title: Characterization of cytoprotective and toxic properties of iron chelator SIH, prochelator BSIH and their degradation products.
abstract: 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.
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: Jan
authors.initials: J
authors.lastname: Bureš
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: 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: Jaroslav
authors.initials: J
authors.lastname: Roh
authors.affiliation: Department of Chemistry, Duke University, Durham, NC 22708, USA.
authors.forename: Qin
authors.initials: Q
authors.lastname: Wang
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.
authors.forename: Petra
authors.initials: P
authors.lastname: Kovaříková
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: Šimůnek
mesh_terms: D000447:Aldehydes / Q000494:pharmacology* / Q000633:toxicity; D000818:Animals; D001897:Boronic Acids / Q000494:pharmacology* / Q000633:toxicity; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D006207:Half-Life; D006835:Hydrazones / Q000494:pharmacology* / Q000633:toxicity; D006861:Hydrogen Peroxide / Q000633:toxicity; D007501:Iron / Q000378:metabolism; D007502:Iron Chelating Agents / Q000494:pharmacology* / Q000633:toxicity; D007539:Isonicotinic Acids / Q000494:pharmacology* / Q000633:toxicity; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D032386:Myoblasts, Cardiac / Q000187:drug effects* / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism*
chemical_list: C541518:(isonicotinic acid (2-(4,4,5,5-tetramethyl-(1,3,2)dioxaborolan-2-yl)benzylidene)hydrazide); D000447:Aldehydes; D001897:Boronic Acids; D006835:Hydrazones; D007502:Iron Chelating Agents; D007539:Isonicotinic Acids; D017382:Reactive Oxygen Species; C413684:salicylaldehyde isonicotinoyl hydrazone; D006861:Hydrogen Peroxide; D007501:Iron
keywords: Boronyl salicylaldehyde isonicotinoyl hydrazone (BSIH); Iron chelation; Prochelator; Salicylaldehyde; Salicylaldehyde isonicotinoyl hydrazone (SIH)