title: Synthesis and characterization of the anticancer and metal binding properties of novel pyrimidinylhydrazone derivatives.
abstract: Three novel pyrimidinylhydrazones substituted at either the aromatic moiety or at the imine carbon atom were synthesized and characterized by standard analytical methods. All compounds were found to be toxic in the micro- to submicromolar range against a diverse panel of cancer cell lines including multidrug resistant (MDR) derivatives expressing P-glycoprotein (Pgp). UV-visible spectrophotometry experiments demonstrated that the most active compound (3) forms highly stable complexes with iron(III) and copper(II) in a wide pH range with a stronger preference towards iron(III). The redox activity of the iron and copper complexes of ligand 3 was investigated using cyclic voltammetry and was tested with cellular reductants. The impact of reactive oxygen species (ROS) on the mechanism of toxicity was assessed using the ROS-sensitive cell permeable dye 2',7'-dichlorofluorescin diacetate (DCFDA). Our results demonstrate that the studied pyrimidinylhydrazones form redox-active iron and copper complexes that are capable of producing intracellular ROS, which might lead to cellular damage and cell death in cancer cells regardless of their resistance status.
authors.affiliation: Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Magyar Tudósok körútja 2, H-1117 Budapest, Hungary; Department of Pharmaceutical Chemistry, University of Bonn, An der Immenburg 4, D-53121 Bonn, Germany.
authors.forename: Veronika F S
authors.initials: VF
authors.lastname: Pape
authors.affiliation: Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Magyar Tudósok körútja 2, H-1117 Budapest, Hungary.
authors.forename: Dóra
authors.initials: D
authors.lastname: Türk
authors.affiliation: Institute of Organic Chemistry, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Magyar Tudósok körútja 2, H-1117 Budapest, Hungary.
authors.forename: Pál
authors.initials: P
authors.lastname: Szabó
authors.affiliation: Department of Pharmaceutical Chemistry, University of Bonn, An der Immenburg 4, D-53121 Bonn, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Wiese
authors.affiliation: Department of Inorganic and Analytical Chemistry, University of Szeged, Dóm tér 7, H-6720 Szeged, Hungary. Electronic address: enyedy@chem.u-szeged.hu.
authors.forename: Eva A
authors.initials: EA
authors.lastname: Enyedy
authors.affiliation: Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Magyar Tudósok körútja 2, H-1117 Budapest, Hungary. Electronic address: szakacs.gergely@ttk.mta.hu.
authors.forename: Gergely
authors.initials: G
authors.lastname: Szakács
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D003300:Copper / Q000737:chemistry; D004285:Dogs; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D005452:Fluoresceins; D006835:Hydrazones / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D007501:Iron / Q000737:chemistry; D008024:Ligands; D061985:Madin Darby Canine Kidney Cells; D010084:Oxidation-Reduction; D017382:Reactive Oxygen Species / Q000378:metabolism; D013053:Spectrophotometry
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D005452:Fluoresceins; D006835:Hydrazones; D008024:Ligands; D017382:Reactive Oxygen Species; C029569:diacetyldichlorofluorescein; D003300:Copper; D007501:Iron
keywords: Arylhydrazones; Metal complexes; Multidrug resistance; Reactive oxygen species; Stability constants