Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 59, Issue 14, Pages 6739-6752Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.6b00342
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Funding
- Austrian Science Fund (FWF) [P22072-B11]
- Hungarian Research Foundation OTKA [PD103905]
- J. Bolyai Research Scholarship of the Hungarian Academy of Sciences
- Initiative Krebsforschung
- Mahlke geb. Obermann-Stiftung
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One of the most promising classes of iron chelators are alpha-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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