![]() (14) Notably, in anaerobic conditions, physiologically relevant concentrations of GSH reduced Cu II-3AP much faster than Cu II-Dp44mT. (12−14) Moreover, a correlation has been recently found between the cytotoxicity of several TSCs, including 3AP and Dp44mT and the reduction rate of their Cu II complexes by the intracellular reductant GSH. It is worth mentioning that Dp44mT has approximately a 100-fold higher Cu II-affinity than 3AP. Of note, several structure–activity studies have shown that the dimethylation of the terminal N 4 nitrogen (see Scheme 1) enhances the affinity for Cu II and the cytotoxicity. ![]() Since then multiple other effects have been described. The best-known mode of action of anticancer TSCs is iron chelation and the inhibition of the Fe-dependent enzyme ribonucleotide reductase, which is essential for DNA synthesis and cell proliferation, was the first identified target. Later, the di-2-pyridylketone TSC Dp44mT (di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone, see Scheme 1) and its derivative DpC (di-2-pyridylketone 4-cyclohexyl-4-methyl-3-thiosemicarbazone), which is currently implicated in clinical trials (NCT02688101), showed higher cytotoxicity (nM range) than 3AP (μM range) and more advantageous pharmacokinetics. (6) Triapine (3-aminopyridine-2-carboxaldehyde thiosemicarbazone, 3AP, see Scheme 1) was the first TSC representative undergoing more than 30 clinical trials as an anticancer agent, which finally failed because of some adverse effects. These are tridentate ligands that form metal complexes upon deprotonation of the thioamide group (see Scheme 1). (5) Among the developed metal-based anticancer agents, α-pyridyl thiosemicarbazones (TSCs) are promising candidates. (2−4) However, the intracellular stability of Cu-complexes is challenged by endogenous Cu-binding molecules, such as glutathione (GSH) and metallothioneins. (1) Accordingly, Cu-activated (pro)drugs are gaining increasing interest because they could potentially enhance the selectivity toward cancer vs healthy cells. Cancer cells show increased Cu levels, which are required to sustain cell proliferation, angiogenesis and metastasis.
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