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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.

Triapine, the most prominent anticancer drug candidate from the substance class of thiosemicarbazones, was investigated in >30 clinical phase I and II studies. However, the results were rather disappointing against solid tumors, which can be explained (at least partially) due to inefficient delivery to the tumor site. Hence, we synthesized the first biotin-functionalized thiosemicarbazone derivatives in order to increase tumor specificity and accumulation. Additionally, for Triapine and one biotin conjugate the iron(III) and copper(II) complexes were prepared. Subsequently, the novel compounds were biologically evaluated on a cell line panel with different biotin uptake. The metal-free biotin-conjugated ligands showed comparable activity to the reference compound Triapine. However, astonishingly, the metal complexes of the biotinylated derivative showed strikingly decreased anticancer activity. To further analyze possible differences between the metal complexes, detailed physico- and electrochemical experiments were performed. However, neither lipophilicity or complex solution stability, nor the reduction potential or behavior in the presence of biologically relevant reducing agents showed strong variations between the biotinylated and non-biotinylated derivatives (only some differences in the reduction kinetics were observed). Nonetheless, the metal-free biotin-conjugate of Triapine revealed distinct activity in a colon cancer mouse model upon oral application comparable to Triapine. Therefore, this type of biotin-conjugated thiosemicarbazone is of interest for further synthetic strategies and biological studies., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Triapine has been investigated as anticancer drug in multiple clinical phase I/II trials. Although promising anti-leukemic activity was observed, Triapine was ineffective against solid tumors. The reasons are currently widely unknown. The biological activity of Triapine is strongly connected to its iron complex (Fe-Triapine) which is pharmacologically not investigated. Here, novel analytical tools for Triapine and Fe-Triapine were developed and applied for cell extracts and body fluids of treated mice. Triapine and its iron complex showed a completely different behavior: for Triapine, low protein binding was observed in contrast to fast protein adduct formation of Fe-Triapine. Notably, both drugs were rapidly cleared from the body (serum half-life time <1h). Remarkably, in contrast to Triapine, where (in accordance to clinical data) basically no renal excretion was found, the iron complex was effectively excreted via urine. Moreover, no Fe-Triapine was detected in serum or cytosolic extracts after Triapine treatment. Taken together, our study will help to further understand the biological behavior of Triapine and its Fe-complex and allow the development of novel thiosemicarbazones with pronounced activity against solid tumor types., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Stoichiometry and stability of Ga(III), Fe(III), Fe(II) complexes of Triapine and five related α-N heterocyclic thiosemicarbazones with potential antitumor activity have been determined by pH-potentiometry, UV-vis spectrophotometry, (1)H NMR spectroscopy, and spectrofluorimetry in aqueous solution (with 30% DMSO), together with the characterization of the proton dissociation processes. Additionally, the redox properties of the iron complexes were studied by cyclic voltammetry at various pH values. Formation of high stability bis-ligand complexes was found in all cases, which are predominant at physiological pH with Fe(III)/Fe(II), whilst only at the acidic pH range with Ga(III). The results show that among the thiosemicarbazones with various substituents the N-terminal dimethylation does not exert a measurable effect on the redox potential, but has the highest impact on the stability of the complexes as well as the cytotoxicity, especially in the absence of a pyridine-NH(2) group in the molecule. In addition the fluorescence properties of the ligands in aqueous solution and their changes caused by Ga(III) were studied.

The first metal complexes of 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (Triapine) were synthesized. Triapine was prepared by a novel three-step procedure in 64% overall yield. In addition, a series of related ligands, namely, 2-formylpyridine thiosemicarbazone, 2-acetylpyridine thiosemicarbazone, 2-pyridineformamide thiosemicarbazone, and their N(4)-dimethylated derivatives (including the N(4)-dimethylated analogue of Triapine) were prepared, along with their corresponding gallium(III) and iron(III) complexes with the general formula [M(L)(2)](+), where HL is the respective thiosemicarbazone. The compounds were characterized by elemental analysis, (1)H and (13)C NMR, IR and UV-vis spectroscopies, mass spectrometry, and cyclic voltammetry. In addition, Triapine and its iron(III) and gallium(III) complexes were studied by X-ray crystallography. All ligands and complexes were tested for their in vitro antiproliferative activity in two human cancer cell lines (41M and SK-BR-3), and structure-activity relationships were established. In general, the coordination to gallium(III) increased the cytotoxicity while the iron(III) complexes show reduced cytotoxic activity compared to the metal-free thiosemicarbazones. Selected compounds were investigated for the capacity of inhibiting ribonucleotide reductase by incorporation of (3)H-cytidine into DNA.

The electrochemical properties of a series of alpha-N-heterocyclic chalcogensemicarbazones (HL), namely, thiosemicarbazones, selenosemicarbazones, and semicarbazones, and their gallium(III), iron(III), and ruthenium(III) complexes with the general formula [ML(2)][Y] (M = Ga, Fe or Ru; Y = PF(6)(-), NO(3)(-), or FeCl(4)(-)) were studied by cyclic voltammetry. The novel compounds were characterized by elemental analysis, a number of spectroscopic methods (NMR, UV-vis, IR), mass spectrometry and by X-ray crystallography. All complexes show several, mostly reversible, redox waves attributable to the reduction of the noninnocent chalcogensemicarbazone ligands at lower potentials (<-0.4 V vs NHE) than the metal-centered iron or ruthenium redox waves (>0 V vs NHE) in organic electrolyte solutions. The cyclic voltammograms of the gallium complexes display at least two consecutive reversible one-electron reduction waves. These reductions are shifted by approximately 0.6 V to lower potentials in the corresponding iron and ruthenium complexes. The electrochemical, chemical, and spectroscopic data indicate that the ligand-centered reduction takes place at the CH(3)CN double bond. Quantum chemical calculations on the geometric and electronic structures of 2-acetylpyridine (4)N,(4)N-dimethylthiosemicarbazone (HL(B)), the corresponding metal complexes [Ga(L(B))(2)](+) and [Fe(II)(L(B))(2)], and the one-electron reduction product for each of these species support the assignment of the reduction site and elucidate the observed order of the ligand-centered redox potentials, E(1/2)([Fe(II)(L)(2)]) < E(1/2)(HL) < E(1/2)([Ga(L)(2)](+)). The influence of water on the redox potentials of the complexes is reported and the physiological relevance of the electrochemical data for cytotoxicity as well as for ribonucleotide reductase inhibitory capacity are discussed.

A series of gallium(III) and iron(III) complexes with five different 4N-substituted alpha-N-heterocyclic thiosemicarbazones, viz., 2-acetylpyridine N,N-dimethylthiosemicarbazone (1), 2-acetylpyridine N-pyrrolidinylthiosemicarbazone (2), acetylpyrazine N,N-dimethylthiosemicarbazone (3), acetylpyrazine N-pyrrolidinylthiosemicarbazone (4), and acetylpyrazine N-piperidinylthiosemicarbazone (5), with the general formula [GaLCl2] (HL = 1 and 2) and [ML2][Y] (M = Ga, HL = 1-5, Y = PF6; M = Fe, HL = 1-5, Y = FeCl4 and PF6) were synthesized and characterized by elemental analysis, a number of spectroscopic methods (NMR, IR, UV-vis), mass spectrometry, and X-ray crystallography. The in vitro antitumor potency was studied in two human cancer cell lines (41M and SK-BR-3). The central metal ions exert pronounced effects in a divergent manner: gallium(III) enhances, whereas iron(III) weakens the cytotoxicity of the ligands. The capacity of ligand 1 and its Ga(III) and Fe(III) complexes to destroy the tyrosyl radical of the presumed target ribonucleotide reductase is reported.