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

Christian R. Kowol, Walter Miklos, Sarah Pfaff, Sonja Hager, Sebastian Kallus, Karla Pelivan, Mario Kubanik, Éva A. Enyedy, Walter Berger, Petra Heffeter, Bernhard K. Keppler

Research output: Contribution to journalArticle

22 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)6739-6752
Number of pages14
JournalJournal of Medicinal Chemistry
Volume59
Issue number14
DOIs
Publication statusPublished - Jul 28 2016

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Fingerprint Dive into the research topics of 'Impact of Stepwise NH<sub>2</sub>-Methylation of Triapine on the Physicochemical Properties, Anticancer Activity, and Resistance Circumvention'. Together they form a unique fingerprint.

  • Cite this

    Kowol, C. R., Miklos, W., Pfaff, S., Hager, S., Kallus, S., Pelivan, K., Kubanik, M., Enyedy, É. A., Berger, W., Heffeter, P., & Keppler, B. K. (2016). Impact of Stepwise NH2-Methylation of Triapine on the Physicochemical Properties, Anticancer Activity, and Resistance Circumvention. Journal of Medicinal Chemistry, 59(14), 6739-6752. https://doi.org/10.1021/acs.jmedchem.6b00342