Significance: During the past decades, thiosemicarbazones were 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 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (Triapine), was intensively developed in multiple clinical phase I/II trials. Recent Advances: Very recently, two new derivatives, namely COTI-2 and di-2-pyridylketone 4-cyclohexyl-4-methyl-3-thiosemicarbazone (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 of bridging 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 in a complex and multi-faceted 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.
Keywords: collateral sensitivity; drug resistance; iron; metal complex; ribonucleotide reductase; thiosemicarbazones.