In this work four vanadium complexes (compounds 1, 2, 3 and 4) and one molybdenum complex (compound 5) with hydrazone ligands derived from pyridoxal were synthesized and characterized. All compounds are mononuclear species, two of them (compounds 3 and 5) are dioxide complexes and the other three (compounds 1, 2 and 4) monoxide complexes. The vanadium atom of the compound 3 is five-coordinated and all the other compounds have a six coordinated environment polyhedron. The poses for the potential intercalation of the compounds 2 and 3 with DNA were obtained by using AutoDock software. Optimizations were also performed at PM6-D3H4 semi-empirical level whereas the study of the nature of the interaction was carried out by means of the Energy Decomposition Analysis and the Non-Covalent Interaction index by using in both cases Density Functional Theory computations. The cytotoxicity in lung cancer cells (A549 cell line) of all the compounds was also evaluated. After 24 h of treatment, vanadium complexes showed high values of IC50, between 419.93 ± 22.58 and 685.88 ± 46.55 μM. After 48 h, the results showed that the compound 3 had the lowest IC50 value, 65.32 ± 9.95 μM, and the compound 2 the highest value, 375.28 ± 32.09 μM. The molybdenum complex showed the lowest IC50 value at 48 h (11.22 ± 1.34 μM). The toxicity of the compounds 3, 4 and 5 was tested in vivo, using zebrafish model, and the molybdenum complex showed higher toxic effects than the studied vanadium complexes.

• Klíčová slova
• A549 cell line, Cytotoxicity, Intercalator, Stability, Vanadium, Zebrafish model,
• MeSH
• dánio pruhované MeSH
• ligandy MeSH
• molybden * chemie   farmakologie   MeSH
• pyridoxal farmakologie   MeSH
• vanad * chemie   farmakologie   MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• ligandy MeSH
• molybden * MeSH
• pyridoxal MeSH
• vanad * MeSH

The aim of this study was to analyze the ECG time intervals in the course of the development of chronic anthracycline cardiomyopathy in rabbits. Furthermore, this approach was employed to study the effects of a model cardioprotective drug (dexrazoxane) and two novel iron chelating compounds--salicylaldehyde isonicotinoyl hydrazone (SIH) and pyridoxal 2-chlorobenzoyl hydrazone (o-108). Repeated daunorubicin administration induced a significant and progressive prolongation of the QRS complex commencing with the eighth week of administration. At the end of the study, we identified a significant correlation between QRS duration and the contractility index dP/dt(max) (r = -0.81; P<0.001) as well as with the plasma concentrations of cardiac troponin T (r = 0.78; P<0.001). In contrast, no alterations in ECG time intervals were revealed in the groups co-treated with either dexrazoxane or both novel cardioprotective drugs (SIH, o-108). Hence, in this study, the QRS duration is for the first time shown as a parameter suitable for the non-invasive evaluation of the anthracycline cardiotoxicity and cardioprotective effects of both well established and investigated drugs. Moreover, our results strongly suggest that novel iron chelators (SIH and o-108) merit further study as promising cardioprotective drugs against anthracycline cardiotoxicity.

• MeSH
• aldehydy farmakologie   MeSH
• časové faktory MeSH
• chelátory železa farmakologie   terapeutické užití   MeSH
• chronická nemoc MeSH
• daunomycin MeSH
• elektrokardiografie * MeSH
• hydrazony farmakologie   MeSH
• kardiomyopatie krev   chemicky indukované   patofyziologie   prevence a kontrola   MeSH
• kardiotonika farmakologie   terapeutické užití   MeSH
• kontrakce myokardu účinky léků   MeSH
• králíci MeSH
• modely nemocí na zvířatech MeSH
• preklinické hodnocení léčiv metody   MeSH
• převodní systém srdeční účinky léků   patofyziologie   MeSH
• pyridoxal analogy a deriváty   farmakologie   MeSH
• razoxan farmakologie   MeSH
• troponin T krev   MeSH
• zvířata MeSH
• Check Tag
• králíci MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• aldehydy MeSH
• chelátory železa MeSH
• daunomycin MeSH
• hydrazony MeSH
• kardiotonika MeSH
• pyridoxal 2-chlorobenzoyl hydrazone MeSH Prohlížeč
• pyridoxal MeSH
• razoxan MeSH
• salicylaldehyde isonicotinoyl hydrazone MeSH Prohlížeč
• troponin T MeSH

BACKGROUND AND PURPOSE: The anticancer drugs doxorubicin and bleomycin are well-known for their oxidative stress-mediated side effects in heart and lung, respectively. It is frequently suggested that iron is involved in doxorubicin and bleomycin toxicity. We set out to elucidate whether iron chelation prevents the oxidative stress-mediated toxicity of doxorubicin and bleomycin and whether it affects their antiproliferative/proapoptotic effects. EXPERIMENTAL APPROACH: Cell culture experiments were performed in A549 cells. Formation of hydroxyl radicals was measured in vitro by electron paramagnetic resonance (EPR). We investigated interactions between five iron chelators and the oxidative stress-inducing agents (doxorubicin, bleomycin and H(2)O(2)) by quantifying oxidative stress and cellular damage as TBARS formation, glutathione (GSH) consumption and lactic dehydrogenase (LDH) leakage. The antitumour/proapoptotic effects of doxorubicin and bleomycin were assessed by cell proliferation and caspase-3 activity assay. KEY RESULTS: All the tested chelators, except for monohydroxyethylrutoside (monoHER), prevented hydroxyl radical formation induced by H(2)O(2)/Fe(2+) in EPR studies. However, only salicylaldehyde isonicotinoyl hydrazone and deferoxamine protected intact A549 cells against H(2)O(2)/Fe(2+). Conversely, the chelators that decreased doxorubicin and bleomycin-induced oxidative stress and cellular damage (dexrazoxane, monoHER) were not able to protect against H(2)O(2)/Fe(2+). CONCLUSIONS AND IMPLICATIONS: We have shown that the ability to chelate iron as such is not the sole determinant of a compound protecting against doxorubicin or bleomycin-induced cytotoxicity. Our data challenge the putative role of iron and hydroxyl radicals in the oxidative stress-mediated cytotoxicity of doxorubicin and bleomycin and have implications for the development of new compounds to protects against this toxicity.

• MeSH
• aldehydy farmakologie   MeSH
• apoptóza účinky léků   MeSH
• bleomycin toxicita   MeSH
• časové faktory MeSH
• chelátory železa chemie   farmakologie   MeSH
• deferoxamin farmakologie   MeSH
• doxorubicin toxicita   MeSH
• elektronová paramagnetická rezonance MeSH
• hydrazony farmakologie   MeSH
• isoniazid analogy a deriváty   farmakologie   MeSH
• lidé MeSH
• nádorové buněčné linie MeSH
• nádory plic metabolismus   patologie   MeSH
• oxidační stres účinky léků   MeSH
• peroxid vodíku chemie   MeSH
• peroxidace lipidů účinky léků   MeSH
• proliferace buněk účinky léků   MeSH
• protinádorová antibiotika toxicita   MeSH
• pyridoxal analogy a deriváty   farmakologie   MeSH
• razoxan farmakologie   MeSH
• sloučeniny železa chemie   metabolismus   MeSH
• viabilita buněk účinky léků   MeSH
• volné radikály chemie   MeSH
• železo chemie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• aldehydy MeSH
• bleomycin MeSH
• chelátory železa MeSH
• deferoxamin MeSH
• doxorubicin MeSH
• Fenton's reagent MeSH Prohlížeč
• hydrazony MeSH
• isoniazid MeSH
• peroxid vodíku MeSH
• protinádorová antibiotika MeSH
• pyridoxal isonicotinoyl hydrazone MeSH Prohlížeč
• pyridoxal MeSH
• razoxan MeSH
• salicylaldehyde isonicotinoyl hydrazone MeSH Prohlížeč
• sloučeniny železa MeSH
• volné radikály MeSH
• železo MeSH

Iron chelation is the only pharmacological intervention against anthracycline cardiotoxicity whose effectiveness has been well documented both experimentally and clinically. In this study, we aimed to assess whether pyridoxal 2-chlorobenzoyl hydrazone (o-108, a strong iron chelator) can provide effective protection against daunorubicin (DAU)-induced chronic cardiotoxicity in rabbits. First, using the HL-60 leukemic cell line, it was shown that o-108 has no potential to blunt the antiproliferative efficacy of DAU. Instead, o-108 itself moderately inhibited cell proliferation. In vivo, chronic DAU treatment (3 mg/kg weekly for 10 weeks) induced mortality (33%), left ventricular (LV) dysfunction, a troponin T rise, and typical morphological LV damage. In contrast, all animals treated with 10 mg/kg o-108 before DAU survived without a significant drop in the LV ejection fraction (63.2 +/- 0.5 versus 59.2 +/- 1.0%, beginning versus end, not significant), and their cardiac contractility (dP/dt(max)) was significantly higher than in the DAU-only group (1131 +/- 125 versus 783 +/- 53 kPa/s, p < 0.05), which corresponded with histologically assessed lower extent and intensity of myocardial damage. Although higher o-108 dose (25 mg/kg) was well tolerated when administered alone, in combination with DAU it led to rather paradoxical and mostly negative results regarding both cardioprotection and overall mortality. In conclusion, we show that shielding of free intracellular iron using a potent lipophilic iron chelator is able to offer a meaningful protection against chronic anthracycline cardiotoxicity. However, this approach lost its potential with the higher chelator dose, which suggests that iron might play more complex role in the pathogenesis of this disease than previously assumed.

• MeSH
• buněčné dělení účinky léků   MeSH
• chelátory železa farmakologie   MeSH
• činčila MeSH
• daunomycin * MeSH
• elektrokardiografie účinky léků   MeSH
• funkce levé komory srdeční účinky léků   MeSH
• HL-60 buňky MeSH
• hydrazony farmakologie   MeSH
• kardiotonika * MeSH
• kontrakce myokardu účinky léků   MeSH
• králíci MeSH
• krevní tlak účinky léků   MeSH
• lidé MeSH
• minutový srdeční výdej účinky léků   MeSH
• myokard metabolismus   patologie   MeSH
• nemoci srdce chemicky indukované   patologie   prevence a kontrola   MeSH
• protinádorová antibiotika * MeSH
• pyridoxal analogy a deriváty   farmakologie   MeSH
• srdeční frekvence účinky léků   MeSH
• tělesná hmotnost účinky léků   MeSH
• tepový objem účinky léků   MeSH
• troponin T metabolismus   MeSH
• zvířata MeSH
• Check Tag
• králíci MeSH
• lidé MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• chelátory železa MeSH
• daunomycin * MeSH
• hydrazony MeSH
• kardiotonika * MeSH
• protinádorová antibiotika * MeSH
• pyridoxal 2-chlorobenzoyl hydrazone MeSH Prohlížeč
• pyridoxal MeSH
• troponin T MeSH

Risk of cardiotoxicity is the most serious drawback of the clinical usefulness of anthracycline antineoplastic antibiotics, which however, remain among the most powerful and widely employed anticancer drugs. In this study we have used daunorubicin-induced cardiomyopathy in rabbits as a model to investigate possible cardioprotective effects of pyridoxal isonicotinoyl hydrazone (PIH)-a principal representative of a novel group of aroylhydrazone iron chelators. Three groups of animals were used: a control group (n=11; i.v. saline), daunorubicin-treated animals (n=11; 3mg/kg, i.v.), and animals pretreated with PIH (n=9, 25 mg/kg, i.p.) 60 min before daunorubicin administration. All substances were administered once weekly for 10 weeks. Repeated administration of daunorubicin caused premature death in four animals and induced conspicuous histopathological changes in the myocardium, progressive and significant impairment of systolic heart function (a decrease in left ventricular dP/dt(max), ejection fraction, an increase in the pre-ejection period/left ventricular ejection time index), and a gradual increase in cardiac troponin T plasma concentrations. On the contrary, all the PIH-treated animals have survived all daunorubicin applications. Furthermore, in this group, the daunorubicin-induced cardiac changes were in most functional, biochemical as well as morphological parameters less pronounced than in the group receiving daunorubicin alone. Hence, PIH and other aroylhydrazones merit further investigation as potentially protective agents against anthracycline-induced cardiotoxicity.

• MeSH
• daunomycin toxicita   MeSH
• isoniazid analogy a deriváty   farmakologie   MeSH
• kardiotonika farmakologie   MeSH
• králíci MeSH
• myokard metabolismus   patologie   MeSH
• pyridoxal analogy a deriváty   farmakologie   MeSH
• srdeční komory účinky léků   metabolismus   patologie   MeSH
• zvířata MeSH
• Check Tag
• králíci MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• srovnávací studie MeSH
• Názvy látek
• daunomycin MeSH
• isoniazid MeSH
• kardiotonika MeSH
• pyridoxal isonicotinoyl hydrazone MeSH Prohlížeč
• pyridoxal MeSH

A major obstacle to the therapeutic use of anthracyclines, highly effective anticancer agents, is the fact that their administration results in dose-dependent cardiomyopathy. According to the currently accepted hypothesis, anthracyclines injure the heart by generating oxygen free radicals. The ability of pyridoxal isonicotinoyl hydrazone (PIH) and salicylaldehyde isonicotinoyl hydrazone (SIH) -- new iron chelators -- to protect against peroxidation as well as their suitable biological, physical and chemical properties make the compounds promising candidates for pre-clinical and clinical studies. Activities of carbonyl reductase CR (1.1.1.184), dihydrodiol dehydrogenase DD2 (1.3.1.20), aldehyde reductase ALR1 (1.1.1.2) and P450 isoenzymes (CYP1A1, CYP1A2, CYP2B, CYP3A) involved in the metabolism of daunorubicin, doxorubicin and other drugs or xenobiotics were studied. Various concentrations of the chelators were used either alone or together with daunorubicin or doxorubicin for in vitro studies in isolated hepatocytes. A significant decrease of activity was observed for all enzymes only at PIH and SIH concentrations higher than those presumed to be used for therapy. The results show that PIH and SIH have no effect on the activities of the enzymes studied in vitro and allow us to believe that they will not interfere with the metabolism of co-administered drugs and other xenobiotics. Daunorubicin (Da) and doxorubicin (Dx) significantly reduce cytochrome P450 activity, but the addition of SIH and PIH chelators (50 microM) reverses the reduction and restores the activity to 70-90 % of the activity of relevant controls.

• MeSH
• aktivace enzymů účinky léků   MeSH
• aldehydy farmakologie   MeSH
• antracykliny metabolismus   farmakologie   MeSH
• chelátory farmakologie   MeSH
• cytosol účinky léků   metabolismus   MeSH
• hepatocyty účinky léků   metabolismus   MeSH
• hydrazony farmakologie   MeSH
• isoniazid analogy a deriváty   farmakologie   MeSH
• králíci MeSH
• kultivované buňky MeSH
• oxidoreduktasy účinky léků   metabolismus   MeSH
• protinádorová antibiotika metabolismus   farmakologie   MeSH
• protinádorové látky metabolismus   farmakologie   MeSH
• pyridoxal analogy a deriváty   farmakologie   MeSH
• systém (enzymů) cytochromů P-450 účinky léků   metabolismus   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• zvířata MeSH
• Check Tag
• králíci MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• srovnávací studie MeSH
• Názvy látek
• aldehydy MeSH
• antracykliny MeSH
• chelátory MeSH
• hydrazony MeSH
• isoniazid MeSH
• oxidoreduktasy MeSH
• protinádorová antibiotika MeSH
• protinádorové látky MeSH
• pyridoxal isonicotinoyl hydrazone MeSH Prohlížeč
• pyridoxal MeSH
• salicylaldehyde isonicotinoyl hydrazone MeSH Prohlížeč
• systém (enzymů) cytochromů P-450 MeSH

Iron overload is a major life-threatening complication of thalassemia major and other iron-loading anemias treated by regular blood transfusions. Although the clinical manifestations of iron overload may be prevented by desferrioxamine, the only iron-chelating drug in routine clinical use, this treatment requires subcutaneous infusion of desferrioxamine for 12 hours each day. New orally effective iron chelators are urgently needed, and pyridoxal isonicotinoyl hydrazone (PIH), which was first recognized as an effective iron chelator in vitro and subsequently in vivo, shows promise for the treatment of iron overload. More recently, over 40 analogs of PIH were synthesized, and some of them proved to be very potent in mobilizing 59Fe in vitro from 59Fe-labeled cells. In this study, we show that PIH analogs such as pyridoxal benzoyl hydrazone, pyridoxal p-methoxybenzoyl hydrazone (PMBH), pyridoxal m-fluorobenzoyl hydrazone (PFBH), and pyridoxal-2-thiophenecarboxyl hydrazone, compounds previously shown to mobilize iron from cells in vitro, are also effective in vivo. All of these chelators significantly enhanced biliary excretion of iron (measured by atomic absorption spectrophotometry) following their intraperitoneal (IP) and/or oral administration to rats. The most effective was PFBH, which increased iron concentration in the bile about 150-fold, as compared with basal biliary iron concentration, within 1 hour following a single IP dose of 0.2 mmol/kg body weight. In contrast, desferrioxamine increased the biliary iron concentration only 20-fold to 30-fold under the same conditions. Moreover, while control rats excreted approximately 0.8 microg Fe in 2 hours, treatment with PFBH, PMBH, and desferrioxamine resulted in cumulative excretions of 87, 59, and 22 microg Fe, respectively, in the same period of time. Interestingly, PMBH was also quite effective following gastric administration, resulting in a 6-hour cumulative value of 34 microg Fe. These compounds are nontoxic and are inexpensive and easy to make. Their further evaluation as candidate drugs for the treatment of iron overload is warranted.

• MeSH
• chelátory železa chemie   farmakologie   MeSH
• isoniazid analogy a deriváty   chemie   farmakologie   MeSH
• krysa rodu Rattus MeSH
• potkani Wistar MeSH
• pyridoxal analogy a deriváty   chemie   farmakologie   MeSH
• železo metabolismus   MeSH
• žluč metabolismus   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• chelátory železa MeSH
• isoniazid MeSH
• pyridoxal isonicotinoyl hydrazone MeSH Prohlížeč
• pyridoxal MeSH
• železo MeSH