Jaromír Vinklárek

Differences in Vanadocene Dichloride and Cisplatin Effect on MOLT-4 Leukemia and Human Peripheral Blood Mononuclear Cells

Modern chemotherapy is interested in developing new agents with high efficiency of treatment in low-dose medication strategies, lower side toxicity and stronger specificity to the tumor cells. Vanadocene dichloride (VDC) belongs to the group of the most promising metallocene antitumor agents; however, its mechanism of action and cytotoxicity profile are not fully understood. In this paper we assess cytotoxic effects of VDC in comparison to cisplatin using opposite prototype of cells; human peripheral blood mononuclear (PBMCs) cells and human acute lymphoblastic leukemia cell line (MOLT-4). Our findings showed cytotoxic effect of VDC on leukemia cells, but unfortunately on human peripheral blood mononuclear cells as well. VDC induces apoptosis in leukemia cells; the induction is, however, lower than that of cisplatin, and in contrary to cisplatin, VDC does not induce p53 up-regulation. Cytotoxic effect of VDC on leukemia cells is less pronounced than that of cisplatin and more pronounced in PBMCs than in MOLT-4 cells.

Behaviour of the Antitumor Agent Vanadocene Dichloride in Physiological and Therapeutic Media, Blood Plasma and Human Blood - An EPR Study.

By means of EPR spectroscopy the behaviour of the vanadocene dichloride (I), Cp2VCl2 (Cp=η5-C5H5), in various deoxygenated and non-deoxygenated physiological media and therapeutic solution as well as in blood plasma and stabilized human blood was studied. On the basis of measured values of isotropic spectroscopic splitting factor giso and isotropic hyperfine coupling constant Aiso, the vanadocene species, [Cp2V(H2O)Cl]+ (II; giso= 1.985, |Aiso| = 7.68 mT), [Cp2V(H2O)2]2+ (III; giso= 1.983, |Aiso| = 7.92 mT), [Cp2V(OH2 (IV; giso= 1.991, |Aiso| = 6.285 mT), [Cp2VCl(DMSO)]+ (V; giso= 1.985, |Aiso| = 7.69 mT), the vanadyl species [VO(DMSO)5]2+ (VI; giso= 1.964, |Aiso| = 10.78mT) and [VO(H2O)5]2+ (VII; giso= 1.955, |Aiso| = 11.56 mT) have been identified. From the measurements it follows that I does not react in its first coordination sphere with any component of a system used other than water and DMSO, resp. As to water-containing media, its behaviour is fully consistent with that of I in pure aqueous media. It was found the only vanadocene species present after application of the therapeutic solution of I into human blood to be IV not interacting in its first coordination sphere with any blood component.

Study of antitumor effect of selected vanadium and molybdenum organometallic complexes in human leukemic T-cells

This work describes cytotoxic effect of non-platinum metal-based compounds on the human T-leukemic cells with different p53 status (p53 wild-type MOLT-4 and p53-deficient Jurkat cells). The cytotoxic and apoptosis-inducing effect of the vanadium complex [(η(5)-C5H5)2V(5-NH2-phen)]OTf (V1) and molybdenum complex [(η(3)-C3H5)Mo(CO)2(phen)Cl] (Mo1) were studied using flow cytometry, spectrophotometry and Western blotting. We found that the cytotoxic effect of both tested complexes after 24 h is higher against the both examined cell lines than that of cis-platin (cis-DDP). At later investigated time intervals of 48 and 72 h, the cytotoxic effect of the cis-DDP increased but the values of the cytotoxicity of the tested V1 and Mo1 complexes remained unchanged, with the cytotoxicity of V1 comparable to that of cis-DDP. Furthermore we observed that the apoptotic process was induced by the activation of the caspases 9 (intrinsic pathway) and 8 (extrinsic pathway) in cells exposed to evaluated complexes. In case of the p53 wild-type MOLT-4 cells, the expression of the tumor-suppressor protein p53 and its form phosphorylated at the serine 15 increased after both V1 and Mo1 treatment, similar to the effect of cis-DDP.

Inclusion compounds of cystostatic active (C5H5)2VCl2 and (CH3C5H4)2VCl2 with α-, β- and γ-cyclodextrines: Synthesis, EPR study and microbiological behavior toward Escherichia coli

The inclusion of vanadocene dichloride (VDC) and 1,1′-dimethyl vanadocene dichloride (MeVDC) into cyclodextrines (α-CD, β-CD and γ-CD) was studied by EPR spectroscopy. It was found that VDC and MeVDC with β-CD and γ-CD form true inclusion compounds, but with α-CD, VDC and MeVDC gave only fine dispersion mixtures. The inclusion was validated by anisotropic EPR spectra of solid samples. In addition, the antimicrobial was validated by anisotropic EPR spectra of solid samples. In addition, the antimicrobial behavior (against E. coli) of each of the complexes was determined. It was established that not only did VDC and MeVDC cause elongation of E. coli, but also the new vanadocene inclusion complexes were effective in this regard.

Vanadocene complexes of amino acids containing secondary amino group: the first evidence of O,O-bonded carboxylic group to vanadocene(IV) moiety.

Reaction of vanadocene dichlorides (Cp(2)VCl(2) and (eta(5)-C(5)H(4)Me)(2)VCl(2)) with amino acids containing secondary amino groups gives three types of complexes: a) compounds with N,O-bonded amino acid, b) O-bonded amino acids and c) O,O-bonded amino acid. The complexes with N,O-bonded amino acid and O-bonded amino acids were observed in the case of l-proline and N-methylglycine (NMG). Reactions with N-phenylglycine (NPG) give O,O-chelates as the sole products. All three types of the complexes were characterized by spectroscopic methods. Structures of [(eta(5)-C(5)H(4)Me)(2)V(O-Pro)][BPh(4)], [Cp(2)V(O-Pro)(2)][PF(6)](2), [Cp(2)V(N,O-NMG)][BPh(4)].MeOH, [(eta(5)-C(5)H(4)Me)(2)V(N,O-NMG)][BPh(4)].MeOH, [Cp(2)V(O-NMG)(2)][Cl](2).2H(2)O, [(eta(5)-C(5)H(4)Me)(2)V(O-NMG)(2)][Cl](2).H(2)O and [(eta(5)-C(5)H(4)Me)(2)V(O,O-NPG)][BPh(4)] were determined by X-ray crystallography.

Stabilization of η3-indenyl compounds by sterically demanding N,N-chelating ligands in the molybdenum coordination sphere

A series of η3-indenyl molybdenum compounds [(η3-4,7-Me2C9H5)Mo(CO)2(N,NL)Cl] (N,NL = bpy, phen, pyma), isostructural with well-known η3-allyl compounds, was synthesized from the recently established halide synthon [{(η5-4,7-Me2C9H5)Mo(CO)2(μ-Cl)}2]. The low stability of the hexacoordinated η3-indenyl molybdenum species in solution has been overcome by a modification of the chelating ligand. Hence, the dissociation of the compounds bearing ligands with methyl groups beside nitrogen donor atoms (e.g. 6,6′-Me2-bpy, 2,9-Me2-phen; 2,9-Me2-4,7-Ph2-phen) is strongly disfavored due to the steric requirements of the substituents. The considerable discrimination of the pentacoordinated species enables the use of [(η5-4,7-Me2C9H5)Mo(CO)2(2,9-Me2-phen)][BF4] for the assembly of derivatives bearing other halides and pseudohalides in the coordination sphere of molybdenum. The current study further describes some other new indenyl complexes accessible from [{(η5-4,7-Me2C9H5)Mo(CO)2(μ-Cl)}2]. All structural types presented in this experimental study were supported by X-ray crystallographic data.

Drying activity of oxovanadium(IV) 2-ethylhexanoate in solvent-borne alkyd paints

Oxovanadium(IV) 2-ethylhexanoate was established as a new primary drier for alkyd-based paints. A series of experiments has demonstrated an excellent drying activity toward solvent-borne alkyd resins of different oil length at considerably lower metal concentration than optimal for commercial cobalt(II) 2-ethylhexanoate. The behavior in real paint was simulated on formulations bearing inhibitor of autooxidation. The detailed studies of the drying process have shown that the relatively slow initial step of autooxidation reaction, when compared with cobalt compounds, is compensated for by the absence of the induction times. Furthermore, the active oxovanadium(IV) species are not consumed during the drying processes as evidenced by EPR spectroscopic measurements.

Synthesis, characterization and structure of the Bis(methyl-cyclopentadienyl)vanadium(IV) carboxylates

The 1,1’-dimethylvanadocene dichloride ((C5H4CH3)2VCl2) reacts in aqueous solution with various carboxylic acids giving two different types of complexes. The 1,1’-dimethylvanadocene complexes of monocarboxylic acids (C5H4CH3)2V(OOCR)2 (R=H,CCl3, CF3, C6H5) contain two monodentate carboxylic ligands, whereas oxalic and malonic acids act as chelate compounds of the formula (C5H4CH3)2V(OOC-A-COO) (A=−, CH2). The structure of the (C5H4CH3)2 V(OOCCF3)2 complex was determined by single crystal X-ray diffraction analysis. The isotropic and anisotropic EPR spectra of all the complexes prepared were recorded. The obtained EPR parameter values were found to be in agreement with proposed structures.

Novel indenyl ligands bearing electron-withdrawing functional groups

A series of molybdenum complexes bearing new ligands is reported. The study covers a series of molybdenum compounds with the Z 5 -coordinated indenyl ligand substituted with acyl-, ester- and amide-functions. This portfolio was extended by adding one representative with a Z 3 -coordinated estersubstituted indenyl ligand. The functionalized indenes, necessary for the assembly, were prepared by convenient routes starting from inexpensive and readily available materials, enabling their production on a multigram scale. All structural types presented in this experimental study were supported by X-ray crystallographic data.

Titanocene(iii) pseudohalides: an ESR and structural study

A series of complexes of the type [Ti(′Cp)2Y] {′Cp = η5-C5H5 (Cp), η5-C5H4SiMe3 (SiCp), η5-1,3-C5H3(Me3Si)2 (Si2Cp); Y = Cl−, CN−, NCS−, NCSe−, dicyanamide (dca), tricyanomethanide (tcm) and 1,2,3,4-thiatriazol-5-thiolate (ttt)} were prepared and studied by ESR spectroscopy. Ring-substituted compounds [Ti(SiCp)2Cl], [Ti(Si2Cp)2Cl], [Ti(SiCp)2CN] and [Ti(Si2Cp)2CN] dissolved in coordinating solvents exist in an equilibrium with solvated species. The thiatriazolthiolate ligand in complexes [Ti(′Cp)2(ttt)] behaves as a S,N-chelator to yield a thermally unstable 4-membered chelate ring having the ESR signal with significant splitting due to coupling with one 14N nucleus. Solutions of [Ti(′Cp)2Y] (Y = NCS−, NCSe−, dca and tcm) readily dissolve the additional pseudohalide salt giving anionic species [Ti(′Cp)2Y2]− with a characteristic ESR pattern caused by super-hyperfine splitting by two 14N nuclei. Cyanide complexes dissolve additional KCN as well, but no coupling to ligand nuclei (neither 14N nor 13C) was observed. The frozen-solution ESR spectra of [Ti(Si2Cp)2Cl], [Ti(Si2Cp)2CN] and [Ti(′Cp)2Y] (Y = NCS−, NCSe− and ttt) are typical for monomeric species of rhombic symmetry. The remaining complexes form dimeric {[Ti(Cp)2Cl]2, [Ti(SiCp)2Cl]2, [Ti(′Cp)2dca]2, and [Ti(′Cp)2tcm]2} or trimeric {[Ti(SiCp)2CN]3} adducts under these conditions. The nuclearity of [Ti(Cp)2CN] cannot be accurately determined by ESR spectroscopy due to its poor solubility but the presence of species with a higher spin ground state was confirmed (similar to the case of the above-mentioned dimers and trimer) by the observation of formally forbidden half-field transition. The reported results of the crystal structure analysis of [Ti(SiCp)2Cl], [Ti(Cp)2tcm], [Ti(SiCp)2tcm], [Ti(SiCp)2dca], [Ti(SiCp)2CN], and [TiCp2(NCS)]2O corroborate the findings based on spectroscopic measurements.