Thiosemicarbazones continue to attract the interest of researchers as potential anticancer drugs. For example, 3-aminopyridine-2-carboxaldehyde thiosemicarbazone, or triapine, is the most well-known representative of this class of compounds that has entered multiple phase I and II clinical trials. Two new triapine derivatives HL¹ and HL² were prepared by condensation reactions of 2-pyridinamidrazone and S-methylisothiosemicarbazidium chloride with 3-N-(tert-butyloxycarbonyl) amino-pyridine-2-carboxaldehyde, followed by a Boc-deprotection procedure. Subsequent reaction of HL¹ and HL² with CuCl₂·2H₂O in 1:1 molar ratio in methanol produced the complexes [Cu^II(HL¹)Cl₂]·H₂O (1·H₂O) and [Cu^II(HL²)Cl₂] (2). The reaction of HL² with Fe(NO₃)₃∙9H₂O in 2:1 molar ratio in the presence of triethylamine afforded the complex [Fe^III(L²)₂]NO₃∙0.75H₂O (3∙0.75H₂O), in which the isothiosemicarbazone acts as a tridentate monoanionic ligand. The crystal structures of HL¹, HL² and metal complexes 1 and 2 were determined by single crystal X-ray diffraction. The UV-Vis and EPR spectroelectrochemical measurements revealed that complexes 1 and 2 underwent irreversible reduction of Cu(II) with subsequent ligand release, while 3 showed an almost reversible electrochemical reduction in dimethyl sulfoxide (DMSO). Aqueous solution behaviour of HL¹ and 1, as well as of HL² and its complex 2, was monitored as well. Complexes 1-3 were tested against ovarian carcinoma cells, as well as noncancerous embryonic kidney cells, in comparison to respective free ligands, triapine and cisplatin. While the free ligands HL¹ and HL² were devoid of antiproliferative activity, their respective metal complexes showed remarkable antiproliferative activity in a micromolar concentration range. The activity was not related to the inhibition of ribonucleotide reductase (RNR) R2 protein, but rather to cancer cell homeostasis disturbance-leading to the disruption of cancer cell signalling.

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