Significance: During the last decades, thiosemicarbazones have been clinically developed for a variety of diseases including tuberculosis, viral infections, malaria and cancer. With regard to malignant diseases, the class of α-N-heterocyclic thiosemicarbazones, and here especially Triapine, was intensively developed in multiple clinical phase I/II trials. Recent Advances: Very recently two new derivatives, namely COTI-2 and DpC have entered phase I evaluation. Based on the strong metal-chelating/metal-interacting properties of thiosemicarbazones, interference with the cellular iron (and copper) homeostasis is assumed to play an important role in their biological activity. Critical Issues: In this review, we summarize and analyze the data on the interaction of (α-N-heterocyclic) thiosemicarbazones with iron, with the special aim to bridge the current knowledge on their mode of action from chemistry to (cell) biology. In addition, we highlight the difference to classical iron(III) chelators such as desferrioxamine (DFO) which are used for the treatment of iron overload. Future Directions: We want to emphasize that thiosemicarbazones are not solely removing iron from the cells/organism. In contrast, they should be considered as iron-interacting drugs influencing diverse biological pathways with a complex and multi-facetted mode of action. Consequently, in addition to the discussion of physicochemical properties (e.g. complex stability, redox activity), this review contains an overview on the diversity of cellular thiosemicarbazone targets and drug resistance mechanisms.

Due to their high biological activity, thiosemicarbazones have been developed for treatment of diverse diseases, including cancer, resulting in multiple clinical trials especially of the lead compound Triapine. During the last years, a novel subclass of anticancer thiosemicarbazones has attracted substantial interest based on their enhanced cytotoxic activity. Increasing evidence suggests that the double-dimethylated Triapine derivative Me₂NNMe₂ differs from Triapine not only in its efficacy but also in its mode of action. Here we show that Me₂NNMe₂- (but not Triapine)-treated cancer cells exhibit all hallmarks of paraptotic cell death including, besides the appearance of endoplasmic reticulum (ER)-derived vesicles, also mitochondrial swelling and caspase-independent cell death via the MAPK signaling pathway. Subsequently, we uncover that the copper complex of Me₂NNMe₂ (a supposed intracellular metabolite) inhibits the ER-resident protein disulfide isomerase, resulting in a specific form of ER stress based on disruption of the Ca²⁺ and ER thiol redox homeostasis. Our findings indicate that compounds like Me₂NNMe₂ are of interest especially for the treatment of apoptosis-resistant cancer and provide new insights into mechanisms underlying drug-induced paraptosis.

A relationship between pK_a values, binding abilities to copper(ii) and iron(iii) and anticancer activity of 8-hydroxyquinoline derived Mannich bases.

Solution stability, chloride ion affinity and multidrug resistance selectivity of half-sandwich Rh(η⁵-C₅Me₅) and Ru(η⁶-p-cymene) complexes of 8-hydroxyquinolines.