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.

A comparative study of α- N -pyridyl thiosemicarbazones: Spectroscopic properties, solution stability and copper(II) complexation

“…Some compounds have been also reported to efficiently inhibit topoisomerase-II a [17,18]. Notably, TSCs which possess a N-terminal dimethylation often reveal a more than 100-fold enhanced anticancer activity in vitro [19,20]. In our recent work such highly cytotoxic derivatives also showed a very strong synergistic activity with Cu(II) accompanied by induction of ROS production and massive necrotic cell death [19].…”

“…Notably, TSCs which possess a N-terminal dimethylation often reveal a more than 100-fold enhanced anticancer activity in vitro [19,20]. In our recent work such highly cytotoxic derivatives also showed a very strong synergistic activity with Cu(II) accompanied by induction of ROS production and massive necrotic cell death [19]. This is also true for Richardson type complexes like di-2-pyridylketone-4,4,-dimethyl-3-thiosemicarbazone (Dp44mT) or DpC where coordination to cellular Cu(II) seems to play an important role in the mode of action [21,22].…”

Anticancer Thiosemicarbazones: Chemical Properties, Interaction with Iron Metabolism, and Resistance Development

“…In case of these thiosemicarbazones, we can only speculate, whether they are indeed still able to bind iron(II)/(III) ions at their nanomolar IC 50 concentrations. Noteworthy, detailed structureactivity relationship studies revealed that this increased activity only occurs if no NH 2 or even NH group (with the exception of the hydrazinic NH) is present in the molecule (101,102). Consequently, the terminally dimethylated derivative of Triapine has a cytotoxic activity comparable to Triapine itself (102) and only dimethylation of both amino groups results in a nanomolar activity (101).…”

Mononuclear Pd(ii) and Pt(ii) complexes with an α-N-heterocyclic thiosemicarbazone: cytotoxicity, solution behaviour and interaction versus proven models from biological media

“…However, these effects do not seem to be responsible for the increased cytotoxic activity of some derivatives into the nanomolar range. 8 Para-substituted phenyl thiosemicarbazones are another example of strong antitumor compounds and their metallation using palladium and platinum are reported to afford complexes that highly enhance the antitumor action of the ligands. The data from these complexes showed a good correlation of their cytotoxic activity with their structures and mode of action.…”

“…The distances and angles around the Pd atom are within the range expected for these kind of mononuclear 21 and other polynuclear complexes published previously by our group of research 10 (Table 1). (4) N1-Pd1-N1 N1-Pd1-S1 S1-Pd1-S1 180.0 83.33 (8) 180.0…”