Labile redox-active iron ions have been implicated in various neurodegenerative disorders, including the Parkinson's disease (PD). Iron chelation has been successfully used in clinical practice to manage iron overload in diseases such as thalassemia major; however, the use of conventional iron chelators in pathological states without systemic iron overload remains at the preclinical investigative level and is complicated by the risk of adverse outcomes due to systemic iron depletion. In this study, we examined three clinically-used chelators, namely, desferrioxamine, deferiprone and deferasirox and compared them with experimental agent salicylaldehyde isonicotinoyl hydrazone (SIH) and its boronate-masked prochelator BSIH for protection of differentiated PC12 cells against the toxicity of catecholamines 6-hydroxydopamine and dopamine and their oxidation products. All the assayed chelating agents were able to significantly reduce the catecholamine toxicity in a dose-dependent manner. Whereas hydrophilic chelator desferrioxamine exerted protection only at high and clinically unachievable concentrations, deferiprone and deferasirox significantly reduced the catecholamine neurotoxicity at concentrations that are within their plasma levels following standard dosage. SIH was the most effective iron chelator to protect the cells with the lowest own toxicity of all the assayed conventional chelators. This favorable feature was even more pronounced in prochelator BSIH that does not chelate iron unless its protective group is cleaved in disease-specific oxidative stress conditions. Hence, this study demonstrated that while iron chelation may have general neuroprotective potential against catecholamine auto-oxidation and toxicity, SIH and BSIH represent promising lead molecules and warrant further studies in more complex animal models.

• MeSH
• buňky PC12 MeSH
• chelátory železa * farmakologie   MeSH
• deferasirox farmakologie   MeSH
• deferipron farmakologie   MeSH
• deferoxamin farmakologie   MeSH
• dopamin farmakologie   MeSH
• katecholaminy farmakologie   MeSH
• krysa rodu Rattus MeSH
• oxidační stres MeSH
• oxidopamin farmakologie   MeSH
• přetížení železem * MeSH
• železo farmakologie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• chelátory železa * MeSH
• deferasirox MeSH
• deferipron MeSH
• deferoxamin MeSH
• dopamin MeSH
• katecholaminy MeSH
• oxidopamin MeSH
• železo MeSH

The bisdioxopiperazine topoisomerase IIβ inhibitor ICRF-193 has been previously identified as a more potent analog of dexrazoxane (ICRF-187), a drug used in clinical practice against anthracycline cardiotoxicity. However, the poor aqueous solubility of ICRF-193 has precluded its further in vivo development as a cardioprotective agent. To overcome this issue, water-soluble prodrugs of ICRF-193 were prepared, their abilities to release ICRF-193 were investigated using a novel UHPLC-MS/MS assay, and their cytoprotective effects against anthracycline cardiotoxicity were tested in vitro in neonatal ventricular cardiomyocytes (NVCMs). Based on the obtained results, the bis(2-aminoacetoxymethyl)-type prodrug GK-667 was selected for advanced investigations due to its straightforward synthesis, sufficient solubility, low cytotoxicity and favorable ICRF-193 release. Upon administration of GK-667 to NVCMs, the released ICRF-193 penetrated well into the cells, reached sufficient intracellular concentrations and provided effective cytoprotection against anthracycline toxicity. The pharmacokinetics of the prodrug, ICRF-193 and its rings-opened metabolite was estimated in vivo after administration of GK-667 to rabbits. The plasma concentrations of ICRF-193 reached were found to be adequate to achieve cardioprotective effects in vivo. Hence, GK-667 was demonstrated to be a pharmaceutically acceptable prodrug of ICRF-193 and a promising drug candidate for further evaluation as a potential cardioprotectant against chronic anthracycline toxicity.

• MeSH
• antracykliny škodlivé účinky   MeSH
• dexrazoxan chemie   farmakologie   MeSH
• diketopiperaziny chemie   farmakologie   MeSH
• DNA-topoisomerasy typu II metabolismus   MeSH
• inhibitory topoisomerasy II chemie   farmakologie   MeSH
• kardiomyocyty účinky léků   metabolismus   MeSH
• kardiotonika chemie   farmakologie   MeSH
• kardiotoxicita farmakoterapie   metabolismus   MeSH
• králíci MeSH
• piperazin chemie   farmakologie   MeSH
• prekurzory léčiv chemie   farmakologie   MeSH
• razoxan chemie   farmakologie   MeSH
• voda chemie   MeSH
• zvířata MeSH
• Check Tag
• králíci MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• 4,4'-(1,2-dimethyl-1,2-ethanediyl)bis-2,6-piperazinedione MeSH Prohlížeč
• antracykliny MeSH
• dexrazoxan MeSH
• diketopiperaziny MeSH
• DNA-topoisomerasy typu II MeSH
• inhibitory topoisomerasy II MeSH
• kardiotonika MeSH
• piperazin MeSH
• prekurzory léčiv MeSH
• razoxan MeSH
• voda MeSH

Sobuzoxane (MST-16) is an approved anticancer agent, a pro-drug of bisdioxopiperazine analog ICRF-154. Due to the structural similarity of ICRF-154 to dexrazoxane (ICRF-187), MST-16 deserves attention as a cardioprotective drug. This study presents for the first time UHPLC-MS/MS assay of MST-16, ICRF-154 and its metabolite (EDTA-diamide) in cell culture medium, buffer, plasma and cardiac cells and provides data on MST-16 bioactivation under conditions relevant to investigation of cardioprotection of this drug. The analysis of these compounds that differ considerably in their lipophilicity was achieved on the Zorbax SB-Aq column using a mixture of aqueous ammonium formate and methanol as a mobile phase. The biological samples were either diluted or precipitated with methanol, which was followed by acidification for the assay of MST-16. The method was validated for determination of all compounds in the biological materials. The application of the method for analysis of samples from in vitro experiments provided important findings, namely, that (1) MST-16 is quickly decomposed in biological environments, (2) the cardiac cells actively metabolize MST-16, and (3) MST-16 readily penetrates into the cardiac cells and is converted into ICRF-154 and EDTA-diamide. These data are useful for the in-depth examination of the cardioprotective potential of this drug.

• MeSH
• EDTA chemie   MeSH
• kardiomyocyty cytologie   metabolismus   MeSH
• krysa rodu Rattus MeSH
• kultivované buňky MeSH
• piperaziny analýza   MeSH
• potkani Wistar MeSH
• protinádorové látky analýza   metabolismus   MeSH
• razoxan analogy a deriváty   chemie   metabolismus   MeSH
• tandemová hmotnostní spektrometrie MeSH
• vysokoúčinná kapalinová chromatografie MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• 1,2-bis(3,5-dioxopiperazin-1-yl)ethane MeSH Prohlížeč
• EDTA MeSH
• piperaziny MeSH
• protinádorové látky MeSH
• razoxan MeSH
• sobuzoxane MeSH Prohlížeč

OBJECTIVES: Rutin, quercetin-3-O-rutinoside, a natural flavonol glycoside, has shown various in vitro benefits with potential use treating human diseases, especially cardiovascular system disorders. Antioxidant properties are assumed to underlie the majority of these benefits. Yet rutin pro-oxidant properties have been reported as well. Our research group has recently shown aggravating effects on isoprenaline (ISO)-induced cardiotoxicity in Wistar:Han rats after 24 hours. METHODS: This study was designed to examine in more detail the reasons for the negative effects of rutin (11.5 and 46 mg/kg, i.v.) after administration of ISO (100 mg/kg, s.c.) in rats within 2 hours of continuous experiment and in the H9c2 cardiomyoblast-derived cell line. RESULTS: Like our previous findings, rutin did not (11.5 or 46 mg/kg, i.v.) reduce the ISO-induced mortality within 2 hours although the lower dose significantly reduced cardiac troponin T (cTnT) and partly improved the histological findings. In contrast, the higher dose increased the mortality in comparison with solvent (1.26% w/v sodium bicarbonate). This was not caused by any specific haemodynamic disturbances. It appears to be associated with oxidative stress as rutin enhanced intracellular reactive oxygen species formation in vitro and had the tendency to increase it in vivo. CONCLUSIONS: Rutin, likely due to its pro-oxidative effects, can exacerbate catecholamine cardiotoxicity depending on the dose used.

• Klíčová slova
• Catecholamine, Flavonoid, H9c2 cell line, Isoprenaline, Reactive oxygen species, Rutin, Wistar rat,
• MeSH
• buněčné linie MeSH
• dinoprost analogy a deriváty   krev   MeSH
• elektrokardiografie MeSH
• glutathion krev   MeSH
• injekce intravenózní MeSH
• isoprenalin škodlivé účinky   MeSH
• Kaplanův-Meierův odhad MeSH
• kardiotoxicita etiologie   mortalita   MeSH
• myokard patologie   MeSH
• potkani Wistar MeSH
• reaktivní formy kyslíku metabolismus   MeSH
• rutin aplikace a dávkování   škodlivé účinky   farmakokinetika   MeSH
• srdce účinky léků   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• 8-epi-prostaglandin F2alpha MeSH Prohlížeč
• dinoprost MeSH
• glutathion MeSH
• isoprenalin MeSH
• reaktivní formy kyslíku MeSH
• rutin MeSH

Iron and copper release participates in the myocardial injury under ischemic conditions and hence protection might be achieved by iron chelators. Data on copper chelation are, however, sparse. The effect of the clinically used copper chelator D-penicillamine in the catecholamine model of acute myocardial injury was tested in cardiomyoblast cell line H9c2 and in Wistar Han rats. D-Penicillamine had a protective effect against catecholamine-induced injury both in vitro and in vivo. It protected H9c2 cells against the catecholamine-induced viability loss in a dose-dependent manner. In animals, both intravenous D-penicillamine doses of 11 (low) and 44 mg/kg (high) decreased the mortality caused by s.c. isoprenaline (100 mg/kg) from 36% to 14% and 22%, respectively. However, whereas the low D-penicillamine dose decreased the release of cardiac troponin T (specific marker of myocardial injury), the high dose resulted in an increase. Interestingly, the high dose led to a marked elevation in plasma vitamin C. This might be related to potentiation of oxidative stress, as suggested by additional in vitro experiments with D-penicillamine (iron reduction and the Fenton reaction). In conclusion, D-penicillamine has protective potential against catecholamine-induced cardiotoxicity; however the optimal dose selection seems to be crucial for further application.

• MeSH
• buněčné linie MeSH
• chelátory železa farmakologie   MeSH
• deferoxamin farmakologie   MeSH
• ionty MeSH
• kardiotonika chemie   farmakologie   MeSH
• katecholaminy MeSH
• koncentrace vodíkových iontů MeSH
• myokard patologie   MeSH
• penicilamin chemie   farmakologie   MeSH
• potkani Wistar MeSH
• troponin T metabolismus   MeSH
• viabilita buněk účinky léků   MeSH
• železo metabolismus   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• chelátory železa MeSH
• deferoxamin MeSH
• ionty MeSH
• kardiotonika MeSH
• katecholaminy MeSH
• penicilamin MeSH
• troponin T MeSH
• železo MeSH

Catecholamines may undergo iron-promoted oxidation resulting in formation of reactive intermediates (aminochromes) capable of redox cycling and reactive oxygen species (ROS) formation. Both of them induce oxidative stress resulting in cellular damage and death. Iron chelation has been recently shown as a suitable tool of cardioprotection with considerable potential to protect cardiac cells against catecholamine-induced cardiotoxicity. However, prolonged exposure of cells to classical chelators may interfere with physiological iron homeostasis. Prochelators represent a more advanced approach to decrease oxidative injury by forming a chelating agent only under the disease-specific conditions associated with oxidative stress. Novel prochelator (lacking any iron chelating properties) BHAPI [(E)-Ń-(1-(2-((4-(4,4,5,5-tetramethyl-1,2,3-dioxoborolan-2-yl)benzyl)oxy)phenyl)ethylidene) isonicotinohydrazide] is converted by ROS to active chelator HAPI with strong iron binding capacity that efficiently inhibits iron-catalyzed hydroxyl radical generation. Our results confirmed redox activity of oxidation products of catecholamines isoprenaline and epinephrine, that were able to activate BHAPI to HAPI that chelates iron ions inside H9c2 cardiomyoblasts. Both HAPI and BHAPI were able to efficiently protect the cells against intracellular ROS formation, depletion of reduced glutathione and toxicity induced by catecholamines and their oxidation products. Hence, both HAPI and BHAPI have shown considerable potential to protect cardiac cells by both inhibition of deleterious catecholamine oxidation to reactive intermediates and prevention of ROS-mediated cardiotoxicity.

• Klíčová slova
• BHAPI, Cardiotoxicity, Catecholamines, HAPI, Iron chelation, Prochelator,
• MeSH
• adrenalin antagonisté a inhibitory   toxicita   MeSH
• biokatalýza MeSH
• buněčné linie MeSH
• chelátory železa farmakologie   MeSH
• glutathion metabolismus   MeSH
• hydroxylový radikál metabolismus   MeSH
• isoprenalin antagonisté a inhibitory   toxicita   MeSH
• kardiotonika farmakologie   MeSH
• katecholaminy antagonisté a inhibitory   toxicita   MeSH
• krysa rodu Rattus MeSH
• kyseliny boronové farmakologie   MeSH
• lidé MeSH
• membránový potenciál mitochondrií účinky léků   MeSH
• oxidační stres účinky léků   MeSH
• prekurzory léčiv farmakologie   MeSH
• reaktivní formy kyslíku metabolismus   MeSH
• semikarbazony farmakologie   MeSH
• sloučeniny boru farmakologie   MeSH
• železo chemie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• adrenalin MeSH
• chelátory železa MeSH
• glutathion MeSH
• hydroxylový radikál MeSH
• isoprenalin MeSH
• kardiotonika MeSH
• katecholaminy MeSH
• kyseliny boronové MeSH
• N'-(1-(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyloxy)phenyl)ethylidene)isonicotinohydrazide MeSH Prohlížeč
• prekurzory léčiv MeSH
• reaktivní formy kyslíku MeSH
• semikarbazony MeSH
• sloučeniny boru MeSH
• železo MeSH

Free cellular iron catalyzes the formation of toxic hydroxyl radicals and therefore chelation of iron could be a promising therapeutic approach in pathological states associated with oxidative stress. Salicylaldehyde isonicotinoyl hydrazone (SIH) is a strong intracellular iron chelator with well documented potential to protect against oxidative damage both in vitro and in vivo. Due to the short biological half-life of SIH and risk of toxicity due to iron depletion, boronate prochelator BSIH has been designed. BSIH cannot bind iron until it is activated by certain reactive oxygen species to active chelator SIH. The aim of this study was to examine the toxicity and cytoprotective potential of BSIH, SIH, and their decomposition products against hydrogen peroxide-induced injury of H9c2 cardiomyoblast cells. Using HPLC, we observed that salicylaldehyde was the main decomposition products of SIH and BSIH, although a small amount of salicylic acid was also detected. In the case of BSIH, the concentration of formed salicylaldehyde consistently exceeded that of SIH. Isoniazid and salicylic acid were not toxic nor did they provide any antioxidant protective effect in H9c2 cells. In contrast, salicylaldehyde was able to chelate intracellular iron and significantly preserve cellular viability and mitochondrial inner membrane potential induced by hydrogen peroxide. However it was consistently less effective than SIH. The inherent toxicities of salicylaldehyde and SIH were similar. Hence, although SIH - the active chelating agent formed following the BSIH activation - undergoes rapid hydrolysis, its principal decomposition product salicylaldehyde accounts markedly for both cytoprotective and toxic properties.

• Klíčová slova
• Boronyl salicylaldehyde isonicotinoyl hydrazone (BSIH), Iron chelation, Prochelator, Salicylaldehyde, Salicylaldehyde isonicotinoyl hydrazone (SIH),
• MeSH
• aldehydy farmakologie   toxicita   MeSH
• buněčné linie MeSH
• chelátory železa farmakologie   toxicita   MeSH
• hydrazony farmakologie   toxicita   MeSH
• krysa rodu Rattus MeSH
• kyseliny boronové farmakologie   toxicita   MeSH
• kyseliny isonikotinové farmakologie   toxicita   MeSH
• membránový potenciál mitochondrií účinky léků   MeSH
• myoblasty srdeční účinky léků   metabolismus   MeSH
• oxidační stres účinky léků   MeSH
• peroxid vodíku toxicita   MeSH
• poločas MeSH
• reaktivní formy kyslíku metabolismus   MeSH
• viabilita buněk účinky léků   MeSH
• vysokoúčinná kapalinová chromatografie MeSH
• železo metabolismus   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• (isonicotinic acid (2-(4,4,5,5-tetramethyl-(1,3,2)dioxaborolan-2-yl)benzylidene)hydrazide) MeSH Prohlížeč
• aldehydy MeSH
• chelátory železa MeSH
• hydrazony MeSH
• kyseliny boronové MeSH
• kyseliny isonikotinové MeSH
• peroxid vodíku MeSH
• reaktivní formy kyslíku MeSH
• salicylaldehyde isonicotinoyl hydrazone MeSH Prohlížeč
• železo MeSH

Salicylaldehyde isonicotinoyl hydrazone (SIH) is an intracellular iron chelator with well documented potential to protect against oxidative injury both in vitro and in vivo. However, it suffers from short biological half-life caused by fast hydrolysis of the hydrazone bond. Recently, a concept of boronate prochelators has been introduced as a strategy that might overcome these limitations. This study presents two complementary analytical methods for detecting the prochelator-boronyl salicylaldehyde isonicotinoyl hydrazone-BSIH along with its active metal-binding chelator SIH in different solution matrices and concentration ranges. An LC-UV method for determination of BSIH and SIH in buffer and cell culture medium was validated over concentrations of 7-115 and 4-115 μM, respectively, and applied to BSIH activation experiments in vitro. An LC-MS assay was validated for quantification of BSIH and SIH in plasma over the concentration range of 0.06-23 and 0.24-23 μM, respectively, and applied to stability studies in plasma in vitro as well as analysis of plasma taken after i.v. administration of BSIH to rats. A Zorbax-RP bonus column and mobile phases containing either phosphate buffer with EDTA or ammonium formate and methanol/acetonitrile mixture provided suitable conditions for the LC-UV and LC-MS analysis, respectively. Samples were diluted or precipitated with methanol prior to analysis. These separative analytical techniques establish the first validated protocols to investigate BSIH activation by hydrogen peroxide in multiple matrices, directly compare the stabilities of the prochelator and its chelator in plasma, and provide the first basic pharmacokinetic data of this prochelator. Experiments reveal that BSIH is stable in all media tested and is partially converted to SIH by H2O2. The observed integrity of BSIH in plasma samples from the in vivo study suggests that the concept of prochelation might be a promising strategy for further development of aroylhydrazone cytoprotective agents.

• Klíčová slova
• Aroylhydrazone, Boronyl salicylaldehyde isonicotinoyl hydrazone, Pharmacokinetics, Prochelator salicylaldehyde isonicotinoyl hydrazone, Stability,
• MeSH
• aldehydy analýza   krev   MeSH
• chelátory analýza   MeSH
• chromatografie kapalinová metody   MeSH
• hmotnostní spektrometrie metody   MeSH
• hydrazony analýza   krev   MeSH
• kultivační média chemie   MeSH
• kyseliny boronové analýza   krev   MeSH
• kyseliny isonikotinové analýza   krev   MeSH
• molekulární struktura MeSH
• potkani Wistar MeSH
• referenční standardy MeSH
• senzitivita a specificita MeSH
• spektrofotometrie ultrafialová metody   MeSH
• stabilita léku MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• (isonicotinic acid (2-(4,4,5,5-tetramethyl-(1,3,2)dioxaborolan-2-yl)benzylidene)hydrazide) MeSH Prohlížeč
• aldehydy MeSH
• chelátory MeSH
• hydrazony MeSH
• kultivační média MeSH
• kyseliny boronové MeSH
• kyseliny isonikotinové MeSH
• salicylaldehyde isonicotinoyl hydrazone MeSH Prohlížeč

Salicylaldehyde isonicotinoyl hydrazone (SIH) is a lipophilic, tridentate iron chelator with marked anti-oxidant and modest cytotoxic activity against neoplastic cells. However, it has poor stability in an aqueous environment due to the rapid hydrolysis of its hydrazone bond. In this study, we synthesized a series of new SIH analogs (based on previously described aromatic ketones with improved hydrolytic stability). Their structure-activity relationships were assessed with respect to their stability in plasma, iron chelation efficacy, redox effects and cytotoxic activity against MCF-7 breast adenocarcinoma cells. Furthermore, studies assessed the cytotoxicity of these chelators and their ability to afford protection against hydrogen peroxide-induced oxidative injury in H9c2 cardiomyoblasts. The ligands with a reduced hydrazone bond, or the presence of bulky alkyl substituents near the hydrazone bond, showed severely limited biological activity. The introduction of a bromine substituent increased ligand-induced cytotoxicity to both cancer cells and H9c2 cardiomyoblasts. A similar effect was observed when the phenolic ring was exchanged with pyridine (i.e., changing the ligating site from O, N, O to N, N, O), which led to pro-oxidative effects. In contrast, compounds with long, flexible alkyl chains adjacent to the hydrazone bond exhibited specific cytotoxic effects against MCF-7 breast adenocarcinoma cells and low toxicity against H9c2 cardiomyoblasts. Hence, this study highlights important structure-activity relationships and provides insight into the further development of aroylhydrazone iron chelators with more potent and selective anti-neoplastic effects.

• MeSH
• aldehydy chemie   farmakologie   toxicita   MeSH
• antioxidancia chemie   farmakologie   MeSH
• buněčné linie MeSH
• chelátory železa chemie   farmakologie   MeSH
• hydrazony chemie   farmakologie   toxicita   MeSH
• lidé MeSH
• MFC-7 buňky MeSH
• myoblasty účinky léků   MeSH
• oxidační stres účinky léků   MeSH
• peroxid vodíku toxicita   MeSH
• protinádorové látky chemie   toxicita   MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• aldehydy MeSH
• antioxidancia MeSH
• chelátory železa MeSH
• hydrazony MeSH
• peroxid vodíku MeSH
• protinádorové látky MeSH
• salicylaldehyde isonicotinoyl hydrazone MeSH Prohlížeč

Oxidative stress is a common denominator of numerous cardiovascular disorders. Free cellular iron catalyzes the formation of highly toxic hydroxyl radicals, and iron chelation may thus be an effective therapeutic approach. However, using classical iron chelators in diseases without iron overload poses risks that necessitate more advanced approaches, such as prochelators that are activated to chelate iron only under disease-specific oxidative stress conditions. In this study, three cell-membrane-permeable iron chelators (clinically used deferasirox and experimental SIH and HAPI) and five boronate-masked prochelator analogs were evaluated for their ability to protect cardiac cells against oxidative injury induced by hydrogen peroxide. Whereas the deferasirox-derived agents TIP and TRA-IMM displayed negligible protection and even considerable toxicity, the aroylhydrazone prochelators BHAPI and BSIH-PD provided significant cytoprotection and displayed lower toxicity after prolonged cellular exposure compared to their parent chelators HAPI and SIH, respectively. Overall, the most favorable properties in terms of protective efficiency and low inherent cytotoxicity were observed with the aroylhydrazone prochelator BSIH. BSIH efficiently protected both H9c2 rat cardiomyoblast-derived cells and isolated primary rat cardiomyocytes against hydrogen peroxide-induced mitochondrial and lysosomal dysregulation and cell death. At the same time, BSIH was nontoxic at concentrations up to its solubility limit (600 μM) and in 72-h incubation. Hence, BSIH merits further investigation for prevention and/or treatment of cardiovascular disorders associated with a known (or presumed) component of oxidative stress.

• Klíčová slova
• BSIH, Deferasirox, Free radicals, ICL670A, Iron chelation, Prochelator, Salicylaldehyde isonicotinoyl hydrazone,
• MeSH
• aldehydy chemie   farmakologie   MeSH
• apoptóza účinky léků   MeSH
• benzoáty chemie   farmakologie   MeSH
• buněčné linie MeSH
• chelátory železa chemie   farmakologie   MeSH
• cytoprotekce * MeSH
• deferasirox MeSH
• hydrazony chemie   farmakologie   MeSH
• kardiomyocyty účinky léků   fyziologie   MeSH
• krysa rodu Rattus MeSH
• kyseliny boronové chemie   farmakologie   MeSH
• kyseliny isonikotinové chemie   farmakologie   MeSH
• membránový potenciál mitochondrií účinky léků   MeSH
• oxidační stres účinky léků   MeSH
• permeabilita buněčné membrány účinky léků   MeSH
• peroxid vodíku metabolismus   MeSH
• potkani Wistar MeSH
• semikarbazony chemie   farmakologie   MeSH
• sloučeniny boru chemie   farmakologie   MeSH
• srdeční mitochondrie účinky léků   fyziologie   MeSH
• triazoly chemie   farmakologie   MeSH
• železo chemie   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• srovnávací studie MeSH
• Názvy látek
• (isonicotinic acid (2-(4,4,5,5-tetramethyl-(1,3,2)dioxaborolan-2-yl)benzylidene)hydrazide) MeSH Prohlížeč
• aldehydy MeSH
• benzoáty MeSH
• chelátory železa MeSH
• deferasirox MeSH
• hydrazony MeSH
• kyseliny boronové MeSH
• kyseliny isonikotinové MeSH
• N'-(1-(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyloxy)phenyl)ethylidene)isonicotinohydrazide MeSH Prohlížeč
• peroxid vodíku MeSH
• salicylaldehyde isonicotinoyl hydrazone MeSH Prohlížeč
• semikarbazony MeSH
• sloučeniny boru MeSH
• triazoly MeSH
• železo MeSH