title: Design, synthesis and biological evaluation of thiosemicarbazones, hydrazinobenzothiazoles and arylhydrazones as anticancer agents with a potential to overcome multidrug resistance.
abstract: There is a constant need for new therapies against multidrug resistant (MDR) cancer. An attractive strategy is to develop chelators that display significant antitumor activity in multidrug resistant cancer cell lines overexpressing the drug efflux pump P-glycoprotein. In this study we used a panel of sensitive and MDR cancer cell lines to evaluate the toxicity of picolinylidene and salicylidene thiosemicarbazone, arylhydrazone, as well as picolinylidene and salicylidene hydrazino-benzothiazole derivatives. Our results confirm the collateral sensitivity of MDR cells to isatin-β-thiosemicarbazones, and identify several chelator scaffolds with a potential to overcome multidrug resistance. Analysis of structure-activity-relationships within the investigated compound library indicates that NNS and NNN donor chelators show superior toxicity as compared to ONS derivatives regardless of the resistance status of the cells.
authors.affiliation: Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Budapest, Hungary; Department of Pharmaceutical Chemistry, University of Bonn, 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, Budapest, Hungary.
authors.forename: Szilárd
authors.initials: S
authors.lastname: Tóth
authors.affiliation: Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Budapest, Hungary.
authors.forename: András
authors.initials: A
authors.lastname: Füredi
authors.affiliation: Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Budapest, Hungary.
authors.forename: Kornélia
authors.initials: K
authors.lastname: Szebényi
authors.affiliation: Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Budapest, Hungary.
authors.forename: Anna
authors.initials: A
authors.lastname: Lovrics
authors.affiliation: Institute of Organic Chemistry, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Budapest, Hungary.
authors.forename: Pál
authors.initials: P
authors.lastname: Szabó
authors.affiliation: Department of Pharmaceutical Chemistry, University of Bonn, Bonn, Germany. Electronic address: mwiese@uni-bonn.de.
authors.forename: Michael
authors.initials: M
authors.lastname: Wiese
authors.affiliation: Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Budapest, Hungary. Electronic address: szakacs.gergely@ttk.mta.hu.
authors.forename: Gergely
authors.initials: G
authors.lastname: Szakács
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D052160:Benzothiazoles / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D018432:Drug Resistance, Multiple / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D006801:Humans; D006835:Hydrazones / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013882:Thiosemicarbazones / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D052160:Benzothiazoles; D006835:Hydrazones; D013882:Thiosemicarbazones
keywords: Antitumor agents; Cancer; Chelators; Multidrug resistance; Schiff bases