ABSTRACT
The cytotoxicity and the antivirus activity of Pd(II) and Pt(II) complexes with pyridine-2-carbaldehyde thiosemicarbazone (HFoTsc) against HSV replication were evaluated on four HSV strains-two wt strains Victoria (HSV-1) and BJA (HSV-2) and two ACV(R) mutants with different tk gene mutations R-100 (TK(A), HSV-1) and PU (TK(N), HSV-2). The experiments were performed on continuous MDBK cells and four HSV 1 and HSV 2 strains were used, two sensitive to acyclovir and two resistant mutants. The five complexes of HFoTsc, [Pt(FoTsc)Cl], [Pt(FoTsc)(H(2)FoTsc)]Cl(2), [Pt(FoTsc)(2)], [Pd(FoTsc)(H(2)FoTsc)]Cl(2), and [Pd(FoTsc)(2)], were found to be effective inhibitors of HSV replication. The most promising, active, and selective anti-HSV agent was found to be complex [Pt(FoTsc)(H(2)FoTsc)]Cl(2). This complex could be useful in the treatment of HSV infections, since it is resistant to ACV mutants. PCR study of immediate early 300 bp ReIV Us1 region reveals that the complex [Pt(FoTsc)(H(2)FoTsc)]Cl(2) specifically suppressed wt HSV-1 genome 2 hours after the infection, not inducing apoptosis/necrosis on the 8 hours after virus infection. The target was found to be most probably the viral, instead of the host cell DNA.
ABSTRACT
The reaction of platinum(II) [Pt(II)] or palladium(II) [Pd(II)] with 2-acetyl pyridine 4N-ethyl thiosemicarbazone, HAc4Et (1) results in the complexes [Pt(Ac4Et)(2)] (2) and [Pd(Ac4Et)(2)] (3). In a panel of human tumor cell lines of different origins (breast, colon, and ovary cancers), and containing also cisplatin-refractory/resistant cell lines, the in vitro growth inhibitory effect of 1-3 was compared to that of cisplatin by using the sulforodamine B assay. After a 96-hour continuous treatment, both the thiosemicarbazone HAc4Et and the metal compounds [Pt(Ac4Et)(2)] and [Pd(Ac4Et)(2)] exhibit very remarkable growth inhibitory activities with mean IC(50) values of 0.9 nM (0.22-2.47 nM), 0.7 nM (0.15-2 nM) and 0.5 nM (0.17-1.02 nM), respectively. In contrast, cisplatin shows a markedly lower growth inhibitory potency, the mean IC(50) in the panel being 2.8 muM (0.2-8 muM). In addition to their major cell growth inhibitory potency, complexes 1-3 are characterized by a growth inhibitory profile different from that of cisplatin, being active towards cisplatin-refractory tumor cell lines. These findings, along with the ability of completely overcoming acquired cisplatin resistance from either multifocal or reduced uptake origin, confirm the antitumor potential of HAc4Et and support the hypothesis that both [Pt(Ac4Et)(2)] and [Pd(Ac4Et)(2)] complexes can be characterized by cellular pharmacological properties distinctly different from those of cisplatin.
Subject(s)
Antineoplastic Agents/pharmacology , Cisplatin/pharmacology , Organometallic Compounds/pharmacology , Thiosemicarbazones/pharmacology , Cell Line, Tumor , Cell Proliferation/drug effects , Drug Resistance, Neoplasm , Drug Screening Assays, Antitumor , Humans , Palladium/chemistry , Platinum/chemistry , Thiosemicarbazones/chemistryABSTRACT
An interesting series of new platinum complexes has been synthesized by the reaction of Na(2)PtCl(4) with 2-acetyl pyridine thiosemicarbazone, HAcTsc. The new complexes, [Pt(AcTsc)Cl], [Pt(HAcTsc)(2)]Cl(2) and [Pt(AcTsc)(2)], have been characterized by elemental analyses and spectroscopic studies. The crystal structure of the complex [Pt(AcTsc)Cl] has been solved by single-crystal X-ray diffraction. The anion of HAcTsc coordinates in a planar conformation to the central platinum(II) through the pyridyl N, azomethine N and thiolato S atoms. Double intermolecular hydrogen bonds (NH-Cl), pi-pi and weak Pt-Pt and Pt-pi contacts lead to aggregation and to a two-dimensional supramolecular assembly. The antibacterial and antifungal effect of the novel platinum(II) complexes and the related palladium(II) complexes, [Pd(AcTsc)Cl], [Pd(HAcTsc)(2)]Cl(2) and [Pd(AcTsc)(2)], were studied in vitro. The complexes were found to have a completely lethal effect on Gram+ bacteria, while the same complexes showed no bactericidal effect on Gram- bacteria. Additionally, the complexes [Pt(AcTsc)(2)] and [Pd(AcTsc)(2)] showed effective antifungal activity towards yeast. Among these compounds [33], the most effective in inducing antitumour and cytogenetic effects are the complexes [Pt(AcTsc)(2)] and [Pd(AcTsc)(2)] while the rest, display marginal cytogenetic and antitumour effects.
Subject(s)
Anti-Infective Agents/chemical synthesis , Anti-Infective Agents/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Organoplatinum Compounds/chemical synthesis , Organoplatinum Compounds/pharmacology , Thiosemicarbazones/chemical synthesis , Thiosemicarbazones/pharmacology , Anti-Bacterial Agents , Anti-Infective Agents/chemistry , Antifungal Agents/chemical synthesis , Antifungal Agents/chemistry , Antifungal Agents/pharmacology , Antineoplastic Agents/chemistry , Candida albicans/drug effects , Crystallography, X-Ray , Escherichia coli/drug effects , Magnetic Resonance Spectroscopy , Molecular Structure , Organoplatinum Compounds/chemistry , Spectrophotometry , Staphylococcus aureus/drug effects , Thiosemicarbazones/chemistryABSTRACT
The effect of three novel complexes of Pt(II) and three complexes of Pd(II) with 2-acetylpyridine thiosemicarbazone (HAcTsc) on sister chromatid exchange (SCE) rates and human lymphocyte proliferation kinetics on a molar basis was studied. Also, the effect of Pt(II) and Pd(II) complexes against leukemia P388 was investigated. Among these compounds, the most effective in inducing antitumor and cytogenetic effects were the complexes [Pt(AcTsc)2] x H2O and [Pd(AcTsc)2] while the rest, i.e. (HAcTsc), [Pt(AcTsc)Cl], [Pt(HAcTsc)2]Cl2 x 2H2O, [Pd(AcTsc)Cl] and [Pd(HAcTsc)2]Cl2, displayed marginal cytogenetic and antitumor effects.
Subject(s)
Antineoplastic Agents/pharmacology , Palladium/pharmacology , Platinum/pharmacology , Thiosemicarbazones/pharmacology , Animals , Drug Screening Assays, Antitumor , Drug-Related Side Effects and Adverse Reactions , Female , Humans , Male , Mice , Mice, Inbred Strains , Organometallic Compounds , Organoplatinum Compounds , Sister Chromatid ExchangeABSTRACT
The reactions of Na2PtCl4 with pyridine-2-carbaldehyde and 2-acetyl pyridine N(4)-ethyl-thiosemicarbazones, HFo4Et and HAc4Et respectively, afforded the complexes [Pt(Fo4Et)Cl], [Pt(HFo4Et)2]Cl2, [Pt(Fo4Et)2] and [Pt(Ac4Et)Cl], [Pt(HAc4Et)2]Cl2 x 2H2O, [Pt(Ac4Et)2]. The new complexes have been characterized by elemental analyses and spectroscopic studies. The crystal structure of the complex [Pt(Ac4Et)Cl] has been solved. The anion of Ac4E coordinates in a planar conformation to the central platinum(II) through the pyridyl N, azomethine N and thiolato S atoms. Intermolecular hydrogen, non-hydrogen bonds, pi-pi and weak Pt-pi contacts lead to aggregation and a supramolecular assembly. The cytotoxic activity for the platinum(II) complexes in comparison to that of cisplatin and thiosemicarbazones was evaluated in a pair of cisplatin-sensitive and -resistant ovarian cancer cell lines A2780 and A2780/Cp8. The platinum(II) complexes showed a cytotoxic potency in a very low micromolar range and were found able to overcome the cisplatin resistance of A2780/Cp8 cells.
Subject(s)
Thiosemicarbazones/chemical synthesis , Thiosemicarbazones/metabolism , Cell Division/drug effects , Cell Survival/drug effects , Crystallography, X-Ray , Humans , Hydrogen Bonding , Inhibitory Concentration 50 , Ligands , Magnetic Resonance Spectroscopy , Models, Chemical , Models, Molecular , Spectrophotometry, Infrared , Spectroscopy, Fourier Transform Infrared , Thiosemicarbazones/chemistry , Tumor Cells, CulturedABSTRACT
The effect of six novel complexes of Pt(II) and Pd(II) with pyridine-2-carboxyaldehyde thiosemicarbazone (HPyTsc) on sister chromatid exchange rate and human lymphocyte proliferation kinetic was studied. Also, the effect of Pt(II) and Pd(II) complexes against leukemia P388 was investigated. Among these compounds, the most effective in inducing cytogenetic and antineoplastic effects are the complexes [Pd(PyTsc)2] and [Pt(PyTsc)2]. Next in order of magnitude in inducing antineoplastic and cytogenetic effects is the compound [Pt(HPyTsc)2]Cl2 while the rest, i.e. [Pd(PyTsc)Cl], HPyTsc, [Pd(HPyTsc)2]Cl2, and [Pt(PyTsc)Cl], show marginal cytogenetic and antineoplastic effects.
Subject(s)
Antineoplastic Agents/pharmacology , Lymphocyte Activation/drug effects , Organometallic Compounds/pharmacology , Organoplatinum Compounds/pharmacology , Palladium/pharmacology , Sister Chromatid Exchange/drug effects , Thiosemicarbazones/pharmacology , Animals , Female , Humans , Leukemia P388/drug therapy , Male , Mice , Mice, Inbred C57BL , Mice, Inbred DBA , Palladium/chemistry , Thiosemicarbazones/chemistryABSTRACT
A new sensitive, rapid and accurate spectrofluorimetric method, suitable for the determination of micromolar concentrations of iron(III) in bovine liver, using 4-hydroxyquinoline (4-HQ) in an alkaline medium (KOH 2.0 x 10(-2) mol/l) as fluorescent agent, is described. The fluorescence intensity of the working solutions was measured at lambda ex 305 nm and lambda em 380 nm. The observed decrease of the above mentioned intensity was mainly due to the quenching, caused by the interaction between the iron(III) to be analysed and the potentially fluorescent 4-HQ. The accuracy and the precision of the proposed method, after an experimental investigation, could be considered as very satisfactory. Potassium fluoride and triethylenetetramine solutions were successfully used for the masking of those metal cations existing in the bovine liver which interfere seriously with the determination of iron(III).
Subject(s)
Fluorescent Dyes/chemistry , Hydroxyquinolines/chemistry , Iron/analysis , Liver/chemistry , Spectrometry, Fluorescence/methods , Animals , Artifacts , Cattle , Hydrogen-Ion Concentration , Indicators and Reagents , Reference Standards , Reproducibility of Results , Sensitivity and SpecificityABSTRACT
The reactions of 2-acetylpyridine N(4)-methyl, (HAc4Me) N(4)-ethyl (HAc4Et) and N(4)-Phenyl (HAc4Ph) thiosemicarbazone with palladium(II) were studied. The ligands and the palladium(II) complexes have been characterized by spectroscopic techniques. The structure of [Pd(Ac4Me)Cl] has been determined by single-crystal x-ray diffraction. The protonation constants of HAc4Me and HAc4Et, Ka1 and Ka2, were determined by spectrophotometry. The effect of palladium compounds on DNA synthesis of P388 and L1210 cell cultures is also reported. Some of these compounds increased the life span of mice bearing tumors.
Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Organometallic Compounds/chemistry , Organometallic Compounds/pharmacology , Palladium/pharmacology , Thiosemicarbazones/chemistry , Thiosemicarbazones/pharmacology , Animals , Antineoplastic Agents/chemical synthesis , Crystallization , Drug Screening Assays, Antitumor , Leukemia, Experimental/drug therapy , Magnetic Resonance Spectroscopy , Male , Mice , Mice, Inbred Strains , Models, Molecular , Organometallic Compounds/chemical synthesis , Spectrophotometry , Structure-Activity Relationship , Thiosemicarbazones/chemical synthesisABSTRACT
A new high-sensitive and at the same time accurate and well documented indirect spectrofluorimetric method for the determination of sub-micromolar concentrations of manganese(II) being as a normal trace element in the bovine liver, was described. The purpose of the experimental work is performed by means of two fluorescence intensity measurements; the measurement of the fluorescence (F1) of a 2.0 x 10(-5) mol/l solution of pure 2-hydroxyquinoline (2-HQ) (lambda ex: 320 nm: lambda em: 375 nm), and that of the fluorescence of the above solution after the addition of Mn(II) to be analyzed (F2). The observed difference of the fluorescence intensities measured (F1-F2) = delta F, is exclusively owed to the quenching of the Mn(II) on the free 2-HQ. The presence of various metal ions considerably interferes with the above described determination of Mn(II). For this reason, the separation and/or masking of these undesirable metal ions it is advisable to apply before any analytical praxis.
