Insight into the Anticancer Activity of Copper(II) 5-Methylenetrimethylammonium-Thiosemicarbazonates and Their Interaction with Organic Cation Transporters
Miljan N. M. Milunović,
Oleg Palamarciuc,
Angela Sirbu,
Sergiu Shova,
Dan Dumitrescu,
Dana Dvoranová,
Peter Rapta,
Tatsiana V. Petrasheuskaya,
Eva A. Enyedy,
Gabriella Spengler,
Marija Ilic,
Harald H. Sitte,
Gert Lubec,
Vladimir B. Arion
Affiliations
Miljan N. M. Milunović
Institute of Inorganic Chemistry, Faculty of Chemistry, University of Vienna, Währinger Strasse 42, A-1090 Vienna, Austria
Oleg Palamarciuc
Department of Chemistry, Moldova State University, A. Mateevici Street 60, MD-2009 Chisinau, Moldova
Angela Sirbu
Department of Chemistry, Moldova State University, A. Mateevici Street 60, MD-2009 Chisinau, Moldova
Sergiu Shova
Petru Poni Institute of Macromolecular Chemistry, Laboratory of Inorganic Polymers, Aleea Grigore Ghica Voda, Nr. 41A, 700487 Iasi, Romania
Dan Dumitrescu
Elettra—Sincrotrone Trieste S.C.p.A, Strada Statale 14—km 163,5 in AREA Science Park, 34149 Basovizza, Trieste, Italy
Dana Dvoranová
Institute of Physical Chemistry and Chemical Physics, Faculty of Chemical and Food Technology, Slovak University of Technology in Bratislava, Radlinského 9, SK-81237 Bratislava, Slovakia
Peter Rapta
Institute of Physical Chemistry and Chemical Physics, Faculty of Chemical and Food Technology, Slovak University of Technology in Bratislava, Radlinského 9, SK-81237 Bratislava, Slovakia
Tatsiana V. Petrasheuskaya
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
Gabriella Spengler
MTA-SZTE Lendület Functional Metal Complexes Research Group, University of Szeged, Dóm tér 7, H-6720 Szeged, Hungary
Marija Ilic
Department of Pharmaceutical Chemistry, Faculty of Life Sciences, University of Vienna, A-1090 Vienna, Austria
Harald H. Sitte
Institute of Pharmacology, Centre for Physiology and Pharmacology, Medical University of Vienna, A-1090 Vienna, Austria
Gert Lubec
Neuroproteomics, Paracelsus Private Medical University, 5020 Salzburg, Austria
Vladimir B. Arion
Institute of Inorganic Chemistry, Faculty of Chemistry, University of Vienna, Währinger Strasse 42, A-1090 Vienna, Austria
A series of four water-soluble salicylaldehyde thiosemicarbazones with a positively charged trimethylammonium moiety ([H2LR]Cl, R = H, Me, Et, Ph) and four copper(II) complexes [Cu(HLR)Cl]Cl (1–4) were synthesised with the aim to study (i) their antiproliferative activity in cancer cells and, (ii) for the first time for thiosemicarbazones, the interaction with membrane transport proteins, specifically organic cation transporters OCT1–3. The compounds were comprehensively characterised by analytical, spectroscopic and X-ray diffraction methods. The highest cytotoxic effect was observed in the neuroblastoma cell line SH-5YSY after 24 h exposure and follows the rank order: 3 > 2 > 4 > cisplatin > 1 >> [H2LR]Cl. The copper(II) complexes showed marked interaction with OCT1–3, comparable to that of well-known OCT inhibitors (decynium 22, prazosin and corticosterone) in the cell-based radiotracer uptake assays. The work paves the way for the development of more potent and selective anticancer drugs and/or OCT inhibitors.
