Biljana Petrović

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.

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.

Binding of Platinum(II) to Some Biologicaly Important Thiols.

The reactions between [Pt(terpy)Cl+ and thiols, such as glutathione, L-cysteine, D-penicillamine and thioglycolic acid have been Studied by conventional UV-VIS spectrophotometry and H NMR spectroscopy. The second-ordero rate constants, K2, are similar for these four thiols, varying between 1.06 x 10-2 and 6.10 x 10+3 M-1 s-1 at 25°C. The activation entropies have large negative values between -100 and -200 J mol-1 which are compatible with an associative A mechanism. However, L-methionine, as thioether ligand, is unreactive under the same experimental conditions. The obtained results have been analyzed in relation to the antitumor activity and toxicity of platinum(II) complexes.

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.

Kinetic and Mechanistic Study on the Reactions of [Pd(dien)H2O]2+ and [Pt(dien)H2O]2+ with L-Cysteine and S-Methyl-L-cysteine

The reactions of [Pd(dien)H2O]2+ and [Pt(dien)H2O]2+ (dien = diethylenetriamine or 1,5-diamino-3-azapentane) with l-cysteine and S-methyl-l-cysteine were studied in an aqueous 0.10 M NaClO4 solution using stopped-flow and conventional UV-vis spectrophotometry. The second-order rate constants for the reactions of [Pd(dien)H2O]2+ at pH 1.0 are k1298 = (9.11 ± 0.11) × 102 M−1 s−1 for l-cysteine, and k1298 = (33.79 ± 0.63) × 102 M−1 s−1 for S-methyl-l-cysteine. The second-order rate constants for the reactions of [Pt(dien)H2O]2+ at pH 1.0 with l-cysteine is k1298 = (1.28 ± 0.08) × 10−2 M−1 s−1 and for S-methyl-l-cysteine is k1298 = (3.87 ± 0.02) × 10−2 M−1 s−1. Activation parameters were determined for all reactions, and the negative values of entropy of activation support an associative complex formation mechanism. Substitution reactions were also studied at pH 0.5, 1.0, and 1.5. The rate constants increase with increase in pH. These results are discussed in terms of protolitic equilibrium.

KINETICS AND MECHANISM OF COMPLEX FORMATION BETWEEN [PtCl(DIEN)]+ AND THIOLS AND THIOETHERS

Abstract Reactions of the monofunctional platinum(II) complex, [PtCl(dien)]+, with different thiols and thioethers, including biologically important molecules, have been studied as a function of temperature (288.2–308.2K) using conventional electronic spectrophotometry in 0.10 M aqueous hydrochloric acid and by 1H NMR spectroscopy. The second-order rate constants, k2, are similar, varying between 1.43 × 10−3 and 46.1 × 10−3 M−1s−1 at 25°C. The reactivity follows the sequences: D-penicillamine ≤ L-cysteine ≤ glutathione ≤ thiodiglycolic acid ≤ thioglycolic acid ≤ L-methionine ≤ S-methylthioglycolic acid ≤ glycyl-D,L-methionine. However, variation in size, bulkiness and solvation of the entering ligands reflect in their properties as nucleophiles. Large negative values of the entropy of activation (ΔS≠), between −140 and −190 J K−1 mol−1, indicate that all thiols and thioethers react via the same associative mechanism. Results have been analyzed in relation to the antitumor activity and toxicity of platinum(II) complexes.

UV-Vis, HPLC, and 1H-NMR studies of the substitution reactions of some Pt(IV) complexes with 5′-GMP and L-histidine

Substitution reactions of [PtCl4(en)] and [PtCl4(dach)] with guanosine-5′-monophosphate (5′-GMP) and L-histidine were studied by different experimental methods. By UV-Vis spectrophotometry, these reactions were investigated under pseudo-first-order conditions at 310 K in 25 mmol Hepes buffer (pH = 7.2) and 10 mmol NaCl to prevent the hydrolysis of the complexes. [PtCl4(en)] reacts slightly faster than the [PtCl4(dach)]. Also, L-histidine is a better nucleophile than 5′-GMP. Final 1H-HMR spectra of the substitution of Pt(IV) were in a good agreement with the spectra of Pt(II) complexes with the same nucleophiles, confirming the assumption of the reduction of Pt(IV) complexes during substitution. The same reactions were studied by high-performance liquid chromatography comparing the chromatograms during the reaction. The changes in the intensity of signals and their retention time show that at the end of substitution, there is only one dominant product in the system. We conclude that substitution of these Pt(IV) complexes is followed by rapid reductive elimination and final product is substituted Pt(II) complex.

Effects of cisplatin and other Pt(II) complexes on spontaneous motility of isolated human oviduct

The toxicity of platinum(II) ion could be significantly modified by coordination with some organic compounds. In our study, the cytotoxicity and the influence of platinum(II) complexes, such as cisplatin, cis-[PtCl(2)(NH(3))(2)], [PtCl(2)(SMC)] and [PtCl(2)(DMSO)(2)] (where SMC is S-methyl-l-cysteine and DMSO is dimethyl sulphoxide) on spontaneous motility of isolated human fallopian tubes were investigated. Cisplatin showed potent pro-apoptotic effects on peripheral blood mononuclear cells (PBMC). However, peripheral blood mononuclear cells were substantially less sensitive to [PtCl(2)(SMC)] and [PtCl(2)(DMSO)], and these compounds showed no toxic effect on PBMC in all concentrations examined. Cisplatin showed concentration-dependent inhibition of spontaneous contractions of the isolated ampulla. (EC(50)=1.14+/-0.03 x 10(-6)M/l, r=0.714, p<0.05) while [PtCl(2)(SMC)] and [PtCl(2)(DMSO)(2)] did not affect spontaneous contractions of isolated fallopian tube ampulla.

Kinetics and mechanism of the substitution reactions of some monofunctional Pd(II) complexes with different nitrogen-donor heterocycles

Substitution reactions of five monofunctional Pd(II) complexes, [Pd(terpy)Cl]+ (terpy = 2,2′;6′,2″-terpyridine), [Pd(bpma)Cl]+ (bpma = bis(2-pyridylmethyl)amine), [Pd(dien)Cl]+ (dien = diethylenetriamine or 1,5-diamino-3-azapentane), [Pd(Me4dien)Cl]+ (Me4dien = 1,1,7,7-tetramethyldiethylenetriamine), and [Pd(Et4dien)Cl]+ (Et4dien = 1,1,7,7-tetraethyldiethylenetriamine), with unsaturated N-heterocycles such as 3-amino-4-iodo-pyrazole (pzI), 5-amino-4-bromo-3-methyl-pyrazole (pzBr), 1,2,4-triazole, pyrazole, pyrazine, and imidazole were investigated in aqueous 0.10 M NaClO4 in the presence of 10 mM NaCl using variable-temperature stopped-flow spectrophotometry. The second-order rate constants k2 indicate that the reactivity of the Pd(II) complexes decrease in the order [Pd(terpy)Cl]+ > [Pd(bpma)Cl]+ > [Pd(dien)Cl]+ > [Pd(Me4dien)Cl]+ > [Pd(Et4dien)Cl]+. The most reactive nucleophile of the heterocycles is pyrazine, while the slowest reactivity is with pyrazole. Activation parameters were determined for all reactions and negative entropies of activation, ΔS≠, supporting an associative mode of substitution. The reactions between [Pd(bpma)Cl]+ and 1,2,4-triazole, pzI, and pzBr were also investigated by 1H NMR to define the manner of coordination. These results could be useful for better explanation of structure-reactivity relationships of Pd(II) complexes as well as for the prediction of potential targets of Pd(II) complexes toward common N-heterocycles, constituents of biomolecules and different N-bonding pharmaceutical agents. Substitution reactions of five monofunctional Pd(II) complexes with unsaturated N-heterocycles were investigated using variable-temperature stopped-flow spectrophotometry and 1H NMR. The results are useful for better explanation of structure-reactivity relationship of Pd(II) complexes as well as for prediction of potential targets of Pd(II) complexes toward common N-heterocycles, constituents of biomolecules and different N-bonding pharmaceutical agents.