Comparison of clinically used and experimental iron chelators for protection against oxidative stress-induced cellular injury

Bendova, Petra; Mackova, Eliska; Haskova, Pavlina; Vavrova, Anna; Jirkovsky, Eduard; Sterba, Martin; Popelova, Olga; Kalinowski, Danuta S.; Kovarikova, Petra; Vavrova, Katerina; Richardson, Des R.; Simunek, Tomas

doi:10.1021/tx100125t

Cited by 73Iron Metabolism and DisordersAntioxidant Activity and Oxidative StressFree Radicals and Antioxidants

Comparison of clinically used and experimental iron chelators for protection against oxidative stress-induced cellular injury

Bendova, Petra, Mackova, Eliska, Haskova, Pavlina, Vavrova, Anna, Jirkovsky, Eduard, Sterba, Martin, Popelova, Olga, Kalinowski, Danuta S. +4 more·2010·Chemical Research in Toxicology

DOI 10.1021/tx100125t

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Abstract

Iron imbalance plays an important role in oxidative stress associated with numerous pathological conditions. Therefore, iron chelation may be an effective therapeutic approach, but progress in this area is hindered by the lack of effective ligands. Also, the potential favorable effects of chelators against oxidative injury have to be balanced against their own toxicity due to iron depletion and the ability to generate redox-active iron complexes. In this study, we compared selected iron chelators (both drugs used in clinical practice as well as experimental agents) for their efficacy to protect cells against model oxidative injury induced by tert-butyl hydroperoxide (t-BHP). In addition, intracellular chelation efficiency, redox activity, and the cytotoxicity of the chelators and their iron complexes were assayed. Ethylenediaminetetraacetic acid failed to protect cells against t-BHP cytotoxicity, apparently due to the redox activity of the formed iron complex. Hydrophilic desferrioxamine exerted some protection but only at very high clinically unachievable concentrations. The smaller and more lipophilic chelators, deferiprone, deferasirox, and pyridoxal isonicotinoyl hydrazone, were markedly more effective at preventing oxidative injury of cells. The most effective chelator in terms of access to the intracellular labile iron pool was di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone. However, overall, the most favorable properties in terms of protective efficiency against t-BHP and the chelator's own inherent cytotoxicity were observed with salicylaldehyde isonicotinoyl hydrazone. This probably relates to the optimal lipophilicity of this latter agent and its ability to generate iron complexes that do not induce marked redox activity.

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An ideal metal chelator for Alzheimer's disease should meet essential qualities including moderate binding for metals, effective transit through biological membranes (particularly the blood-brain barrier), and thereby lower toxicity.
“A metal chelator as an ideal drug for AD should meet essential qualities including moderate binding for metals, effective transit through biological membranes (particularly the BBB) and thereby lower toxicity (Bendova et al., 2010).”
From An update on the novel and approved drugs for Alzheimer disease (2022) · cites this paper as Bendova et al., 2010

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“The chelating agents must possess properties like having moderate binding affinity for copper, zinc and iron metals, ability to cross BBB and should not toxic (Bendova et al., 2010).”
Background
Synthesis and Initial in Vitro Evaluations of Novel Antioxidant Aroylhydrazone Iron Chelators with Increased Stability against Plasma Hydrolysis
Hrušková, K., Kovařı́ková, P., Bendová, P., Hašková, P., Macková, E., Stariat, J., Jirkovská, A., Vávrová, K., & Šimůnek, T. (2011) · Chemical Research in Toxicology · doi:10.1021/tx100359t · Cited by 56 · see citing works
Oxidative Stress Levels in Myelodysplastic Syndrome Patients: Their Relationship to Serum Ferritin and Haemoglobin Values
Saigo, K., Takenokuchi, M., Hiramatsu, Y., Tada, H., Hishita, T., Takata, M., Misawa, M., Imoto, S., & Imashuku, S. (2011) · Journal of International Medical Research · doi:10.1177/147323001103900539 · Cited by 52 · see citing works
Iron chelation with salicylaldehyde isonicotinoyl hydrazone protects against catecholamine autoxidation and cardiotoxicity
Hašková, P., Kovařı́ková, P., Koubková, L., Jirkovská, A., Macková, E., & Šimůnek, T. (2010) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2010.12.004 · Cited by 49 · see citing works
Stimulus-Responsive Prochelators for Manipulating Cellular Metals
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Novel and potent anti-tumor and anti-metastatic di-2-pyridylketone thiosemicarbazones demonstrate marked differences in pharmacology between the first and second generation lead agents
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“4) was prepared according to a previously published procedure [35].”
Method
Aroylhydrazone iron chelators: Tuning antioxidant and antiproliferative properties by hydrazide modifications
Hrušková, K., Potůčková, E., Hergeselová, T., Liptáková, L., Hašková, P., Mingas, P.-D., Kovařı́ková, P., Šimůnek, T., & Vávrová, K. (2016) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2016.05.015 · Cited by 47 · see citing works
Methyl and ethyl ketone analogs of salicylaldehyde isonicotinoyl hydrazone: Novel iron chelators with selective antiproliferative action
Macková, E., Hrušková, K., Bendová, P., Jirkovská, A., Jansová, H., Hašková, P., Kovařı́ková, P., Vávrová, K., & Šimůnek, T. (2012) · Chemico-Biological Interactions · doi:10.1016/j.cbi.2012.03.010 · Cited by 45 · see citing works
“The good effectiveness of SIH was also noted in protection of H9c2 cardiomyoblasts against oxidative injury induced by tertbutyl hydroperoxide and catecholamines and/or their reactive intermediates [23,24].”
Background
Prochelator BHAPI protects cells against paraquat-induced damage by ROS-triggered iron chelation
Kielar, F., Helsel, M. E., Wang, Q., & Franz, K. J. (2012) · Metallomics · doi:10.1039/c2mt20069d · Cited by 44 · see citing works
The Anticancer Agent, Di-2-Pyridylketone 4,4-Dimethyl-3-Thiosemicarbazone (Dp44mT), Up-Regulates the AMPK-Dependent Energy Homeostasis Pathway in Cancer Cells
Krishan, S., Richardson, D. R., & Sahni, S. (2016) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2016.09.011 · Cited by 44 · see citing works
Copper( ii ) complexes with NNO ligands: synthesis, crystal structures, DNA cleavage, and anticancer activities
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Comparison of various iron chelators used in clinical practice as protecting agents against catecholamine-induced oxidative injury and cardiotoxicity
Hašková, P., Koubková, L., Jirkovská, A., Macková, E., Hrušková, K., Kovařı́ková, P., Vávrová, K., & Šimůnek, T. (2011) · Toxicology · doi:10.1016/j.tox.2011.08.006 · Cited by 40 · see citing works
Comparison of various iron chelators and prochelators as protective agents against cardiomyocyte oxidative injury
Jansová, H., Macháček, M., Wang, Q., Hašková, P., Jirkovská, A., Potůčková, E., Kielar, F., Franz, K. J., & Šimůnek, T. (2014) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2014.06.019 · Cited by 31 · see citing works
“Indeed, SIH has previously shown the best “therapeutic” ratio of inherent toxicity and cytoprotective efficiency against diverse ROS-mediated injuries (H2O2, tert-butylhydroperoxide, catecholamines, and their oxidation products) compared with other Fe chelators, including the clinically approved agents DFO, ICL670A, a…”
Cell Penetrating Peptide (CPP)-Conjugated Desferrioxamine for Enhanced Neuroprotection: Synthesis and in Vitro Evaluation
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Characterization of a Photoswitching Chelator with Light-Modulated Geometric, Electronic, and Metal-Binding Properties
Franks, A. T., Peng, D., Yang, W., & Franz, K. J. (2014) · Inorganic Chemistry · doi:10.1021/ic402221x · Cited by 30 · see citing works
A prochelator with a modular masking group featuring hydrogen peroxide activation with concurrent fluorescent reporting
Franks, A. T., & Franz, K. J. (2014) · Chemical Communications · doi:10.1039/c4cc05076b · Cited by 30 · see citing works
Quantitative Analysis of the Anti-Proliferative Activity of Combinations of Selected Iron-Chelating Agents and Clinically Used Anti-Neoplastic Drugs
Potůčková, E., Jansová, H., Macháček, M., Jirkovská, A., Hašková, P., Tichotová, L., Richardson, V., Kalinowski, D. S., Richardson, D. R., & Šimůnek, T. (2014) · PLoS ONE · doi:10.1371/journal.pone.0088754 · Cited by 30 · see citing works
Drug-like chelating agents: a potential lead for Alzheimer's disease
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Evolution of Theories on Doxorubicin-Induced Late Cardiotoxicity-Role of Topoisomerase
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Structure-Activity Relationships of Novel Salicylaldehyde Isonicotinoyl Hydrazone (SIH) Analogs: Iron Chelation, Anti-Oxidant and Cytotoxic Properties
Potůčková, E., Hrušková, K., Bureš, J., Kovařı́ková, P., Špirková, I. A., Pravdíková, K., Kolbabová, L., Hergeselová, T., Hašková, P., Jansová, H., et al. (2014) · PLoS ONE · doi:10.1371/journal.pone.0112059 · Cited by 25 · see citing works
“More recently, iron chelators have been also studied in pathological conditions associated with oxidative stress unrelated to ironoverload diseases [15].”
Background
The effect of iron loading and iron chelation on the innate immune response and subclinical organ injury during human endotoxemia: a randomized trial
van Eijk, L. T., Heemskerk, S., van der Pluijm, R. W., van Wijk, S. M., Peters, W. H. M., van der Hoeven, J. G., Kox, M., Swinkels, D. W., & Pickkers, P. (2013) · Haematologica · doi:10.3324/haematol.2013.088047 · Cited by 24 · see citing works
Atrial fibrillation in β‐thalassemia patients with a focus on the role of iron‐overload and oxidative stress: A review
Nomani, H., Bayat, G., Sahebkar, A., Fazelifar, A. F., Vakilian, F., Jomezade, V., Johnston, T. P., & Mohammadpour, A. H. (2018) · Journal of Cellular Physiology · doi:10.1002/jcp.27968 · Cited by 26 · see citing works
“In summary, the advantage of using chelators for β‐TM to protect against oxidative stress‐induced cellular damage and alterations in various biochemical indices outweighs their unfavorable toxicity (Bendova et al., 2010).”
BackgroundInfluential
Nickel complexes of aroylhydrazone ligand: synthesis, crystal structure and DNA binding properties
Yang, P., Zhang, L., Wang, Z., Zhang, D., Liu, Y., Shi, Q., & Xie, X. (2019) · Journal of Inorganic Biochemistry · doi:10.1016/j.jinorgbio.2019.110919 · Cited by 23 · see citing works
A boronate prochelator built on a triazole framework for peroxide-triggered tridentate metal binding
Kielar, F., Wang, Q., Boyle, P. D., & Franz, K. J. (2012) · Inorganica Chimica Acta · doi:10.1016/j.ica.2012.06.011 · Cited by 22 · see citing works
Cardioprotective Potential of Iron Chelators and Prochelators
Jansová, H., & Šimůnek, T. (2019) · Current Medicinal Chemistry · doi:10.2174/0929867324666170920155439 · Cited by 21 · see citing works
Differences in protein binding and excretion of Triapine and its Fe(III) complex
Pelivan, K., Miklos, W., van Schoonhoven, S., Koellensperger, G., Gille, L., Berger, W., Heffeter, P., Kowol, C. R., & Keppler, B. K. (2015) · Journal of Inorganic Biochemistry · doi:10.1016/j.jinorgbio.2015.10.006 · Cited by 21 · see citing works
Deferasirox has strong anti-leukemia activity but may antagonize theanti-leukemia effect of doxorubicin
Chang, Y.-C., Lo, W.-J., Huang, Y., Lin, C.-L., Feng, C.-C., Lin, H.-T., Cheng, H., & Yeh, S. (2017) · Leukemia & lymphoma/Leukemia and lymphoma · doi:10.1080/10428194.2017.1280604 · Cited by 20 · see citing works
“However, the use of an iron chelator, including DFX, can protect the cell against oxidative stress-induced cellular injury [17] and may therefore antagonize the anti-leukemia effect of DOX.”
Background
Antioxidant and Pro‐Oxidant Evaluation of a Potentilla alba L. Rhizome Extract
Dorman, H. J. D., Shikov, A. N., Pozharitskaya, O. N., & Hiltunen, R. (2011) · Chemistry & Biodiversity · doi:10.1002/cbdv.201100043 · Cited by 19 · see citing works
Prooxidant and antioxidant properties of salicylaldehyde isonicotinoyl hydrazone iron chelators in HepG2 cells
Caro, A. A., Commissariat, A., Dunn, C., Kim, H., García, S. L., Smith, A. D., Strang, H. E., Stuppy, J., Desrochers, L. P., & Goodwin, T. E. (2015) · Biochimica et Biophysica Acta (BBA) - General Subjects · doi:10.1016/j.bbagen.2015.08.005 · Cited by 19 · see citing works
“SIH showed a trend to increase the intracellular production of ROS in H9c2 cells [3,9].”
Background
Effects of the iron‐chelating agent deferoxamine on triethylene glycol dimethacrylate, 2‐hydroxylethyl methacrylate, hydrogen peroxide‐induced cytotoxicity
Zhu, T., Lim, B., Park, H. C., Son, K. M., & Yang, H. (2011) · Journal of Biomedical Materials Research Part B Applied Biomaterials · doi:10.1002/jbm.b.31939 · Cited by 18 · see citing works
Cardioprotective effects of iron chelator HAPI and ROS-activated boronate prochelator BHAPI against catecholamine-induced oxidative cellular injury
Hašková, P., Jansová, H., Bureš, J., Macháček, M., Jirkovská, A., Franz, K. J., Kovařı́ková, P., & Šimůnek, T. (2016) · Toxicology · doi:10.1016/j.tox.2016.10.004 · Cited by 18 · see citing works
“SIH is able to bind intracellular redox-active Fe and thus prevent the production of ROS (Bendova et al. 2010; Haskova et al. 2011; Horackova et al. 2000; Jansová et al. 2014; Simunek et al. 2005; Sterba et al. 2007).”
Background
Identifying a Deferiprone–Resveratrol Hybrid as an Effective Lipophilic Anti-Plasmodial Agent
Maneekesorn, S., Chuljerm, H., Koonyosying, P., Uthaipibull, C., Ma, Y., & Srichairatanakool, S. (2021) · Molecules · doi:10.3390/molecules26134074 · Cited by 18 · see citing works
“Furthermore, they were consequently more effective at preventing the oxidative injury of cells [33].”
Background
Synthesis, characterization and in vitro anticancer evaluations of two novel derivatives of deferasirox iron chelator
Salehi, S., Saljooghi, A. S., & Shiri, A. (2016) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2016.04.026 · Cited by 16 · see citing works
Characterization of cytoprotective and toxic properties of iron chelator SIH, prochelator BSIH and their degradation products
Jansová, H., Bureš, J., Macháček, M., Hašková, P., Jirkovská, A., Roh, J., Qin, W., Franz, K. J., Kovařı́ková, P., & Šimůnek, T. (2016) · Toxicology · doi:10.1016/j.tox.2016.03.004 · Cited by 14 · see citing works
“Previous results from our laboratory as well as those of other groups have shown its promising cardioprotective potential both in vitro and in vivo (Bendova et al. 2010; Hašková et al. 2011; Horackova et al. 2000; Sterba et al. 2007).”
BackgroundResultInfluential
LC–UV/MS methods for the analysis of prochelator—Boronyl salicylaldehyde isonicotinoyl hydrazone (BSIH) and its active chelator salicylaldehyde isonicotinoyl hydrazone (SIH)
Bureš, J., Jansová, H., Stariat, J., Filipský, T., Mladěnka, P., Šimůnek, T., Kučera, R., Klimeš, J., Wang, Q., Franz, K. J., et al. (2014) · Journal of Pharmaceutical and Biomedical Analysis · doi:10.1016/j.jpba.2014.11.044 · Cited by 12 · see citing works
“ADS buffer was prepared according to the previously published procedure [7].”
BackgroundMethod
Chelators to the Rescue: Different Horses for Different Courses!
Kovačević, Ž., Yu, Y., & Richardson, D. R. (2011) · Chemical Research in Toxicology · doi:10.1021/tx100435c · Cited by 12 · see citing works
2,6-Dihydroxybenzaldehyde Analogues of the Iron Chelator Salicylaldehyde Isonicotinoyl Hydrazone: Increased Hydrolytic Stability and Cytoprotective Activity against Oxidative Stress
Jansová, H., Kubeš, J., Reimerová, P., Štěrbová‐Kovaříková, P., Roh, J., & Šimůnek, T. (2018) · Chemical Research in Toxicology · doi:10.1021/acs.chemrestox.8b00165 · Cited by 11 · see citing works
A multifunctional, light-activated prochelator inhibits UVA-induced oxidative stress
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Five new complexes with deferiprone and N,N-donor ligands: evaluation of cytotoxicity against breast cancer MCF-7 cell line and HSA-binding determination
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“These properties come from the efficiency of dfp molecule in preventing oxidative injury of cells (Bendova et al., 2010; Chaves et al., 2012; Kontoghiorghes et al., 2009).”
Background
Examination of diverse iron-chelating agents for the protection of differentiated PC12 cells against oxidative injury induced by 6-hydroxydopamine and dopamine
Hašková, P., Applová, L., Jansová, H., Homola, P., Franz, K. J., Vávrová, K., Roh, J., & Šimůnek, T. (2022) · Scientific Reports · doi:10.1038/s41598-022-13554-x · Cited by 8 · see citing works
Exploring the therapeutic potential of Cu(II)-complexes with ligands derived from pyridoxal
Nunes, P., Marques, F., Cavaco, I., Pessoa, J. C., & Correia, I. (2020) · Inorganica Chimica Acta · doi:10.1016/j.ica.2020.119558 · Cited by 8 · see citing works
The involvement of reactive oxygen species in causing chronic cardiovascular and neurodegenerative diseases and some cancers
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“93, 94 Future antioxidative therapies in heart failure are considered to include increasing endogenous antioxidant capacity and increasing expression of an- tioxidant-producing enzymes.”
Background
The hydrolytic susceptibility of prochelator BSIH in aqueous solutions
Wang, Q., & Franz, K. J. (2017) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2017.07.019 · Cited by 7 · see citing works
Structure–Activity Relationships of Nitro-Substituted Aroylhydrazone Iron Chelators with Antioxidant and Antiproliferative Activities
Hrušková, K., Potůčková, E., Opálka, L., Hergeselová, T., Hašková, P., Kovařı́ková, P., Šimůnek, T., & Vávrová, K. (2018) · Chemical Research in Toxicology · doi:10.1021/acs.chemrestox.7b00324 · Cited by 7 · see citing works
Cardiotoxicity and ROS Protection Assessment of three Structure‐Related N‐Acylhydrazones with Potential for the Treatment of Neurodegenerative Diseases
Santa-Helena, E., Falco, A. D., Cukierman, D. S., Gioda, A., Gioda, C. R., & Rey, N. A. (2024) · Chemistry & Biodiversity · doi:10.1002/cbdv.202400356 · Cited by 5 · see citing works
Editorial: Contrast‐Induced Acute Kidney Injury: Shifting from Elective to Urgent Coronary Intervention
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Synthesis, characterizations, structural elucidation, computational analysis, and urease inhibitory activity of vitamin B6–derived Schiff base complexes
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Crystal structures of (E)-N′-(2-hydroxy-5-methylbenzylidene)isonicotinohydrazide and (E)-N′-(5-fluoro-2-hydroxybenzylidene)isonicotinohydrazide
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“Chemical context Hydrazone-based chelators for metal ions have received a significant amount of attention (Bendova et al., 2010; Hrušková et al., 2016).”
Background
Deferasirox protects against hydrogen peroxide-induced cell apoptosis by inhibiting ubiquitination and degradation of p21WAF1/CIP1
Miao, J., Xu, M., Kuang, Y., Pan, S., Hou, J., Cao, P., Duan, X., Chang, Y., Habelhah, H., Zhou, N., et al. (2020) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2020.01.155 · Cited by 3 · see citing works
Lower-Risk Myelodysplastic Syndrome (MDS) Patients Exhibit Diminished Proteasome Proteolytic Activity and High Intracellular Reactive Oxygen Species (ROS) Levels
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“Several studies have reported the potential usefulness of antioxidant agents or iron chelation therapy that can act as antioxidants for MDS patients [37,38].”
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Low‐dose iron chelation as anti‐oxidative therapy in patients with sickle cell disease: A single‐centre pilot study
Gaartman, A. E., Beuger, B. M., de Ligt, L. A., Veldthuis, M., Matlung, H. L., Meijers, J. C. M., Schalkwijk, C. G., de Heer, K., Heijmans, J., van Zwieten, R., et al. (2024) · British Journal of Haematology · doi:10.1111/bjh.19943 · Cited by 1 · see citing works
“5,6 Furthermore, iron depletion has been associated with a substantial reduction in sickling, haemolysis and vaso-occlusive events.”
Crystal structure of (E)-N′-(3-fluoro-2-hydroxybenzylidene)isonicotinohydrazide
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“Hydrazone-based chelators of metal ions are interesting compounds that receive a significant amount of interest (Bendová et al., 2010; Jansová et al., 2014; Hrušková et al., 2016).”
Background
AÇÃO DE DESFEROXAMINA E DEFERASIROX EM ERITRÓCITOS DE PORTADORES DE ANEMIAS DEPENDENTES DE TRANSFUSÃO, COM SOBRECARGA OXIDATIVA, IN VITRO
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Development of Stimulus-Responsive Ligands for the Modulation of Copper and Iron Coordination
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Syntheses of Two New Saccharin Hydrazide Derivatives and Evaluation of Their Chelatory Activities
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Deferoxamine and deferasirox action in erythrocytes of patients with transfusion-dependent anemia, under “in vitro” oxidative stress
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Recent Advances in the Design of Iron Chelators Against Oxidative Damage
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Authors: Bendova, P., Mackova, E., Haskova, P., Vavrova, A., Jirkovsky, E., Sterba, M., Popelova, O., Kalinowski, D. S., Kovarikova, P., Vavrova, K., Richardson, D. R., & Simunek, T.
Affiliations: Faculty of Pharmacy in Hradec Kralove and Faculty of Medicine in Hradec Kralove, Charles University in Prague, Heyrovskeho 1203, 500 05 Hradec Kralove, Czech Republic, and Iron Metabolism and Chelation Program, Bosch Institute and Department of Pathology, University of Sydney, Sydney 2006, Australia
The University of Sydney (AU)
Corresponding author: Richardson, Des R.
ORCID: Kalinowski, Danuta S.
Richardson, Des R.
Venue: Chemical Research in Toxicology
Publisher: American Chemical Society (ACS)
Published: 2010-06-03
Volume: 23
Issue: 6
Pages: 1105-1114
ISSN: 0893-228X (ISSN-L)
1520-5010
DOI: 10.1021/tx100125t
OpenAlex: W2037698847
Cited by: 73
References: 61
Citations by year: 2026: 2 · 2024: 4 · 2023: 1 · 2022: 2 · 2021: 2 · 2020: 3 · 2019: 5 · 2018: 5 · 2017: 4 · 2016: 7 · 2015: 5 · 2014: 11 · 2013: 4 · 2012: 8
FWCI: 4.40
Type: journal article
Language: en
Open access: closed
Locations: Chemical Research in Toxicology (publishedVersion)
PubMed (publishedVersion)
Topics: Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
Health Sciences › Medicine › Biochemistry › Antioxidant Activity and Oxidative Stress
Physical Sciences › Chemistry › Organic Chemistry › Free Radicals and Antioxidants
Keywords: iron chelators, oxidative stress, tert-butyl hydroperoxide, cellular injury, labile iron pool, deferoxamine, deferiprone, deferasirox, pyridoxal isonicotinoyl hydrazone, salicylaldehyde isonicotinoyl hydrazone, EDTA, lipophilicity, iron depletion
MeSH terms: Animals, Cell Line, Cell Survival, Iron Chelating Agents, Myocardium, Oxidative Stress, Cytoprotection, tert-Butylhydroperoxide

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Comparison of clinically used and experimental iron chelators for protection against oxidative stress-induced cellular injury

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