title: Aroylhydrazone iron chelators: Tuning antioxidant and antiproliferative properties by hydrazide modifications.
abstract: Aroylhydrazones such as salicylaldehyde isonicotinoyl hydrazone (SIH) are tridentate iron chelators that may possess antioxidant and/or antineoplastic activities. Their main drawback, their low stability in plasma, has recently been partially overcome by exchanging the aldimine hydrogen for an unbranched alkyl group. In this study, ten analogs of methyl- and ethyl-substituted SIH derivatives with modified hydrazide scaffolds were synthesized to further explore their structure-activity relationships. Their iron-chelation efficiencies, anti- or pro-oxidant potentials, abilities to induce protection against model oxidative injury on the H9c2 cell line derived from rat embryonic cardiac tissue, cytotoxicities on the same H9c2 cells and antiproliferative activities on MCF-7 human breast adenocarcinoma and HL-60 human promyelotic leukemia cell lines were evaluated. Compounds derived from lipophilic naphthyl and biphenyl hydrazides displayed highly selective antiproliferative activities against both MCF-7 and HL-60 cell lines, and they showed markedly improved stabilities in plasma compared to SIH. Of particular interest is a hydrazone prepared from 2-hydroxypropiophenone and pyridazin-4-carbohydrazide that showed a considerable antiproliferative effect and protected cardiomyoblasts against oxidative stress with a five-fold higher selectivity compared to the parent compound SIH. Thus, this work highlighted new structure-activity relationships among antiproliferative and antioxidant aroylhydrazones and identified new lead compounds for further development.
authors.affiliation: Charles University in Prague, Faculty of Pharmacy in Hradec Králové, Heyrovského 1203, 500 05 Hradec Králové, Czech Republic.
authors.forename: Kateřina
authors.initials: K
authors.lastname: Hrušková
authors.affiliation: Charles University in Prague, Faculty of Pharmacy in Hradec Králové, Heyrovského 1203, 500 05 Hradec Králové, Czech Republic.
authors.forename: Eliška
authors.initials: E
authors.lastname: Potůčková
authors.affiliation: Charles University in Prague, Faculty of Pharmacy in Hradec Králové, Heyrovského 1203, 500 05 Hradec Králové, Czech Republic.
authors.forename: Tereza
authors.initials: T
authors.lastname: Hergeselová
authors.affiliation: Charles University in Prague, Faculty of Pharmacy in Hradec Králové, Heyrovského 1203, 500 05 Hradec Králové, Czech Republic.
authors.forename: Lucie
authors.initials: L
authors.lastname: Liptáková
authors.affiliation: Charles University in Prague, Faculty of Pharmacy in Hradec Králové, Heyrovského 1203, 500 05 Hradec Králové, Czech Republic.
authors.forename: Pavlína
authors.initials: P
authors.lastname: Hašková
authors.affiliation: Charles University in Prague, Faculty of Pharmacy in Hradec Králové, Heyrovského 1203, 500 05 Hradec Králové, Czech Republic.
authors.forename: Panagiotis
authors.initials: P
authors.lastname: Mingas
authors.affiliation: Charles University in Prague, Faculty of Pharmacy in Hradec Králové, Heyrovského 1203, 500 05 Hradec Králové, Czech Republic.
authors.forename: Petra
authors.initials: P
authors.lastname: Kovaříková
authors.affiliation: Charles University in Prague, Faculty of Pharmacy in Hradec Králové, Heyrovského 1203, 500 05 Hradec Králové, Czech Republic. Electronic address: Tomas.Simunek@faf.cuni.cz.
authors.forename: Tomáš
authors.initials: T
authors.lastname: Šimůnek
authors.affiliation: Charles University in Prague, Faculty of Pharmacy in Hradec Králové, Heyrovského 1203, 500 05 Hradec Králové, Czech Republic. Electronic address: Katerina.Vavrova@faf.cuni.cz.
authors.forename: Kateřina
authors.initials: K
authors.lastname: Vávrová
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D000975:Antioxidants / Q000737:chemistry* / Q000494:pharmacology; D045744:Cell Line, Tumor; D004355:Drug Stability; D006801:Humans; D006834:Hydrazines; D006835:Hydrazones / Q000737:chemistry / Q000494:pharmacology*; D057927:Hydrophobic and Hydrophilic Interactions; D007502:Iron Chelating Agents / Q000737:chemistry* / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D000975:Antioxidants; D006834:Hydrazines; D006835:Hydrazones; D007502:Iron Chelating Agents
keywords: Anticancer; Hydrazone; Iron chelator; Oxidative injury; Structure-activity relationships