title: Impact of Stepwise NH2-Methylation of Triapine on the Physicochemical Properties, Anticancer Activity, and Resistance Circumvention.
abstract: One of the most promising classes of iron chelators are α-N-heterocyclic thiosemicarbazones with Triapine as the most prominent representative. In several clinical trials Triapine showed anticancer activity against hematological diseases, however, studies on solid tumors failed due to widely unknown reasons. Some years ago, it was recognized that "terminal dimethylation" of thiosemicarbazones can lead to a more than 100-fold increased activity, probably due to interactions with cellular copper depots. To better understand the structural requirements for the switch to nanomolar cytotoxicity, we systematically synthesized all eight possible N-methylated derivatives of Triapine and investigated their potential against Triapine-sensitive as well as -resistant cell lines. While only the "completely" methylated compound exerted nanomolar activity, the data revealed that all compounds with at least one N-dimethylation were not affected by acquired Triapine resistance. In addition, these compounds were highly synergistic with copper treatment accompanied by induction of reactive oxygen species and massive necrotic cell death.
authors.affiliation: Institute of Inorganic Chemistry, University of Vienna , Waehringer Str. 42, A-1090 Vienna, Austria.|Research Platform "Translational Cancer Therapy Research", University of Vienna , Waehringer Str. 42, A-1090 Vienna, Austria.
authors.forename: Christian R
authors.initials: CR
authors.lastname: Kowol
authors.affiliation: Institute of Cancer Research, Medical University of Vienna , Borschkeg. 8a, A-1090 Vienna, Austria.
authors.forename: Walter
authors.initials: W
authors.lastname: Miklos
authors.affiliation: Institute of Inorganic Chemistry, University of Vienna , Waehringer Str. 42, A-1090 Vienna, Austria.
authors.forename: Sarah
authors.initials: S
authors.lastname: Pfaff
authors.affiliation: Institute of Cancer Research, Medical University of Vienna , Borschkeg. 8a, A-1090 Vienna, Austria.
authors.forename: Sonja
authors.initials: S
authors.lastname: Hager
authors.affiliation: Institute of Inorganic Chemistry, University of Vienna , Waehringer Str. 42, A-1090 Vienna, Austria.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Kallus
authors.affiliation: Institute of Inorganic Chemistry, University of Vienna , Waehringer Str. 42, A-1090 Vienna, Austria.
authors.forename: Karla
authors.initials: K
authors.lastname: Pelivan
authors.affiliation: Institute of Inorganic Chemistry, University of Vienna , Waehringer Str. 42, A-1090 Vienna, Austria.
authors.forename: Mario
authors.initials: M
authors.lastname: Kubanik
authors.affiliation: Department of Inorganic and Analytical Chemistry, University of Szeged , Dóm tér 7, 6720 Szeged, Hungary.
authors.forename: Éva A
authors.initials: ÉA
authors.lastname: Enyedy
authors.affiliation: Institute of Cancer Research, Medical University of Vienna , Borschkeg. 8a, A-1090 Vienna, Austria.|Research Platform "Translational Cancer Therapy Research", University of Vienna , Waehringer Str. 42, A-1090 Vienna, Austria.
authors.forename: Walter
authors.initials: W
authors.lastname: Berger
authors.affiliation: Institute of Cancer Research, Medical University of Vienna , Borschkeg. 8a, A-1090 Vienna, Austria.|Research Platform "Translational Cancer Therapy Research", University of Vienna , Waehringer Str. 42, A-1090 Vienna, Austria.
authors.forename: Petra
authors.initials: P
authors.lastname: Heffeter
authors.affiliation: Institute of Inorganic Chemistry, University of Vienna , Waehringer Str. 42, A-1090 Vienna, Austria.|Research Platform "Translational Cancer Therapy Research", University of Vienna , Waehringer Str. 42, A-1090 Vienna, Austria.
authors.forename: Bernhard K
authors.initials: BK
authors.lastname: Keppler
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008745:Methylation; D015394:Molecular Structure; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013882:Thiosemicarbazones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D011725:Pyridines; D013882:Thiosemicarbazones; C078157:3-aminopyridine-2-carboxaldehyde thiosemicarbazone