OH)2]2+ and log β22 = −10.56 for [Pd2(dien)2(OH)2]2+. At pH values > 5.5, formation of the dimer becomes significant for the PtII complex, and at pH > 6.5 for the PdII complex. These results have been analyzed in relation to the antitumor activity of PtII complexes.

Hydrolysis of the palladium(II) ion in a sodium chloride medium

SummaryThe hydrolysis of the palladium(II) ion in a sodium chloride medium was studied by the e.m.f. method at 25 °C. The data show that the extent of the palladium hydrolysis depends upon the concentration of both palladium and sodium chloride medium. Thus, at a definite pH, the extent of the hydrolysis increases with increasing concentration of palladium, but decreases with increasing concentration of sodium chloride. The stability constants of the complexes obtained, PdOH+ and Pd4(OH)44+, also differ slightly depending upon the concentraton of sodium chloride. The observed medium effect is in agreement with the linear free energy relationship proposed for the metal ion hydrolysis.

Influence of sodium dodecyl sulfate on the kinetics of complex formation between [PdCl(dien)]+ and sulfur containing ligands l-cysteine and glutathione

Abstract The effect of sodium dodecyl sulfate (SDS) micelles on the kinetics of the complex formation between [PdCl(dien)]+ and sulfur containing ligands l -cysteine and glutathione (GSH) was investigated by using the stopped-flow technique under pseudo-first order conditions (ligand in excess) in the acidity range from pH 1 to 6. The presence of anionic micelles induced the acceleration of the complex formation in the entire acidity range with the maxima corresponding to the first protolytic constant of the ligands. This effect was interpreted in terms of the attractive electrostatic interaction between reacting species and the micellar surface and their effective concentration in the vicinity of micelles. An increase of the ionic strength leads to a decrease of the rate of complex formation in the presence of anionic micelles due to competition of reactive species with cations originating from inert salt for the micellar surface. The calculation of activation parameters revealed that the entropy of activation is strongly negative in the presence and in the absence of micelles, which is compatible with an associative reaction mechanism.

Growth Effects of Some Platinum(II) Complexes with Sulfur-Containing Carrier Ligands on MCF7 Human Breast Cancer Cell Line upon Simultaneous Administration with Taxol

The platinum (II)complexes, cis-[PtCl2(CH3SCH2CH2SCH3)] (Pt1), cis-[PtCl2(dmso)2] (dmso is dimethylsulfoxide; Pt2) and cis-[PtCl2(NH3)2] (cisplatin), and taxol (T) have been tested at different equimolar concentrations. Cells were exposed to complexes for 2 h and left to recover in fresh medium for 24, 48 or 72 h. Growth inhibition was measured by tetrazolium WST1 assay Analyses of the cell cycle, and apoptosis were performed by flow cytometry, at the same exposure times. The IC50 value of each platinum(II) complex as well as combination index (CI; platinum(II) complex + taxol) for various cytotoxicity levels were determined by median effects analysis. MCF7 cells were found to be sensitive to both Pt1 and Pt2 complexe These cisplatin analogues influenced the cell growth more effectively as compared to cisplatin. Cytotoxic effect was concentration and time-dependent. Profound growth inhibitory effect was observed for Pt1 complex, across all its concentrations at all recovery periods. A plateau effect was achieved three days after treatment at Pt1 concentrations ≤ 1 μM. Pt2, however, decreased MCF7 cells survival only for the first 24 h ranging between 50-55%. Pt2 cytotoxicity sharply decreased thereafter, approaching 2 h - treatment cytotoxicity level. The median IC50 values for Pt1 and Pt2 were similar (0.337 and 0.3051 μM, respectively) but only for the first 24 h. The IC50 values for Pt1 strongly depend on the recovery period. On simultaneos exposure of cells to taxol and platinum(II) complexes no consistent effect was found. The Cls for combinations of taxol with Pt1 or Pt2 revealed cytotoxic effects that were in most Cases synergistic (Pt1) or less than addtiive (Pt2). Flow cytometry analysis has shown that each platinum(II) complex induced apoptosis in MCF7 cells. The level of apoptosis correlated with cytotoxicity level for the range concentrations. Both cisplatin analogues, at IC50 concentrations, increased the number of MCF7 cells in G0G1 phase of cell cycle. Pt2-treated cells remained arrested in G0G1 phase up to 72 h after treatment. Combination of Pt2 and taxol caused further arrest of cells in G0G1 phase (24 h) in parallel with strong decrement of G2M phase cells.

Classification of stacking interaction geometries of terpyridyl square-planar complexes in crystal structures

Stacking interactions of terpyridyl square-planar complexes in crystal structures were studied analyzing data from the Cambridge Structural Database. In most of the crystal structures, two terpyridyl complexes were oriented “head-to-tail” or “head-to-head”, with “head-to-tail orientation” being most prevalent. The number of structures with other orientations was very small. Based on the analysis of interacting geometries, we classified overlaps of terpyridyl complexes into six types. The types were defined by values of several geometrical parameters and all interactions of the same type had very similar overlap patterns.

Kinetics and mechanism of the reaction of chelated Pd(II) complexes with thiols in acidic aqueous solution. Synthesis and crystal structure of [Pd(bpma)Cl]Cl·H2O (bpma = bis(2-pyridylmethyl)amine)

The kinetics of the complex-formation reactions between monofunctional palladium(II) complexes [Pd(N–N–N)H2O]2+, where N–N–N is 2,2′:6′,2″-terpyridine (terpy), diethylenetriamine (dien) or bis(2-pyridylmethyl)amine (bpma), with L-cysteine, DL-penicillamine and glutathione, have been studied in an aqueous 0.10 M perchloric acid medium using variable-temperature and -pressure stopped-flow spectrophotometry. Second-order rate constants, k1298, varied between 2.8 × 102 and 4.4 × 104 M−1 s−1. The highest reactivity was observed for the [Pd(terpy)H2O]2+ complex, whereas glutathione is the strongest nucleophile. Activation volumes for these reactions varied between −5.6 ± 0.3 and −10.7 ± 1.0 cm3 mol−1. The negative entropies and volumes of activation support a strong contribution from bond making in the transition state of the substitution process. The crystal structure of [Pd(bpma)Cl]Cl·H2O has been determined by X-ray diffraction at 190 K. Crystals are triclinic with space group P and consist of distorted square-planar [Pd(bpma)Cl]+ cations. The Pd–N distances are all equal to 2.005(7) A. The Pd–Cl distance is 2.305(3) A.