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
• PC12 Cells MeSH
• Iron Chelating Agents * pharmacology   MeSH
• Deferasirox pharmacology   MeSH
• Deferiprone pharmacology   MeSH
• Deferoxamine pharmacology   MeSH
• Dopamine pharmacology   MeSH
• Catecholamines pharmacology   MeSH
• Rats MeSH
• Oxidative Stress MeSH
• Oxidopamine pharmacology   MeSH
• Iron Overload * MeSH
• Iron pharmacology   MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, N.I.H., Extramural MeSH
• Names of Substances
• Iron Chelating Agents * MeSH
• Deferasirox MeSH
• Deferiprone MeSH
• Deferoxamine MeSH
• Dopamine MeSH
• Catecholamines MeSH
• Oxidopamine MeSH
• Iron 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
• Anthracyclines adverse effects   MeSH
• Dexrazoxane chemistry   pharmacology   MeSH
• Diketopiperazines chemistry   pharmacology   MeSH
• DNA Topoisomerases, Type II metabolism   MeSH
• Topoisomerase II Inhibitors chemistry   pharmacology   MeSH
• Myocytes, Cardiac drug effects   metabolism   MeSH
• Cardiotonic Agents chemistry   pharmacology   MeSH
• Cardiotoxicity drug therapy   metabolism   MeSH
• Rabbits MeSH
• Piperazine chemistry   pharmacology   MeSH
• Prodrugs chemistry   pharmacology   MeSH
• Razoxane chemistry   pharmacology   MeSH
• Water chemistry   MeSH
• Animals MeSH
• Check Tag
• Rabbits MeSH
• Male MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• 4,4'-(1,2-dimethyl-1,2-ethanediyl)bis-2,6-piperazinedione MeSH Browser
• Anthracyclines MeSH
• Dexrazoxane MeSH
• Diketopiperazines MeSH
• DNA Topoisomerases, Type II MeSH
• Topoisomerase II Inhibitors MeSH
• Cardiotonic Agents MeSH
• Piperazine MeSH
• Prodrugs MeSH
• Razoxane MeSH
• Water 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
• Edetic Acid chemistry   MeSH
• Myocytes, Cardiac cytology   metabolism   MeSH
• Rats MeSH
• Cells, Cultured MeSH
• Piperazines analysis   MeSH
• Rats, Wistar MeSH
• Antineoplastic Agents analysis   metabolism   MeSH
• Razoxane analogs & derivatives   chemistry   metabolism   MeSH
• Tandem Mass Spectrometry MeSH
• Chromatography, High Pressure Liquid MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• 1,2-bis(3,5-dioxopiperazin-1-yl)ethane MeSH Browser
• Edetic Acid MeSH
• Piperazines MeSH
• Antineoplastic Agents MeSH
• Razoxane MeSH
• sobuzoxane MeSH Browser

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.

• Keywords
• Catecholamine, Flavonoid, H9c2 cell line, Isoprenaline, Reactive oxygen species, Rutin, Wistar rat,
• MeSH
• Cell Line MeSH
• Dinoprost analogs & derivatives   blood   MeSH
• Electrocardiography MeSH
• Glutathione blood   MeSH
• Injections, Intravenous MeSH
• Isoproterenol adverse effects   MeSH
• Kaplan-Meier Estimate MeSH
• Cardiotoxicity etiology   mortality   MeSH
• Myocardium pathology   MeSH
• Rats, Wistar MeSH
• Reactive Oxygen Species metabolism   MeSH
• Rutin administration & dosage   adverse effects   pharmacokinetics   MeSH
• Heart drug effects   MeSH
• Dose-Response Relationship, Drug MeSH
• Animals MeSH
• Check Tag
• Male MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• 8-epi-prostaglandin F2alpha MeSH Browser
• Dinoprost MeSH
• Glutathione MeSH
• Isoproterenol MeSH
• Reactive Oxygen Species 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
• Cell Line MeSH
• Iron Chelating Agents pharmacology   MeSH
• Deferoxamine pharmacology   MeSH
• Ions MeSH
• Cardiotonic Agents chemistry   pharmacology   MeSH
• Catecholamines MeSH
• Hydrogen-Ion Concentration MeSH
• Myocardium pathology   MeSH
• Penicillamine chemistry   pharmacology   MeSH
• Rats, Wistar MeSH
• Troponin T metabolism   MeSH
• Cell Survival drug effects   MeSH
• Iron metabolism   MeSH
• Animals MeSH
• Check Tag
• Male MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Iron Chelating Agents MeSH
• Deferoxamine MeSH
• Ions MeSH
• Cardiotonic Agents MeSH
• Catecholamines MeSH
• Penicillamine MeSH
• Troponin T MeSH
• Iron 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.

• Keywords
• BHAPI, Cardiotoxicity, Catecholamines, HAPI, Iron chelation, Prochelator,
• MeSH
• Epinephrine antagonists & inhibitors   toxicity   MeSH
• Biocatalysis MeSH
• Cell Line MeSH
• Iron Chelating Agents pharmacology   MeSH
• Glutathione metabolism   MeSH
• Hydroxyl Radical metabolism   MeSH
• Isoproterenol antagonists & inhibitors   toxicity   MeSH
• Cardiotonic Agents pharmacology   MeSH
• Catecholamines antagonists & inhibitors   toxicity   MeSH
• Rats MeSH
• Boronic Acids pharmacology   MeSH
• Humans MeSH
• Membrane Potential, Mitochondrial drug effects   MeSH
• Oxidative Stress drug effects   MeSH
• Prodrugs pharmacology   MeSH
• Reactive Oxygen Species metabolism   MeSH
• Semicarbazones pharmacology   MeSH
• Boron Compounds pharmacology   MeSH
• Iron chemistry   MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Epinephrine MeSH
• Iron Chelating Agents MeSH
• Glutathione MeSH
• Hydroxyl Radical MeSH
• Isoproterenol MeSH
• Cardiotonic Agents MeSH
• Catecholamines MeSH
• Boronic Acids MeSH
• N'-(1-(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyloxy)phenyl)ethylidene)isonicotinohydrazide MeSH Browser
• Prodrugs MeSH
• Reactive Oxygen Species MeSH
• Semicarbazones MeSH
• Boron Compounds MeSH
• Iron 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.

• Keywords
• Boronyl salicylaldehyde isonicotinoyl hydrazone (BSIH), Iron chelation, Prochelator, Salicylaldehyde, Salicylaldehyde isonicotinoyl hydrazone (SIH),
• MeSH
• Aldehydes pharmacology   toxicity   MeSH
• Cell Line MeSH
• Iron Chelating Agents pharmacology   toxicity   MeSH
• Hydrazones pharmacology   toxicity   MeSH
• Rats MeSH
• Boronic Acids pharmacology   toxicity   MeSH
• Isonicotinic Acids pharmacology   toxicity   MeSH
• Membrane Potential, Mitochondrial drug effects   MeSH
• Myoblasts, Cardiac drug effects   metabolism   MeSH
• Oxidative Stress drug effects   MeSH
• Hydrogen Peroxide toxicity   MeSH
• Half-Life MeSH
• Reactive Oxygen Species metabolism   MeSH
• Cell Survival drug effects   MeSH
• Chromatography, High Pressure Liquid MeSH
• Iron metabolism   MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, N.I.H., Extramural MeSH
• Names of Substances
• (isonicotinic acid (2-(4,4,5,5-tetramethyl-(1,3,2)dioxaborolan-2-yl)benzylidene)hydrazide) MeSH Browser
• Aldehydes MeSH
• Iron Chelating Agents MeSH
• Hydrazones MeSH
• Boronic Acids MeSH
• Isonicotinic Acids MeSH
• Hydrogen Peroxide MeSH
• Reactive Oxygen Species MeSH
• salicylaldehyde isonicotinoyl hydrazone MeSH Browser
• Iron 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.

• Keywords
• Aroylhydrazone, Boronyl salicylaldehyde isonicotinoyl hydrazone, Pharmacokinetics, Prochelator salicylaldehyde isonicotinoyl hydrazone, Stability,
• MeSH
• Aldehydes analysis   blood   MeSH
• Chelating Agents analysis   MeSH
• Chromatography, Liquid methods   MeSH
• Mass Spectrometry methods   MeSH
• Hydrazones analysis   blood   MeSH
• Culture Media chemistry   MeSH
• Boronic Acids analysis   blood   MeSH
• Isonicotinic Acids analysis   blood   MeSH
• Molecular Structure MeSH
• Rats, Wistar MeSH
• Reference Standards MeSH
• Sensitivity and Specificity MeSH
• Spectrophotometry, Ultraviolet methods   MeSH
• Drug Stability MeSH
• Animals MeSH
• Check Tag
• Male MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, N.I.H., Extramural MeSH
• Names of Substances
• (isonicotinic acid (2-(4,4,5,5-tetramethyl-(1,3,2)dioxaborolan-2-yl)benzylidene)hydrazide) MeSH Browser
• Aldehydes MeSH
• Chelating Agents MeSH
• Hydrazones MeSH
• Culture Media MeSH
• Boronic Acids MeSH
• Isonicotinic Acids MeSH
• salicylaldehyde isonicotinoyl hydrazone MeSH Browser

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
• Aldehydes chemistry   pharmacology   toxicity   MeSH
• Antioxidants chemistry   pharmacology   MeSH
• Cell Line MeSH
• Iron Chelating Agents chemistry   pharmacology   MeSH
• Hydrazones chemistry   pharmacology   toxicity   MeSH
• Humans MeSH
• MCF-7 Cells MeSH
• Myoblasts drug effects   MeSH
• Oxidative Stress drug effects   MeSH
• Hydrogen Peroxide toxicity   MeSH
• Antineoplastic Agents chemistry   toxicity   MeSH
• Structure-Activity Relationship MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Aldehydes MeSH
• Antioxidants MeSH
• Iron Chelating Agents MeSH
• Hydrazones MeSH
• Hydrogen Peroxide MeSH
• Antineoplastic Agents MeSH
• salicylaldehyde isonicotinoyl hydrazone MeSH Browser

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.

• Keywords
• BSIH, Deferasirox, Free radicals, ICL670A, Iron chelation, Prochelator, Salicylaldehyde isonicotinoyl hydrazone,
• MeSH
• Aldehydes chemistry   pharmacology   MeSH
• Apoptosis drug effects   MeSH
• Benzoates chemistry   pharmacology   MeSH
• Cell Line MeSH
• Iron Chelating Agents chemistry   pharmacology   MeSH
• Cytoprotection * MeSH
• Deferasirox MeSH
• Hydrazones chemistry   pharmacology   MeSH
• Myocytes, Cardiac drug effects   physiology   MeSH
• Rats MeSH
• Boronic Acids chemistry   pharmacology   MeSH
• Isonicotinic Acids chemistry   pharmacology   MeSH
• Membrane Potential, Mitochondrial drug effects   MeSH
• Oxidative Stress drug effects   MeSH
• Cell Membrane Permeability drug effects   MeSH
• Hydrogen Peroxide metabolism   MeSH
• Rats, Wistar MeSH
• Semicarbazones chemistry   pharmacology   MeSH
• Boron Compounds chemistry   pharmacology   MeSH
• Mitochondria, Heart drug effects   physiology   MeSH
• Triazoles chemistry   pharmacology   MeSH
• Iron chemistry   metabolism   MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, N.I.H., Extramural MeSH
• Comparative Study MeSH
• Names of Substances
• (isonicotinic acid (2-(4,4,5,5-tetramethyl-(1,3,2)dioxaborolan-2-yl)benzylidene)hydrazide) MeSH Browser
• Aldehydes MeSH
• Benzoates MeSH
• Iron Chelating Agents MeSH
• Deferasirox MeSH
• Hydrazones MeSH
• Boronic Acids MeSH
• Isonicotinic Acids MeSH
• N'-(1-(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyloxy)phenyl)ethylidene)isonicotinohydrazide MeSH Browser
• Hydrogen Peroxide MeSH
• salicylaldehyde isonicotinoyl hydrazone MeSH Browser
• Semicarbazones MeSH
• Boron Compounds MeSH
• Triazoles MeSH
• Iron MeSH