Impact of stepwise NH2-methylation of Triapine on the physico-chemical properties, anticancer activity and resistance circumvention

Kowol, Christian R. and Miklos, Walter and Pfaff, Sarah and Hager, Sonja and Kallus, Sebastian and Enyedy, Éva Anna (2016) Impact of stepwise NH2-methylation of Triapine on the physico-chemical properties, anticancer activity and resistance circumvention. Journal of Medicinal Chemistry. ISSN 0022-2623 (In Press)

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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 ROS and massive necrotic cell death.

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