Janina Kuduk-Jaworska

Calculation of lipophilicity for Pt(II) complexes: experimental comparison of several methods

ics: 21. CIC-Workshop Meeting abstracts - A si ngle PDF containing all abstracts in this Supplement is available here . http://www. biomedcentral.co m/content/pdf/17 52-153X-2-S1-inf o.pdf

Malatoplatinum(II) complexes – carboplatin analogs

A series of new neutral dicarboxylatoplatinum(II) complexes, containing D(+), L(−) or DL-malate dianion and ethylenediamine, 1-ethylimidazole or 1-propylimidazole as amine ligands, have been synthesized and characterized by elemental analysis, t.l.c., conductance, i.r., n.m.r., mass spectra (m/z) and electronic spectra. The new cytotoxic malatoplatinum(II) complexes are very soluble in water and resist hydrolysis. Their reactivity against glutathione is comparable with the reactivity of carboplatin, which suggests that these new complexes may be promising candidates in the search for low toxicity platinum cytostatics.

Impact of K2PtCl4 on the structure of human serum albumin and its binding ability of heme and bilirubin

Absorption, CD, gel-filtration chromatography, and immunological tests were used to evaluate the interactions of K2PtCl4 with human serum albumin. Multidentate coordination of Pt(II) to HSA causes distinct variations in the protein conformation including a considerable decrease of the helical structure. The high excess of Pt(II) ions leads to dimerization of the protein. The metal ion binding weakness the interactions of HSA with other molecules like heme or bilirubin.

Dimethyl Sulfoxide Containing Platinum(II) and Palladium(II) Chelate Complexes of Glyoxylic and Pyruvic Acid Thiosemicarbazones. A New Class of Cytotoxic Metal Complexes

Abstract The complexes [Pt(DMSO)(GT)]·DMSO (1), [Pt(DMSO)(PT)]· 1/2 DMSO (2) and [Pd(DMSO)- (PT)] (3), where DMSO = dimethyl sulfoxide, H2GT = glyoxylic acid thiosemicarbazone and H2PT = pyruvic acid thiosemicarbazone, have been synthesized and characterized by elemental analysis, molar electric conductivity, IR, electronic and NMR (1H and 13C) spectra. The single crystal X-ray diffraction analysis has revealed for 1 (orthorhombic, Pnma, a = 12.941(3), b = 7.108(2), c = 15.148(3) Å , Z = 4) that the doubly deprotonated thiosemicarbazone molecule is coordinated to Pt(II) via the carboxylato O, azomethine N and thiolato S atoms forming two condensed fivemembered chelate rings. The fourth coordination site of Pt(II) is occupied by the S atom of DMSO. All the atoms of the complex molecule are coplanar except the methyl groups. The O atom of DMSO is in cis-position towards the thiolato-S atom (point group Cs). A system of hydrogen bonds of the type N-H· · ·O links the complex molecules between them and with the lattice DMSO molecules. Similar structures have been deduced for the remaining two complexes on the basis of spectroscopic data. The three complexes and the ligand H2GT exhibit cytotoxic activity against F4N leukemia cells, whereas the ligand H2PT is inactive.

Antiproliferative activity in vitro of new malatoplatinum(ll) complexes.

The results of studies on antiproliferative activity in vitro of nine new platinum(II) complexes against cells of eight human and six murine neoplastic cell lines are described. New complexes with the anionic rest originating from enantiomeric forms of hydroxydicarboxylic malic acid were synthesized to obtain agents with increased water solubility and decreased toxicity. Three compounds, coded 1-3, with ethylenediamine as a neutral ligand, showed cytotoxic activity against 12 out of 14 target cell lines. Their cytotoxic activity was similar or even slightly higher than that of the reference carboplatin. The remaining six compounds, coded 4-9, with 1-alkylimidazole as a neutral ligand, revealed rather low cytotoxic activity, and only against the cells of the human bladder cancer cell line Hu1703He, ovarian cancer cell line OAW-42 and mouse leukemia P388. Most of them appeared to be negative against all other cell lines. No compounds, including reference carboplatin, showed any cytotoxicity against the cells of the T47D human breast cancer cell line or B16F-10 mouse melanoma cell line. The results obtained are in accordance with common opinion, i.e. that the presence of neutral amine ligands with NH groups is required for the cytotoxic activity of platinum complexes. Compounds with a primary amine (ethylenediamine) showed higher cytotoxic activity in vitro than complexes with a tertiary amine (1-alkylimidazole).

Non-empirical quantum chemical studies on electron transfer reactions in trans- and cis-diamminedichloroplatinum(II) complexes

The search was made for theoretical confirmation of hypothesis that mechanism of cisplatin cytotoxicity is based on dissociative electron transfer (ET) processes. Applying quantum chemical calculations based on supermolecular approach, the reactions mimicking presumed steps of cisplatin activation were evaluated. The electronic structure of model systems: cis- and transplatin with free electrons, hydrated electrons, and water, was studied by using density functional (DFT) within the Huzinaga basis set and GAUSSIAN-09 package. The respective energy was evaluated with the use of B3LYP density hybrid functional. The calculations were performed for gas phase and water solution; the solvent effects were studied by using the polarizable continuum model. Analysis of the energetic and structural parameters of cisplatin vs. transplatin behavior in the model systems leads to conclusion: there are two possible ways of cisplatin biotransformation, hydrolysis and hydrated electron impact, dependent on the medium redox state.

Immunomodulating polysaccharide fractions of Menyanthes trifoliata L.

Abstract Looking for new plant sources of immunomodulating agents polysaccharide-rich fractions (PS) from Menyanthes trifoliata L. (Menyanthaceae) have been isolated. The herb of Menyanthes trifoliata L. was sequentially extracted with water, 0.1 м NaOH, 8% CH3COOH, and 1 м NaOH. After dialysis and resolution on Biogel P-10 four homogenic (B-4, B-5, C-4, D-5) and two nonhomogenic (A-3 and D-4) PS were isolated. About 0.5% of PS over 3500 Da were found in the dry plant material. They were characterized through chemical analysis, NMR and vibrational spectroscopy. Speciation analysis of chosen metal/metaloid elements was performed and an exceptionally high concentration of Se was found in PS of a pure water extract (A-3). The biological tests on the immunomodulating influence with human blood-derived lymphocytes and granulocytes revealed that two fractions, B-4 and B-5, were strong stimulators of immune cells, whereas fractions D-5 and A-3 were found as potent suppressive and anti-inflammatory agents. The applied isolation procedures led to the separation of active compounds into stimulatory and inhibitory fractions.

Platinum(II) complexes with D-glucosamine and its derivatives

Abstract Neutral and (or) ionic platinum(II) complexes of D-glucosamine, 1,3,4,6-tetra- O -acetyl-D-glucosamine and p -metoxybenzylidene- N -1,3,4,6-tetra-O-acetyl-D- glucosimine were prepared and characterized by chemical analyses, conductance measurements, and vibrational spectroscopy (IR and far-IR). The reactions of PtCl 4 2− with monodentate Schiff base yield complexes of the related aminosugar, indicating the hydrolysis of the primary ligand.

Differential anti-proliferative properties of novel hydroxydicarboxylatoplatinum(II) complexes with high or low reactivity with thiols

We have examined the anti-proliferative effect of 13 recently synthesised platinum dicarboxylate complexes, very similar in their chemical, structural and kinetic properties to carboplatin. We used the L5178Y model: two murine lymphoma sublines, which differ in nucleotide excision repair ability and hence, in sensitivity to those platinum complexes that react with DNA. The anti-proliferative effect of the examined compounds mainly depends on the kind of amine ligand. Complexes with the primary amine (ethylenediamine) are more effective than complexes containing the tertiary amine (1-alkylimidazole). The ethylenediaminemalatoplatinum(II) complexes show a differential in vitro anti-proliferative activity in the L5178Y model; hence, it may be expected that they inflict DNA lesions that are repaired by the nucleotide excision system. The cytotoxicity of these complexes is directly correlated with reactivity with glutathione (GSH). The 1-alkylimidazole complexes are of low toxicity and moderate to low reactivity with GSH; in contrast to the ethylenediaminemalatoplatinum(II) complexes, their cytotoxicity is inversely correlated with reactivity with GSH. Two of the 1-alkylimidazole complexes, bis(1-ethylimidazole)(L-malato)platinum(II) and bis(1-propylimidazole (L-malato)platinum(II), show a considerable ability to arrest cells in G2 phase. We expect that the properties of these two groups of platinum complexes may be exploited in combined platinum complex treatment and irradiation.

In silico approach to cisplatin toxicity. Quantum chemical studies on platinum(II)–cysteine systems

The behaviour of cisplatin in serum, and the drastic differences between the properties of this drug and its trans-isomer were the main motivations for this work. In a search for model “thiol–platin(II)” interactions, the first steps of the following reaction systems were evaluated: (1) cisplatin–thiomethanol; (2) transplatin–thiomethanol; (3) cisplatin–cysteine; and (4) transplatin–cysteine. In each case, calculations for the associative mode of reactions were performed. The electronic structure of these molecular systems was studied at the non-empirical all-electron level using density functional theory (DFT) within the Huzinaga and WTBS basis sets including polarisation Gaussian functions and full geometry optimisation. B3LYP or EPBO density functionals were applied throughout. The calculated molecular electrostatic potentials are presented graphically. Assuming that electrostatic effects are dominant, cisplatin should interact more strongly with the sulfur atom of CH3S− and deprotonated CYS-S− than transplatin. This fact has been documented in the supermolecule model of the relevant interaction energies in both gas phase as well as within the solvent polarisable continuum model. The opposite relationship was observed when we compared values of energy differences between products and substrates for both isomers. The data obtained here could be applied to search for correlation between the biological activity of platinum complexes and their properties as estimated by various physico-chemical and in silico methodologies.