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1.
Cell Biochem Biophys ; 79(4): 845-856, 2021 Dec.
Article in English | MEDLINE | ID: mdl-33950351

ABSTRACT

HNO (nitroxyl, IUPAC name azanone) is an electrophilic reactive nitrogen species of growing pharmacological and biological significance. Here, we present data on the pH-dependent kinetics of azanone reactions with the low molecular thiols glutathione and N-acetylcysteine, as well as with important serum proteins: bovine serum albumin and human serum albumin. The competition kinetics method used is based on two parallel HNO reactions: with RSH/RS- or with O2. The results provide evidence that the reaction of azanone with the anionic form of thiols (RS-) is favored over reactions with the protonated form (RSH). The data are supported with quantum mechanical calculations. A comprehensive discussion of the HNO reaction with thiolates is provided.


Subject(s)
Sulfhydryl Compounds
2.
Arch Biochem Biophys ; 661: 132-144, 2019 01.
Article in English | MEDLINE | ID: mdl-30448388

ABSTRACT

The recent interest in the clinical applications of Piloty's acid derivatives as HNO donors for the treatment of cardiovascular system dysfunction has led us to the examination of factors controlling HNO release from selected ortho-substituted N-hydroxysulfonamides. Here we present the kinetic and quantum mechanical studies on the mechanism of HNO release from selected ortho-substituted N-hydroxysulfonamides and in vivo examination of the antiaggregatory properties of N-hydroxy-(2-bromobenzene)sulfonamide complex with sodium salt of ß-cyclodextrin sulfobutyl ethers-ethyl ethers as compared with Angeli's salt.


Subject(s)
Hydroxamic Acids/chemistry , Nitrites/chemistry , Sulfonamides/chemistry , Boronic Acids/chemistry , Hydrogen-Ion Concentration , Hydroxamic Acids/metabolism , Isomerism , Kinetics , Nitrites/metabolism , Quantum Theory , Sulfonamides/metabolism
3.
Pharmacol Rep ; 70(2): 378-384, 2018 Apr.
Article in English | MEDLINE | ID: mdl-29477947

ABSTRACT

BACKGROUND: Pyruvate improves contractility of normal, hypoxic, and post-ischemic myocardium. However, sodium overload is a major problem with its therapeutic application if sodium pyruvate is used. Development of alternative forms such as N-1-methylnicotinamide (MNA) pyruvate may help to overcome this problem. The aim of the study was to investigate the effect of MNA pyruvate in a murine model of cardiac ischemia. METHODS: Seven month old male ApoE-/-LDLr-/- mice that develop myocardial infarction when exposed to hypoxic stress, were used in this study. Hypoxia (8% O2 in inspired air) was maintained for 8min and was followed by reoxygenation (21% O2 in inspired air). Four groups of mice were treated 10min before the hypoxic event by intravenous injection of MNA, MNA pyruvate, sodium pyruvate, and saline as control. The myocardial ischemia and damage was recorded by ECG. Four hours following the hypoxic episode serum troponin T and creatine kinase activity were measured. RESULTS: Significant hypernatremia was found in the sodium pyruvate group. During hypoxia, control and MNA group developed profound STU depressions on ECG while no changes were observed in MNA pyruvate and sodium pyruvate group. Creatine kinase activity and troponin T content in the mice plasma were significantly higher in the control and MNA group as compared to the MNA pyruvate and sodium pyruvate group. CONCLUSIONS: This study demonstrated that administration of MNA pyruvate prior to a hypoxia-induced cardiac event was cardioprotective. This intervention did not cause hypernatremia in contrast to sodium pyruvate.


Subject(s)
Cardiotonic Agents/pharmacology , Heart/drug effects , Hypoxia/drug therapy , Myocardial Infarction/drug therapy , Niacinamide/analogs & derivatives , Pyruvic Acid/pharmacology , Animals , Apolipoproteins E/metabolism , Creatine Kinase/metabolism , Electrocardiography/methods , Hypoxia/metabolism , Male , Mice , Mice, Inbred C57BL , Models, Theoretical , Myocardial Infarction/metabolism , Myocardium/metabolism , Niacinamide/pharmacology , Receptors, LDL/metabolism , Sodium Chloride/metabolism , Troponin T/metabolism
4.
Nitric Oxide ; 69: 61-68, 2017 Sep 30.
Article in English | MEDLINE | ID: mdl-28527627

ABSTRACT

Recently, azanone (HNO), which is the protonated one-electron reduction product of ·NO, has gained considerable attention due to its unique pharmacological effects. Although there has been much progress in understanding HNO biology and chemistry, it remains the most elusive reactive nitrogen species. Herein, we applied the competition kinetics method, based on two parallel HNO reactions with the different scavengers and molecular oxygen (kO2 = (1.8 ± 0.3) × 104 M-1 s-1), to determine the rate constants for the reactions of HNO with its selected co-reactants. The rate constants for the reactions of HNO with nitrite (k = (5.0 ± 0.9) × 103 M-1s-1), hydroxylamine (k = (2.1 ± 0.4) × 104 M-1s-1), sulfite (k = (1.2 ± 0.2) × 106 M-1 s-1), thiosulfate (k = (2.2 ± 0.7) × 104 M-1 s-1), benzenesulfinate (k = (4.4 ± 0.9) × 104 M-1 s-1), 2-bromobenzenesulfinate (k = (5.0 ± 1.2) × 104 M-1 s-1), nitrosoglutathione (k = (2.4 ± 0.7) × 104 M-1s-1), nitrosobenzene (k > 1.5 × 105 M-1 s-1), 2-nitroso-1-naphthol (k = (1.0 ± 0.2) × 106 M-1 s-1), triphenylphosphine (k > 7.3 × 106 M-1 s-1), triphenylphosphine-3,3',3″-trisulfonate (k = (3.0 ± 0.5) × 106 M-1 s-1), tris-carboxyethylphosphine (k = (1.2 ± 0.3) × 107 M-1 s-1), a triphenylphosphine-based P-CM fluorogenic probe (k > 1.2 × 107 M-1 s-1), the TEMPO-9-AC fluorogenic probe (k = (9 ± 2) × 104 M-1 s-1) and 4-acetamido-TEMPO (k = (8 ± 2) × 104 M-1s-1) are reported. The implications of these HNO reactions are also discussed. The data presented in this paper are a valuable contribution to the incompletely understood reactivity of HNO.


Subject(s)
Free Radical Scavengers/chemistry , Nitrogen Oxides/chemistry , Fluorescent Dyes/chemistry , Kinetics , Nitroso Compounds/chemistry , Oxazines/chemistry , Oxygen/chemistry , Phosphines/chemistry
5.
Chem Res Toxicol ; 29(5): 735-46, 2016 05 16.
Article in English | MEDLINE | ID: mdl-27081868

ABSTRACT

Boronate probes have emerged recently as a versatile tool for the detection of reactive oxygen and nitrogen species. Here, we present the characterization of a fluorescein-based monoboronate probe, a 4-(pinacol boronate)benzyl derivative of fluorescein methyl ester (FBBE), that proved to be useful to detect peroxynitrite in cell culture experiments. The reactivity of FBBE toward peroxynitrite as well hypochlorite, hydrogen peroxide, and tyrosyl hydroperoxide was determined. Second-order rate constants of the reactions of FBBE with peroxynitrite, HOCl, and H2O2 at pH 7.4 were equal to (2.8 ± 0.2) × 10(5) M(-1) s(-1), (8.6 ± 0.5) × 10(3) M(-1) s(-1), and (0.96 ± 0.03) M(-1) s(-1), respectively. The presence of glutathione completely blocked the oxidation of the probe by HOCl and significantly inhibited its oxidation by H2O2 and tyrosyl hydroperoxide but not by peroxynitrite. The oxidative conversion of the probe was also studied in the systems generating singlet oxygen, superoxide radical anion, and nitric oxide in the presence and absence of glutathione. Spectroscopic characterization of FBBE and its oxidation product has been also performed. The differences in the reactivity pattern were supported by DFT quantum mechanical calculations. Finally, the FBBE probe was used to study the oxidative stress in endothelial cells (Ea.hy926) incubated with doxorubicin, a quinone anthracycline antibiotic. In endothelial cells pretreated with doxorubicin, FBBE was oxidized, and this effect was reversed by PEG-SOD and L-NAME but not by catalase.


Subject(s)
Boronic Acids/chemistry , Doxorubicin/pharmacology , Endothelial Cells/drug effects , Fluorescein/chemistry , Molecular Probes , Peroxynitrous Acid/metabolism , Endothelial Cells/metabolism , Humans , Spectrometry, Fluorescence , Spectrophotometry, Ultraviolet
6.
Free Radic Biol Med ; 95: 323-32, 2016 06.
Article in English | MEDLINE | ID: mdl-27021961

ABSTRACT

Amplex® Red (10-acetyl-3,7-dihydroxyphenoxazine) is a fluorogenic probe widely used to detect and quantify hydrogen peroxide in biological systems. Detection of hydrogen peroxide is based on peroxidase-catalyzed oxidation of Amplex® Red to resorufin. In this study we investigated the mechanism of one-electron oxidation of Amplex® Red and we present the spectroscopic characterization of transient species formed upon the oxidation. Oxidation process has been studied by a pulse radiolysis technique with one-electron oxidants (N3(•), CO3(•-),(•)NO2 and GS(•)). The rate constants for the Amplex® Red oxidation by N3(•) ((2)k=2.1·10(9)M(-1)s(-1), at pH=7.2) and CO3(•-) ((2)k=7.6·10(8)M(-1)s(-1), at pH=10.3) were determined. Two intermediates formed during the conversion of Amplex® Red into resorufin have been characterized. Based on the results obtained, the mechanism of transformation of Amplex® Red into resorufin, involving disproportionation of the Amplex® Red-derived radical species, has been proposed. The results indicate that peroxynitrite-derived radicals, but not peroxynitrite itself, are capable to oxidize Amplex® Red to resorufin. We also demonstrate that horseradish peroxidase can catalyze oxidation of Amplex® Red not only by hydrogen peroxide, but also by peroxynitrite, which needs to be considered when employing the probe for hydrogen peroxide detection.


Subject(s)
Hydrogen Peroxide/isolation & purification , Oxazines/chemistry , Oxidants/chemistry , Peroxynitrous Acid/isolation & purification , Catalysis , Horseradish Peroxidase/chemistry , Hydrogen Peroxide/metabolism , Oxidation-Reduction , Peroxynitrous Acid/metabolism , Pulse Radiolysis
7.
Methods Mol Biol ; 1264: 171-81, 2015.
Article in English | MEDLINE | ID: mdl-25631013

ABSTRACT

The development of boronic probes enabled reliable detection and quantitative analysis of hydrogen peroxide and peroxynitrite. The major product, in which boronate moiety of the probe is replaced by the hydroxyl group, is however common for both oxidants. Here, we describe how ortho-isomer of mitochondria-targeted phenylboronic acid can be used to detect and differentiate peroxynitrite-dependent and peroxynitrite-independent probe oxidation. This method highlights the detection and quantification of both the major, phenolic product and the minor, peroxynitrite-specific nitrated product of probe oxidation.


Subject(s)
Hydrogen Peroxide/metabolism , Metabolomics/methods , Mitochondria/metabolism , Peroxynitrous Acid/metabolism , Animals , Boronic Acids/chemistry , Cell Line , Chromatography, High Pressure Liquid , Fluorescent Dyes/chemistry , Hydrogen Peroxide/chemistry , Mice , Peroxynitrous Acid/chemistry , Tandem Mass Spectrometry
8.
J Biol Chem ; 289(51): 35570-81, 2014 Dec 19.
Article in English | MEDLINE | ID: mdl-25378389

ABSTRACT

Nitroxyl (HNO), the protonated one-electron reduction product of NO, remains an enigmatic reactive nitrogen species. Its chemical reactivity and biological activity are still not completely understood. HNO donors show biological effects different from NO donors. Although HNO reactivity with molecular oxygen is described in the literature, the product of this reaction has not yet been unambiguously identified. Here we report that the decomposition of HNO donors under aerobic conditions in aqueous solutions at physiological pH leads to the formation of peroxynitrite (ONOO(-)) as a major intermediate. We have specifically detected and quantified ONOO(-) with the aid of boronate probes, e.g. coumarin-7-boronic acid or 4-boronobenzyl derivative of fluorescein methyl ester. In addition to the major phenolic products, peroxynitrite-specific minor products of oxidation of boronate probes were detected under these conditions. Using the competition kinetics method and a set of HNO scavengers, the value of the second order rate constant of the HNO reaction with oxygen (k = 1.8 × 10(4) m(-1) s(-1)) was determined. The rate constant (k = 2 × 10(4) m(-1) s(-1)) was also determined using kinetic simulations. The kinetic parameters of the reactions of HNO with selected thiols, including cysteine, dithiothreitol, N-acetylcysteine, captopril, bovine and human serum albumins, and hydrogen sulfide, are reported. Biological and cardiovascular implications of nitroxyl reactions are discussed.


Subject(s)
Nitrogen Oxides/chemistry , Oxygen/chemistry , Peroxynitrous Acid/chemistry , Acetylcysteine/chemistry , Algorithms , Animals , Boron Compounds/chemistry , Boronic Acids/chemistry , Captopril/chemistry , Cattle , Chromatography, High Pressure Liquid , Coumarins/chemistry , Cysteine/chemistry , Dithiothreitol/chemistry , Humans , Hydrogen Sulfide/chemistry , Hydrogen-Ion Concentration , Kinetics , Mass Spectrometry , Models, Chemical , Oxidation-Reduction , Serum Albumin/chemistry , Spectrophotometry , Sulfhydryl Compounds/chemistry
9.
J Agric Food Chem ; 62(13): 2853-60, 2014 Apr 02.
Article in English | MEDLINE | ID: mdl-24650005

ABSTRACT

Coffee may exert a preventive effect on arterial thrombosis. Trigonelline is one of the most abundant compounds in coffee that undergoes pyrolysis upon roasting of coffee beans. The aim of the present study was to identify pyridinium compounds formed upon trigonelline pyrolysis and coffee roasting and to investigate the effect of three of them, i.e., 1-methylpyridine and 1,3- and 1,4-dimethylpyridine, on experimentally induced arterial thrombosis in rats. 1,3- and 1,4-dimethylpyridine but not 1-methylpyridine inhibited arterial thrombus formation. 1,3-Dimethylpyridine inhibited platelet aggregation and reduced fibrin formation in platelet-rich plasma, whereas 1,4-dimethylpyridine increased the plasma level of 6-keto-PGF1α. 1,4-Dimethylpyridine slightly increased rat tissue plasminogen activator plasma activity. In summary, we demonstrated that pyridinium compounds display mild antithrombotic properties due to stimulation by prostacyclin release (1,4-dimethylpyridine) and inhibition of platelet aggregation (1,3-dimethylpyridine). Those pyridinium compounds may, to some extent, be responsible for the beneficial effects of coffee drinking.


Subject(s)
Alkaloids/chemistry , Coffea/chemistry , Fibrinolytic Agents/administration & dosage , Plant Extracts/administration & dosage , Pyridinium Compounds/administration & dosage , Thrombosis/prevention & control , Alkaloids/administration & dosage , Animals , Cooking , Fibrinolytic Agents/chemistry , Humans , Male , Plant Extracts/chemistry , Platelet Aggregation/drug effects , Pyridinium Compounds/chemistry , Rats , Rats, Wistar , Thrombosis/blood
10.
Chem Res Toxicol ; 26(6): 856-67, 2013 Jun 17.
Article in English | MEDLINE | ID: mdl-23611338

ABSTRACT

Aromatic boronic acids react rapidly with peroxynitrite (ONOO(-)) to yield phenols as major products. This reaction was used to monitor ONOO(-) formation in cellular systems. Previously, we proposed that the reaction between ONOO(-) and arylboronates (PhB(OH)2) yields a phenolic product (major pathway) and a radical pair PhB(OH)2O(•-)···(•)NO2 (minor pathway). [Sikora, A. et al. (2011) Chem. Res. Toxicol. 24, 687-697]. In this study, we investigated the influence of a bulky triphenylphosphonium (TPP) group on the reaction between ONOO(-) and mitochondria-targeted arylboronate isomers (o-, m-, and p-MitoPhB(OH)2). Results from the electron paramagnetic resonance (EPR) spin-trapping experiments unequivocally showed the presence of a phenyl radical intermediate from meta and para isomers, and not from the ortho isomer. The yield of o-MitoPhNO2 formed from the reaction between o-MitoPhB(OH)2 and ONOO(-) was not diminished by phenyl radical scavengers, suggesting a rapid fragmentation of the o-MitoPhB(OH)2O(•-) radical anion with subsequent reaction of the resulting phenyl radical with (•)NO2 in the solvent cage. The DFT quantum mechanical calculations showed that the energy barrier for the dissociation of the o-MitoPhB(OH)2O(•-) radical anion is significantly lower than that of m-MitoPhB(OH)2O(•-) and p-MitoPhB(OH)2O(•-) radical anions. The nitrated product, o-MitoPhNO2, is not formed by the nitrogen dioxide radical generated by myeloperoxidase in the presence of the nitrite anion and hydrogen peroxide, indicating that this specific nitrated product may be used as a diagnostic marker product for ONOO(-). Incubation of o-MitoPhB(OH)2 with RAW 264.7 macrophages activated to produce ONOO(-) yielded the corresponding phenol o-MitoPhOH as well as the diagnostic nitrated product, o-MitoPhNO2. We conclude that the ortho isomer probe reported here is most suitable for specific detection of ONOO(-) in biological systems.


Subject(s)
Boronic Acids/metabolism , Macrophages/metabolism , Organophosphorus Compounds/metabolism , Peroxynitrous Acid/analysis , Peroxynitrous Acid/metabolism , Animals , Boronic Acids/chemistry , Cells, Cultured , Macrophages/cytology , Mice , Molecular Probes/analysis , Molecular Probes/chemistry , Molecular Probes/metabolism , Molecular Structure , Organophosphorus Compounds/chemical synthesis , Organophosphorus Compounds/chemistry , Peroxynitrous Acid/biosynthesis , Peroxynitrous Acid/chemistry
11.
J Biol Chem ; 287(5): 2984-95, 2012 Jan 27.
Article in English | MEDLINE | ID: mdl-22139901

ABSTRACT

Herein we describe a high-throughput fluorescence and HPLC-based methodology for global profiling of reactive oxygen and nitrogen species (ROS/RNS) in biological systems. The combined use of HPLC and fluorescence detection is key to successful implementation and validation of this methodology. Included here are methods to specifically detect and quantitate the products formed from interaction between the ROS/RNS species and the fluorogenic probes, as follows: superoxide using hydroethidine, peroxynitrite using boronate-based probes, nitric oxide-derived nitrosating species with 4,5-diaminofluorescein, and hydrogen peroxide and other oxidants using 10-acetyl-3,7-dihydroxyphenoxazine (Amplex® Red) with and without horseradish peroxidase, respectively. In this study, we demonstrate real-time monitoring of ROS/RNS in activated macrophages using high-throughput fluorescence and HPLC methods. This global profiling approach, simultaneous detection of multiple ROS/RNS products of fluorescent probes, developed in this study will be useful in unraveling the complex role of ROS/RNS in redox regulation, cell signaling, and cellular oxidative processes and in high-throughput screening of anti-inflammatory antioxidants.


Subject(s)
Models, Biological , Reactive Nitrogen Species/metabolism , Reactive Oxygen Species/metabolism , Animals , Cell Line , Mice , Molecular Probes/chemistry , Molecular Probes/pharmacology , Oxidation-Reduction
12.
J Phys Chem A ; 114(43): 11552-9, 2010 Nov 04.
Article in English | MEDLINE | ID: mdl-20931950

ABSTRACT

Thiophene and its disubstituted derivatives, such as 3,4-ethylenedioxythiophene (EDOT), 3,4-dimethoxythiophene (DMT), 3,4-propylenedioxythiophene (PDOT), and 3,4-butylenedioxythiophene (BuDOT) were oxidized in organic solvents and in ionic liquid 1-butyl-3-methylimidazolium hexafluorophosphate (BMIM(+)PF6⁻) at RT and under cryogenic conditions. Their radical cations were spectrally characterized at 77 K. Annealing of the irradiated matrix, which triggers the diffusion processes, led to spontaneous oligomerization. The oxidative coupling between a radical cation and a neutral monomer was identified as the first step of the oligomerization process. The scale of oligomerization could be extended by the addition of chloroform, which acts as a dissociative electron scavenger, whereas the dichloromethylperoxyl radicals formed in the reaction with the dissolved oxygen act as secondary oxidizing agents.


Subject(s)
Imidazoles/chemistry , Ionic Liquids/chemistry , Thiophenes/chemistry , Molecular Structure , Oxidation-Reduction , Oxygen/chemistry
13.
Eur J Pharmacol ; 640(1-3): 102-11, 2010 Aug 25.
Article in English | MEDLINE | ID: mdl-20447392

ABSTRACT

The aim of the study was to examine the effect of 1-methylnicotinamide (MNA) and 1-methyl-3-nitropyridine (MNP) on mitochondria activity and proliferation of endothelial EA.hy926 cells. The activity of MNA was also referred to nicotinamide (NAM) being MNA metabolic precursor. NAM and MNA used at high concentrations (up to 1 mM) had no effect on mitochondria metabolism and proliferation of EA.hy926 cells. It could be related to the fact that these compounds hardly cross the cell membrane. It supports the results of our previous study suggesting that anti-inflammatory and anti-thrombotic effects of MNA could be associated with its ability to bind to glycosaminoglycans, especially heparins, located on the endothelium membrane without entering into target cells. In contrast, MNP caused substantial changes in mitochondria activity and proliferation of EA.hy926 cells. This compound used at low concentrations (below 100 microM) blocked the cell cycle of EA.hy926 cells in G1 phase and was very effective in inhibiting cell growth (IC50=13.8+/-2.4 microM). At higher concentrations (0.1-1 mM) MNP caused a significant reduction of cell survival. The observed effects of MNP could be related, at least in part, to its ability to influence the ATP and NAD+ intracellular levels. MNP caused also important changes in Ca2+ intracellular concentration, significant decrease in inner mitochondrial membrane potential and high increase in mitochondrial respiration of EA.hy926 cells. The observed effects of MNP may be related in part to its cellular metabolites detected after 45 min incubation with 250 microM MNP.


Subject(s)
Endothelial Cells/cytology , Endothelial Cells/drug effects , Mitochondria/drug effects , Mitochondria/metabolism , NAD/analogs & derivatives , Niacinamide/analogs & derivatives , Pyridines/pharmacology , Pyridinium Compounds/pharmacology , Adenosine Triphosphate/metabolism , Biological Transport/drug effects , Calcium/metabolism , Cell Cycle/drug effects , Cell Line , Cell Proliferation/drug effects , Cell Survival/drug effects , Cytosol/drug effects , Cytosol/metabolism , Endothelial Cells/metabolism , Humans , Membrane Potential, Mitochondrial/drug effects , NAD/metabolism , Niacinamide/chemistry , Niacinamide/pharmacology , Oxygen/metabolism , Pyridines/chemistry , Pyridinium Compounds/chemistry
14.
J Pharm Pharmacol ; 60(5): 647-53, 2008 May.
Article in English | MEDLINE | ID: mdl-18416942

ABSTRACT

The aim of this study was to examine the effect of selected pyridinium salts, 1-methyl-3-nitropyridine chloride (MNP(+)Cl(-)) and 3,3,6,6,10-pentamethyl-3,4,6,7-tetrahydro-[1,8(2H,5H)-dion]acridine chloride (MDION(+)Cl(-)), on the activity of doxorubicin (DOX) and vincristine (VINC) towards human promyelocytic leukaemia HL60 cells as well as its multidrug resistant (MDR) sublines exhibiting two different phenotypes of MDR related to the overexpression of P-glycoprotein (HL60/VINC) or MRP1 (HL60/DOX). MNP and MDION salts were much less cytotoxic themselves (about 100-fold and 2000-fold compared with DOX and VINC, respectively) against HL60 cells but, in contrast to DOX and VINC, they conserved an important cytotoxic activity towards resistant HL60/VINC and HL60/DOX cells (resistance factor, RF = 2-4.5). It was shown that MNP(+)Cl(-) and MDION(+)Cl(-) increased the cytotoxicity of non-bioreductive antitumour agent VINC towards human promyelocytic leukaemia HL60 cells and its resistant sublines HL60/VINC and HL60/DOX. However, in the case of DOX the decrease in its cytotoxic activity towards all studied cell lines was observed in the presence of MNP(+)Cl(-) and MDION(+)Cl(-). Presented data suggest that the bioreductive drug DOX, in contrast to VINC, could compete with pyridinium salts (MNP(+)Cl(-) and MDION(+)Cl(-)) for NADPH-dependent oxidoreductases and for undergoing cellular reductive activation. This could explain the inefficiency of these salts to increase the cytotoxic activity of DOX against examined leukaemic HL60 cell line and its MDR sublines, HL60/VINC and HL60/DOX.


Subject(s)
Acridines/pharmacology , Antibiotics, Antineoplastic/pharmacology , Antineoplastic Agents, Phytogenic/pharmacology , Doxorubicin/pharmacology , Pyridinium Compounds/pharmacology , Vincristine/pharmacology , Cell Proliferation/drug effects , Drug Resistance, Multiple , Drug Resistance, Neoplasm , HL-60 Cells , Humans , Leukemia, Promyelocytic, Acute/drug therapy
15.
Pharmacol Rep ; 60(1): 127-38, 2008.
Article in English | MEDLINE | ID: mdl-18276994

ABSTRACT

For many years, 1-methylnicotinamide (MNA), a primary metabolite of nicotinamide, has been considered inactive. Recently however, it has been discovered that MNA possesses anti-thrombotic and anti-inflammatory activity. In the present study we investigated whether chronic administration of MNA to hypertriglyceridemic or diabetic rats would reverse endothelial dysfunction characterized by the impairment of nitric oxide (NO)-dependent vasodilatation. Hypertriglyceridemia in rats was induced by fructose-rich (60%) diet, while diabetes was induced by streptozotocin injection (70 mg/kg). After eight weeks, in hypertriglyceridemic or diabetic rats treated or non-treated with MNA(100 mg/kg), we analyzed the magnitude of endothelium-dependent or endothelium-independent vasodilatation in aorta induced by acetylcholine or S-nitroso-N-acetyl-penicillamine (SNAP), respectively, as well as plasma concentration of: cholesterol, triglycerides, glucose, HbA(1c), fructosamine, peptide C, endogenous MNA and its metabolites (M2PY, M4PY). In diabetic rats plasma concentration of glucose, HbA(1c) and fructosamine was elevated (402.08 +/- 19.01 vs. 82.06 +/- 5.41 mg/dl, p < 0.001; 9.55 +/- 0.56 vs. 4.93 +/- 0.24%, p = 0.052 and 2.53 +/- 0.10 vs. 1.14 +/- 0.06 mmol DTF/mg protein, p < 0.001 in diabetic and control rats, respectively). In hypertriglyceridemic rats plasma concentration of triglycerides was elevated (4.25 +/- 0.27 vs. 1.55 +/- 0.12 mmol/l, p < 0.001 in hypertriglyceridemic and control rats, respectively). In both models the NO-dependent vasodilatation in aorta induced by acetylcholine was significantly impaired as compared to control rats, while the response to SNAP was largely preserved. In hypertriglyceridemic rats, 4 weeks of treatment with MNA(100 mg/kg, po) resulted in a three to six-fold increase in endogenous levels of MNA and its metabolites (M2PY and M4PY), the fall in triglycerides concentration in plasma (from 4.25 +/- 0.27 to 2.22 +/- 0.14 mmol/l, p < 0.001), and the preservation of the NO-dependent vasodilatation. In diabetic rats chronic treatment with MNA also prevented the impairment of NO-dependent vasodilatation, while it displayed only a mild effect on hyperglycemia and did not lower triglycerides concentration. In summary, MNA treatment decreased plasma triglycerides concentration in hypertriglyceridemic, but not in diabetic rats, while it prevented the development of endothelial dysfunction in aorta in both of these models. Accordingly, the ability of MNA to reverse endothelial dysfunction seems to be independent of its hypolipemic activity.


Subject(s)
Cardiovascular Agents/pharmacology , Diabetes Mellitus, Experimental/drug therapy , Endothelium, Vascular/drug effects , Hypertriglyceridemia/drug therapy , Niacinamide/analogs & derivatives , Vasodilation/drug effects , Animals , Aorta, Thoracic/drug effects , Aorta, Thoracic/physiopathology , Blood Glucose/drug effects , C-Peptide/blood , Diabetes Mellitus, Experimental/metabolism , Diabetes Mellitus, Experimental/physiopathology , Dose-Response Relationship, Drug , Endothelium, Vascular/metabolism , Endothelium, Vascular/physiopathology , Fructosamine/blood , Glycated Hemoglobin/metabolism , Hypertriglyceridemia/metabolism , Hypertriglyceridemia/physiopathology , Lipids/blood , Male , Niacinamide/pharmacology , Nitric Oxide/metabolism , Rats , Rats, Sprague-Dawley , Rats, Wistar , Vasodilator Agents/pharmacology
16.
Chem Res Toxicol ; 20(8): 1093-8, 2007 Aug.
Article in English | MEDLINE | ID: mdl-17630710

ABSTRACT

The primary products of one-electron oxidation of clozapine and olanzapine, very effective atypical antipsychotic drugs, have been spectroscopically characterized. The oxidation process has been studied under glassy matrix conditions and by a pulse radiolysis technique in aqueous solution. The rate constants for the oxidation of clozapine with dibromide radical anion ( k = 2 x 10 (9) M (-1) s (-1)) and azide radical ( k = 2.3 x 10 (9) M (-1) s (-1)) in aqueous solution were measured. The computational DFT results support the identification of the transient species. The mechanistic aspects of reactivity of radical cations, radicals, and nitrenium cations have been investigated. A disproportionation reaction ( k > or = 1 x 10 (8) M (-1) s (-1)) was proposed as a link between the products of one-electron oxidation and formation of the nitrenium cations of clozapine and olanzapine, products likely responsible for the pathogenesis of adverse drug reactions. The rate constants for the reactions of nitrenium cation of clozapine with glutathione ( k = 3.4 x 10 (4) M (-1) s (-1)) and cysteine ( k = 9.8 x 10 (4) M (-1) s (-1)) were determined.


Subject(s)
Antipsychotic Agents/chemistry , Clozapine/chemistry , Free Radicals/chemistry , Nitrogen/chemistry , Algorithms , Antipsychotic Agents/pharmacology , Azides/chemistry , Benzodiazepines/chemistry , Bromides/chemistry , Cations , Electrons , Glutathione/chemistry , Hydrogen-Ion Concentration , Kinetics , Olanzapine , Oxidation-Reduction , Pulse Radiolysis , Spectrum Analysis
17.
Pharmacol Rep ; 59(2): 216-23, 2007.
Article in English | MEDLINE | ID: mdl-17556800

ABSTRACT

The objective of this work was to evaluate the relationship between chemical reactivity of 3-substituted pyridinium salts and their cytotoxic properties against murine leukemia L1210. Chemical reactivity of pyridinium salts towards NADH oxidation following one-step hydride transfer depends strongly on their redox properties. The investigated reaction may reflect the ability of the salts to deplete NADH level in cells and to affect their metabolic functions. On the other hand, the cytotoxic activity against murine leukemia cells, expressed as ED50 values, varied strongly depending upon the compound used. The investigated salts showed also a diverse antileukemic effect in in vivo experiments as measured by the increase in the survival time of L1210 leukemia-bearing mice. These biological effects were correlated with equilibrium constants found for the reaction of pyridinium salts with NADH.


Subject(s)
Antineoplastic Agents/pharmacology , Leukemia L1210/drug therapy , Pyridines/pharmacology , Animals , Hydrogen-Ion Concentration , Leukemia L1210/pathology , Mice , NAD/chemistry , Oxidation-Reduction , Pyridines/chemistry , Structure-Activity Relationship
18.
Free Radic Res ; 40(7): 741-52, 2006 Jul.
Article in English | MEDLINE | ID: mdl-16984001

ABSTRACT

It is claimed that novel beta-adrenolytic drugs possess superior antioxidant properties as compared to classical selective or non-selective beta-adrenoceptor antagonists. Here we tested this notion by analyzing radical scavenging properties of selected beta-adrenolytic drugs and their ability to release nitric oxide in biological preparations. Selective beta1-adrenolytics such as nebivolol, atenolol, metoprolol and non-selective beta-adrenolytics with alpha1-receptor blocking properties such as carvedilol and labetalol were chosen for analysis. NO-releasing properties of nebivolol and carvedilol distinguished third generation beta-adrenolytics from their older counterparts while the reactivity towards hydroxyl and peroxyl radicals discerns only carvedilol but not nebivolol. Thus, superior clinical efficacy of third generation beta-adrenolytics may be related to their ability to release NO rather then to their direct antioxidant properties.


Subject(s)
Adrenergic beta-Antagonists/pharmacology , Coronary Vessels/drug effects , Endothelium, Vascular/drug effects , Free Radical Scavengers/pharmacology , Nitric Oxide/metabolism , Animals , Benzopyrans/pharmacology , Carbazoles/pharmacology , Carvedilol , Coronary Circulation/drug effects , Coronary Vessels/metabolism , Coronary Vessels/physiology , Endothelium, Vascular/metabolism , Epoxy Compounds/chemistry , Epoxy Compounds/metabolism , Ethanolamines/pharmacology , Female , Guinea Pigs , In Vitro Techniques , Male , Methylamines/chemistry , Methylamines/metabolism , Nebivolol , Propanolamines/pharmacology , Pulse Radiolysis , Vasodilation/drug effects
19.
J Org Chem ; 71(14): 5312-9, 2006 Jul 07.
Article in English | MEDLINE | ID: mdl-16808521

ABSTRACT

One-electron reduction significantly enhances the ability of anthralin, 1, to act as a hydrogen atom donor. On annealing of an MTHF glass in which the radical anion of anthralin, 1*-, is generated radiolytically, this species decays mainly by loss of H* to give the anthralyl anion, 2- . On the other hand, radicals formed on radiolysis of matrices that are suitable for the generation of radical anions or cations are capable to abstract H* from anthralin to give the anthralyl radical, 2* . Both 2- and 2* are obtained simultaneously by mesolytic cleavage of the radical anion of the anthralin dimer. Contrary to general assumptions, the anthralyl radical is found to be much more reactive toward oxygen than the anion. All intermediates are characterized spectroscopically and by reference to quantum chemical calculations. Attempts to generate the radical cation of anthralin by X-irradiation of an Ar matrix containing anthralin led also to significant formation of its radical anion, i.e., anthralin acts apparently as an efficient electron trap in such experiments.


Subject(s)
Anthralin/chemistry , Anions/chemistry , Cations/chemistry , Electrons , Free Radicals/chemistry , Molecular Structure , Oxidation-Reduction , Time Factors
20.
J Phys Chem A ; 110(22): 7272-8, 2006 Jun 08.
Article in English | MEDLINE | ID: mdl-16737280

ABSTRACT

The inversion of the keto-enol stability order of dialuric acid on ionization was calculated and verified experimentally. The radical cations in both forms were characterized. The spectrum of the keto form was observed upon direct ionization of dialuric acid under matrix conditions, whereas the enol form was formed upon a sequential electron-proton-proton attachment to alloxan under acidic aqueous condition. Facilitation of the one-electron oxidation of dialuric acid upon its enolization can result in a more effective formation of superoxide radical anion in the process of its auto-oxidation. This process is discussed in reference to the alloxan diabetogenic action. Both neutral keto and enol forms are energetically close, and under favorable conditions, the auto-oxidation of dialuric acid could involve participation of the enol form.


Subject(s)
Alloxan/chemistry , Barbiturates/chemistry , Diabetes Mellitus, Experimental , Alloxan/metabolism , Animals , Barbiturates/metabolism , Diabetes Mellitus, Experimental/chemically induced , Diabetes Mellitus, Experimental/metabolism , Ions , Molecular Structure , Spectrum Analysis , Stereoisomerism
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