Antiviral activity of platinum (II) and palladium (II) complexes of pyridine-2-carbaldehyde thiosemicarbazone.

A heterocyclic compound, pyridine-2-carbaldehyde thiosemicarbazone (HFoTsc), and its six metal coordinated bound complexes, three with platinum (II) and three with palladium (II), were studied for their activity against herpes simplex virus 1 (HSV-1) infection in cultured cells. According to their cytotoxicity the compounds were divided into two groups. Group I (cytotoxic compounds) included all three palladium complexes and [Pt(HFoTsc)2] Cl2, with maximum non-toxic concentration (MNC) of 1-10 micromol/l and a 50% cytotoxic concentration (CC50) of 20-100 micromol/l. Group 2 (low cytotoxic compounds) with MNC of 100 micromol/l and CC50 of 548-5820 micromol/l included compounds in the following order: [Pt(HFoTsc)2] Cl2相似文献   

Synthesis,characterisation and antitumour activity of platinum(II) complexes of novel functionalised poly(amido amine)s

Polyamidoamine polymers were prepared by hydrogen-transfer polyaddition of 2-methylpiperazine to 2,2′-bis(acrylamido)acetic acid sodium salt to yield PAA-1, polyaddition of amino-β-cyclodextrin and 2-methylpiperazine to 2,2′-bis(acrylamido)acetic acid to give PAA-2 and polyaddition of the same amino-β-cyclodextrin and 2-methylpiperazine to 1,4-bis(acryloyl)piperazine to produce PAA-3. These polymers were reacted with cisplatin to give products containing between 8–70 wt.-% platinum. The amount of platinum released from the conjugates during incubation at pH 5.5 and pH 7.4 varied between 0–20%/72 h. PAA-3-Pt showed pH-dependent platinum release. The PAA-platinates were generally less toxic towards lung tumour cell lines in vitro. The IC₅₀ for cisplatin being 2–5 μg/mL and for the PAA-platinates 1–130 μg/mL, this was only to be expected due to their very different cellular pharmacokinetics. In vivo experiments showed that the PAA-1-Pt and PAA-2-Pt were equi-active compared with cisplatin against an i.p. L1210 leukaemia model, confirming their ability to liberate biologically active platinum species. Whereas PAA-1-Pt was significantly less toxic than cisplatin, PAA-2-Pt did show toxicity on repeated dosing, suggesting further investigations are needed to establish the biocompatibility of PAAs containing pendant β-cyclodextrin. PAA-1-Pt is suitable for further in vivo preclinical study in a range of solid tumour models.     

Formation and properties of poly-L(DL)-lysine-copper(II) complexes

Water-soluble poly-L -lysine- and poly-DL -lysine-copper(II) complexes were prepared in aqueous alkaline solutions. The complex-formations of poly-L -lysine and poly-DL -lysine with cupric ions in aqueous solutions were studied with pH titration and electronic spectroscopy and measurements of optical rotatory dispersion, circular dichroism and solution viscosity. From the results it was revealed that the poly-L -lysine forms two kinds of complexes, being formed on the degree of neutralization α < 0.5 and > 0.5, respectively. The former complex consists of a cupric ion coordinated with four amino nitrogen atoms of the side chains. Some extents of helical conformation of poly-L -lysine are held after the complex formation with cupric ions at a pH over 10. The results on the poly-L -lysine-copper(II) complexes were compared with those on the poly-DL -lysine-copper(II) complexes.     

Interaction of Epstein-Barr virus DNA polymerase with aphidicolin, phosphonoformate and 5'-GMP

Epstein-Barr virus (EBV)-specified DNA polymerase was purified from P3HR-1 cells, a Burkitt lymphoma EBV producer cell line, treated with phorbol-12,13-dibutyrate (PDB) and n-butyrate. Its inhibition by aphidicolin, phosphonoformate (PFA) and 5'-GMP was examined. Aphidicolin could inhibit EBV DNA polymerase competitively with respect to dATP and dCTP and noncompetitively with respect to dGTP and dTTP; whereas 5'-GMP was a noncompetitive inhibitor with respect to all four dNTPs. Combinations of aphidicolin and PFA, or PFA and 5'-GMP, produced a mutually exclusive inhibition pattern of EBV DNA polymerase that suggested that the binding sites of these compounds on the enzyme molecule are kinetically overlapping.     

The use of polymeric platinum(IV) prodrugs to deliver multinuclear platinum(II) drugs with reduced systemic toxicity and enhanced antitumor efficacy

Two dinuclear platinum(IV) prodrugs were prepared from cisplatin and oxaliplatin, and tethered to amphiphilic biodegradable block copolymers. The polymeric dinuclear platinum(IV) prodrugs were allowed to self-assemble into nanomicelles, which showed reduced systemic toxicity, relatively long blood circulation, and enhanced antitumor efficacy. In this way, the bottleneck of present multinuclear platinum drugs, especially their severe systemic toxicity, might be overcome.     

Synthesis and cytotoxic activity of dextran carrying cis-dichloro(cyclohexane-trans-l-1,2-diamine)platinum(II) complex

cis-Dichloro(cyclohexane-trans-l-1,2-diamine)platinum(II) (Dach-Pt(chlorato)), is a platinum complex which is expected to exhibit higher antitumor activity than, and show no cross resistance with, cisplatin. However, its strong side-effects and low water-solubility have also been cited. We report that polymer/ antitumor drug conjugates shows reduced side-effects and high antitumor activity. In order to provide a macromolecular prodrug of Dach-Pt having reduced side-effects and high water-solubility, we synthesized polymer conjugates of Dach-Pt and dextran derivatives having carboxylic acid groups, oxidized-dextran (OX-Dex)/Dach-Pt conjugate, and carboxymethyl-dextran(CM-Dex)/Dach-Pt conjugate. The cytotoxic activities of the conjugates were investigated against p388D₁ lymphocytic leukemia cells in vitro. The OX-Dex/Dach-Pt conjugate showed almost the same level of cytotoxic activity as free Dach-Pt(chlorato). Although the cytotoxic activity of free Dach-Pt(chlorato) was decreased by incubation in medium with serum, the OX-Dex/Dach-Pt conjugate kept its cytotoxic activity in higher level after 24 h incubation in medium with serum. These results suggested that the stability of Dach-Pt molecule in the medium was increased and cytotoxic activity of Dach-Pt was not decreased by fixing to OX-Dex.     

Interaction of polystyryl radical with copper(II) complexes

The polymerization of styrene initiated by 2,2′-azoisobutyronitrile (AIBN) was studied in N,N-dimethylformamide (DMF) solution at 60°C in the presence of tetrakis(N,N-dimethylformamide)copper(II) perchlorate, and also in the presence of its monoazido copper(II) complex [Cu(DMF)₃N₃]⁺. The monoazido complex in DMF was prepared in situ by mixing solid sodium azide with tetrakis(N,N-dimethylformamide)copper(II) perchlorate in a mole ratio of 1:1. The nature of the complex was established by Job's method. The equilibrium constant K for the reaction [Cu(DMF)₄]²⁺ + N ? [Cu(DMF)₃N₃]⁺ + DMF determined by the limiting logarithmic method was found to be 1,25 · 10⁴l · mol^?1. The presence of [Cu(DMF)₄]²⁺ ions in the polymerization systems caused retardation, but [Cu(DMF)₃N₃]⁺ ions produced well defined induction periods. The rate constants at 60°C for the interaction of polystyryl radical towards [Cu(DMF)₄]²⁺ and [Cu(DMF)₃N₃]⁺ ions were calculated to be 6,6 · 10² and 5,74 · 10⁴ l · mol^?1 · s^?1, respectively.     

Electrostatic effect on electron-transfer reactions of cobalt(III)-poly(4-vinylpyridine) complexes

Reductions of cis-[Co(en)₂PVPCl]²⁺ ( 1 ) [PVP = poly(4-vinylpyridine)] by ferrous aquoions and ferrous chelate ions were studied. The rate of reduction by Fe²⁺ is small compared to that of the monomeric analogue, cis-chlorobis(ethylenediamine)pyridine cobalt(2⁺) (cis-[Co(en)₂PyCl]²⁺) due to the electrostatic repulsion. On the other hand, the reduction by [Fe-(edta)]^2? is accelerated by a factor of 20. With increasing degree of coordination the acceleration factor increases, and with increasing ionic strength the factor decreases. The acceleration was found to be due to the electrostatic attraction of the reductant by the polymer as a polycation. The electrostatic effect is discussed in comparison with the catalysis of polyelectrolytes in ionic reactions.     

Cellular pharmacology, antineoplastic activity and low in vivo toxicity of a carboxylato-bridged platinum(II) complex bis(acetato)diammine-bis-micro-acetato diplatinum (II) dihydrate

The dinuclear platinum complex bis(acetato)diammine-bis-micro-acetato diplatinum (II) dihydrate has been previously shown to exert profound cytotoxicity in diverse tumor cell lines, while being far less detrimental than the clinically applied platinum drugs against some susceptible to platinum toxicity non-malignant cellular populations. In the present study we report the investigation of the cellular accumulation kinetics and apoptosis induction of the dinuclear complex in K-562, its potent in vivo antineoplastic activity against L1210 leukemia and Lewis lung carcinoma tumor models and its lower nephrotoxicity, myelosuppressive potential and clastogenicity in vivo relative to cisplatin.     

Antimicrobial,insect sterilizing and ovicidal activity of some cobalt(II) and cobalt(III) complexes

Twenty-one mixed-ligand complexes of cobalt(II) and cobalt(III) have been screened for their antimicrobial, insect sterilizing and ovicidal activities. Three of these cobalt(III) complexes exhibit broad antimicrobial spectra, including against human bacterial pathogens, dermatophytes and plant pathogenic fungi, while one exhibits feeble activity against a human pathogenic bacterium. These results have been compared with the activity of the corresponding cobalt(II) complexes, which have been found to be inactive, while the free ligands show reduced activity compared with the cobalt(III) complexes. Change in biological activity induced by a particular complex appears to be dependent on the composition of the first co-ordination sphere. Two of these complexes showed 50% inhibition of the conidial germination ofHelminthosporium oryzae andAlternaria triticina. These results indicate their potential for use against human and plant pathogenic microbes. Minimum inhibitory concentrations of the cobalt(III) complexes were determined. Three of these cobalt(III) complexes have been tested for insect sterilizing and ovicidal activities onDysdercus koenigi F. Positive sterilizing and ovicidal actions of [Co(BSOP)(NH₃)₂]NO₃ (where BSOP—H₂ is the Schiff base derived from salicylaldehyde and orthophenylenediamine) were obtained. Possible mechanism(s) of all these activities are discussed qualitatively.To whom correspondence should be addressed.     

Effects of dinuclear berenil-platinum(II) complexes on fibroblasts redox status

PurposePlatinum(II) complex anticarcinogenic mechanisms are associated with changes in the cellular redox status of cancer as well as healthy cells. Therefore, the goal of the present study was to investigate oxidative modifications in cellular components following fibroblast exposure to novel dinuclear berenil-platinum(II) complexes.Material and MethodROS levels, antioxidant parameters level/activity, and damage to DNA, lipids, and proteins, including pro-apoptotic and anti-apoptotic factors in human skin fibroblasts following berenil-platinum(II) complex treatments i.e. Pt₂(isopropylamine)₄(berenil)₂, Pt₂(piperazine)₄(berenil)₄, Pt₂(2-picoline)₄(berenil)₂, Pt₂(3-picoline)₄(berenil)₂, and Pt₂(4-picoline)₄(berenil)₂ were examined.ResultsTreatment of fibroblasts with platinum(II) complexes has shown that all compounds enhance total ROS and superoxide anion generation as well as change the activity of antioxidant enzymes such as superoxide dismutase, catalase, glutathione peroxidase and glutathione reductase and decrease in the level of non-enzymatic antioxidants (GSH, vitamin C, E and A). Such a situation is conducive to oxidative stress formation and oxidative modifications of cellular macromolecules and to increase in the expression of proapoptotic proteins. Pt₂(isopropylamine)₄(berenil)₂ elicited the most damage, which resulted in oxidative modification of cellular components. The therapeutic use of this complex would cause considerable side effects in patients, therefore the agent lacks drug potential; however Pt₂(piperazine)₄(berenil)₂ and Pt₂(2-picoline)₄(berenil)₂ exhibited reduced redox and increased apoptotic profiles compared to cisplatin.ConclusionResults of this paper and preliminary data show that Pt2(2-picoline)4(berenil)2 is less dangers than cisplatin to fibroblasts and more disruptive than cisplatin to breast cancer cell metabolism, and therefore it is a promising candidate for use in future anticancer drug strategies.     

Synthesis and synergistic antifungal activities of a pyrazoline based ligand and its copper(II) and nickel(II) complexes with conventional antifungals

A pyrazoline based ligand; (5-(4-chlorophenyl)-3-phenyl-4, 5-dihydro-1H-pyrazole-1-carbothioamide) has been synthesized by Claisen-Schmidt condensation of acetophenone with p-chlorobenzaldehyde, followed by sodium hydroxide assisted cyclization of the resulting chalcone with thiosemicarbazide. Metal ion complexes of the synthesized ligand were prepared with Cu(II) and Ni(II) metal ions, separately and respectively. Ligand and the metal complexes were characterized by elemental analysis, FT-IR, UV-Vis, (1)HNMR, ESI-MS and (13)CNMR spectroscopic techniques. Molar conductance measurements in DMSO suggested non-electrolytic nature of the complexes. Tetragonally distorted octahedral geometry for copper and octahedral geometry for the nickel complexes was proposed on the basis of UV-Vis spectroscopic studies and magnetic moment measurements. The complexes were investigated for their ability to kill human fungal pathogen Candida by determining MICs (Minimum inhibitory concentrations), inhibition in solid media and ability to produce a possible synergism with conventional most clinically practiced antifungals by disc diffusion assay and FICI (fractional inhibitory concentration index).     

In vivo changes of heterogeneity of mouse peritoneal macrophages induced by cis-diamminedichloroplatinum (II) (cis-DDP) and related platinum compounds.

The s.c. injection of cis-DDP into ABD2F1 mice (8 mg/kg b.m.) resulted in alterations of size and surface structure of peritoneal macrophages (PM) and in a reduction of the mean number of Concanavalin A (ConA) binding sites of PM. The PM population of control mice which received physiological saline only consisted of 2 subgroups with a higher and a lower mean ConA binding site number per cell. Contrarily, PM of cis-DDP-treated mice failed the subpopulation with higher ConA binding site number. A loss of this subpopulation was also found in mice treated with platinum salt K2PtCl4 or K2PtCl6. X-ray microanalytically determined elemental contents of PM of control and treated mice showed a correlation between ConA binding site number and cellular concentration of phosphorus or sulphur with the exception of a small group of PM which was characterized by a high content of sulphur and a low number of ConA binding site. This correlation was not found in normal mice.     

NMR contact shifts and local conformation in poly(4-vinylpyridine N-oxide)-Ni(II) complexes

The ¹H and ¹³C NMR contact shifts induced by Ni²⁺ ions in aqueous solutions were used to elucidate the conformation of poly[1-(1-oxo-4-pyridyl)ethylene] ( 1 ) and of the model compound 1,3-bis(1-oxo-4-pyridyl)propane ( 2 ). The equilibrium position of the pyridine N-oxide ring relative to the adjacent methine or methylene group was deduced from the angular dependence of the hyperfine coupling of β-protons and -carbons, assuming a twofold potential energy for the rotation about the C⁴? N axis. In the case of 1 it could be shown that the dihedral angle between the plane H^β? C^α? C⁴ and the plane of the ring is 15±5°.     

Hydroquinone oxidation catalyzed by pyridine-Cu(II) complexes attached to polyorganosiloxanes

Cu(II) complexes of polyorganosiloxanes with pyridyl group in the side chains ( 1–6 ) were investigated as catalysts for hydroquinone oxidation. The catalytic oxidations followed Michaelis-Menten-like kinetics. The kinetic parameters were evaluated, and the greatest value of k₂/K_m is 119 dm³ · mol^?1 · s^?1 due to the large value of k₂ (0,262 s^?1) in methanol/water (vol. ratio 2/1) at 25°C. It has been shown that the main factors which influence the substrate-binding process are hydrophobicity, hydrogen bonding between functional groups in the side chains, conjugation and basicity of pyridine, and adsorption of substrate by amido groups. Large k₂ values were obtained in the present system due to flexibility and hydrophobicity of the siloxane backbone. Additionally, in the activation process, hydrogen bonding between amido groups, which is easily formed due to the flexibility of the polymer chains, should contribute to decrease both activation enthalpy and activation entropy.