Triapine Derivatives Act as Copper Delivery Vehicles to Induce Deadly Metal Overload in Cancer Cells
Kateryna Ohui,
Iryna Stepanenko,
Iuliana Besleaga,
Maria V. Babak,
Radu Stafi,
Denisa Darvasiova,
Gerald Giester,
Vivien Pósa,
Eva A. Enyedy,
Daniel Vegh,
Peter Rapta,
Wee Han Ang,
Ana Popović-Bijelić,
Vladimir B. Arion
Affiliations
Kateryna Ohui
Institute of Inorganic Chemistry, University of Vienna, Währinger Strasse 42, A-1090 Vienna, Austria
Iryna Stepanenko
Institute of Inorganic Chemistry, University of Vienna, Währinger Strasse 42, A-1090 Vienna, Austria
Iuliana Besleaga
Institute of Inorganic Chemistry, University of Vienna, Währinger Strasse 42, A-1090 Vienna, Austria
Maria V. Babak
Department of Chemistry, National University of Singapore, 3 Science Drive 2, Singapore 117543, Singapore
Radu Stafi
Institute of Inorganic Chemistry, University of Vienna, Währinger Strasse 42, A-1090 Vienna, Austria
Denisa Darvasiova
Institute of Physical Chemistry and Chemical Physics, Slovak University of Technology in Bratislava, Radlinského 9, SK-81237 Bratislava, Slovakia
Gerald Giester
Department of Mineralogy and Crystallography, University of Vienna, Althan Strasse 14, A-1090 Vienna, Austria
Vivien Pósa
Department of Inorganic and Analytical Chemistry, Interdisciplinary Excellence Centre, University of Szeged, Dóm tér 7, H-6720 Szeged, Hungary
Eva A. Enyedy
Department of Inorganic and Analytical Chemistry, Interdisciplinary Excellence Centre, University of Szeged, Dóm tér 7, H-6720 Szeged, Hungary
Daniel Vegh
Institute of Organic Chemistry, Catalysis and Petrochemistry, Department of Organic Chemistry, Slovak University of Technology in Bratislava, Radlinského 9, SK-81237 Bratislava, Slovakia
Peter Rapta
Institute of Physical Chemistry and Chemical Physics, Slovak University of Technology in Bratislava, Radlinského 9, SK-81237 Bratislava, Slovakia
Wee Han Ang
Department of Chemistry, National University of Singapore, 3 Science Drive 2, Singapore 117543, Singapore
Ana Popović-Bijelić
Faculty of Physical Chemistry, University of Belgrade, 11158 Belgrade, Serbia
Vladimir B. Arion
Institute of Inorganic Chemistry, University of Vienna, Währinger Strasse 42, A-1090 Vienna, Austria
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 [CuII(HL1)Cl2]·H2O (1·H2O) and [CuII(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 [FeIII(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.
