2. Academic Validation
  3. Impact of Stepwise NH2-Methylation of Triapine on the Physicochemical Properties, Anticancer Activity, and Resistance Circumvention

Impact of Stepwise NH2-Methylation of Triapine on the Physicochemical Properties, Anticancer Activity, and Resistance Circumvention

  • J Med Chem. 2016 Jul 28;59(14):6739-52. doi: 10.1021/acs.jmedchem.6b00342.
Christian R Kowol 1 2,  Walter Miklos 3,  Sarah Pfaff 1,  Sonja Hager 3,  Sebastian Kallus 1,  Karla Pelivan 1,  Mario Kubanik 1,  Éva A Enyedy 4,  Walter Berger 3 2,  Petra Heffeter 3 2,  Bernhard K Keppler 1 2
Affiliations

Affiliations

  • 1 Institute of Inorganic Chemistry, University of Vienna , Waehringer Str. 42, A-1090 Vienna, Austria.
  • 2 Research Platform "Translational Cancer Therapy Research", University of Vienna , Waehringer Str. 42, A-1090 Vienna, Austria.
  • 3 Institute of Cancer Research, Medical University of Vienna , Borschkeg. 8a, A-1090 Vienna, Austria.
  • 4 Department of Inorganic and Analytical Chemistry, University of Szeged , Dóm tér 7, 6720 Szeged, Hungary.
PMID: 27336684 DOI: 10.1021/acs.jmedchem.6b00342
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.

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