title: Comparison of various iron chelators and prochelators as protective agents against cardiomyocyte oxidative injury.
abstract: 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.
authors.affiliation: Faculty of Pharmacy, Charles University in Prague, 500 05 Hradec Králové, Czech Republic.
authors.forename: Hana
authors.initials: H
authors.lastname: Jansová
authors.affiliation: Faculty of Pharmacy, Charles University in Prague, 500 05 Hradec Králové, Czech Republic.
authors.forename: Miloslav
authors.initials: M
authors.lastname: Macháček
authors.affiliation: Department of Chemistry, Duke University, Durham, NC 22708, USA.
authors.forename: Qin
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Faculty of Pharmacy, Charles University in Prague, 500 05 Hradec Králové, Czech Republic.
authors.forename: Pavlína
authors.initials: P
authors.lastname: Hašková
authors.affiliation: Faculty of Pharmacy, Charles University in Prague, 500 05 Hradec Králové, Czech Republic.
authors.forename: Anna
authors.initials: A
authors.lastname: Jirkovská
authors.affiliation: Faculty of Pharmacy, Charles University in Prague, 500 05 Hradec Králové, Czech Republic.
authors.forename: Eliška
authors.initials: E
authors.lastname: Potůčková
authors.affiliation: Department of Chemistry, Duke University, Durham, NC 22708, USA.
authors.forename: Filip
authors.initials: F
authors.lastname: Kielar
authors.affiliation: Department of Chemistry, Duke University, Durham, NC 22708, USA.
authors.forename: Katherine J
authors.initials: KJ
authors.lastname: Franz
authors.affiliation: Faculty of Pharmacy, Charles University in Prague, 500 05 Hradec Králové, Czech Republic. Electronic address: Tomas.Simunek@faf.cuni.cz.
authors.forename: Tomáš
authors.initials: T
authors.lastname: Simůnek
mesh_terms: D000447:Aldehydes / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001565:Benzoates / Q000737:chemistry / Q000494:pharmacology; D001896:Boron Compounds / Q000737:chemistry / Q000494:pharmacology; D001897:Boronic Acids / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D002463:Cell Membrane Permeability / Q000187:drug effects; D019610:Cytoprotection; D000077588:Deferasirox; D006835:Hydrazones / Q000737:chemistry / Q000494:pharmacology; D006861:Hydrogen Peroxide / Q000378:metabolism; D007501:Iron / Q000737:chemistry / Q000378:metabolism; D007502:Iron Chelating Agents / Q000737:chemistry / Q000494:pharmacology*; D007539:Isonicotinic Acids / Q000737:chemistry / Q000494:pharmacology; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008929:Mitochondria, Heart / Q000187:drug effects / Q000502:physiology*; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000502:physiology; D018384:Oxidative Stress / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar; D012664:Semicarbazones / Q000737:chemistry / Q000494:pharmacology; D014230:Triazoles / Q000737:chemistry / Q000494:pharmacology
chemical_list: C541518:(isonicotinic acid (2-(4,4,5,5-tetramethyl-(1,3,2)dioxaborolan-2-yl)benzylidene)hydrazide); D000447:Aldehydes; D001565:Benzoates; D001896:Boron Compounds; D001897:Boronic Acids; D006835:Hydrazones; D007502:Iron Chelating Agents; D007539:Isonicotinic Acids; C577566:N'-(1-(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyloxy)phenyl)ethylidene)isonicotinohydrazide; D012664:Semicarbazones; D014230:Triazoles; C413684:salicylaldehyde isonicotinoyl hydrazone; D006861:Hydrogen Peroxide; D007501:Iron; D000077588:Deferasirox
keywords: BSIH; Deferasirox; Free radicals; ICL670A; Iron chelation; Prochelator; Salicylaldehyde isonicotinoyl hydrazone