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Triapine (3-aminopyridine-2-carboxaldehyde thiosemicarbazone, 3-AP) is currently the most promising chemotherapeutic compound among the class of α-N-heterocyclic thiosemicarbazones.Here we report further insights into the mechanism(s) of anticancer drug activity and inhibition of mouse ribonucleotide reductase (RNR) by Triapine. In addition to the metal-free ligand, its iron(III), gallium(III), zinc(II) and copper (II) complexes were studied, aiming to correlate their cytotoxic activities with their effects on the diferric/tyrosyl radical center of the RNR enzyme in vitro. In this study we propose for the first time a potential specific binding pocket for Triapine on the surface of the mouse R2 RNR protein. In our mechanistic model, interaction with Triapine results in the labilization of the diferric center in the R2 protein. Subsequently the Triapine molecules act as iron chelators. In the absence of external reductants, and in presence of the mouse R2 RNR protein, catalytic amounts of the iron(III)-Triapine are reduced to the iron(II)-Triapine complex. In the presence of an external reductant (dithiothreitol), stoichiometric amounts of the potently reactive iron (II)-Triapine complex are formed. Formation of the iron(II)-Triapine complex, as the essential part of the reaction outcome, promotes further reactions with molecular oxygen, which give rise to reactive oxygen species (ROS) and thereby damage the RNR enzyme. Triapine affects the diferric center of the mouse R2 protein and, unlike hydroxyurea, is not a potent reductant, not likely to act directly on the tyrosyl radical.

The interactions of Cu II , Zn II and Fe II with Triapine (3-aminopyridine-2-carbaldehyde thiosemicarbazone), which is currently undergoing phase II clinical trials as a chemotherapeutic antitumour agent, were investigated in a water/DMSO mixture. The proton-dissociation constants of the ligands, the stability constants and the coordination modes of the metal complexes formed were determined by pH-potentiometric, UV/Vis spectrophotometric, EPR, 1 H NMR spectroscopic and ESI-MS methods. Two N-terminally dimethylated derivatives of Triapine were also studied. Mono-and bis-ligand com-[a]

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The stoichiometry and stability of copper(II), zinc(II), iron(II)/ (III) and gallium(III) complexes of salicylaldehyde thiosemicarbazone (STSC, H 2 L) have been determined by pH potentiometry, UV/Vis spectrophotometry, and 1 H NMR and EPR spectroscopy in aqueous solution (with 30 % DMSO), together with the characterization of the proton dissociation processes. Mono-and bis-ligand complexes in different protonation states were identified for Fe II , Fe III and Ga III , whereas Cu II and Zn II ions only form complexes with a 1:1 metal/ligand ratio. The coordination mode in the complex [a]