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

doi:10.3390/biom10091213

Insight into the Anticancer Activity of Copper(II) 5-Methylenetrimethylammonium-Thiosemicarbazonates and Their Interaction with Organic Cation Transporters

Biomolecules. 2020 Aug 20;10(9):1213. doi: 10.3390/biom10091213.

Authors

Miljan N M Milunović¹, Oleg Palamarciuc², Angela Sirbu², Sergiu Shova³, Dan Dumitrescu⁴, Dana Dvoranová⁵, Peter Rapta⁵, Tatsiana V Petrasheuskaya^{6

7}, Eva A Enyedy^{6

7}, Gabriella Spengler^{7

8}, Marija Ilic^{9

10

11}, Harald H Sitte¹⁰, Gert Lubec¹¹, Vladimir B Arion¹

Affiliations

¹ Institute of Inorganic Chemistry, Faculty of Chemistry, University of Vienna, Währinger Strasse 42, A-1090 Vienna, Austria.
² Department of Chemistry, Moldova State University, A. Mateevici Street 60, MD-2009 Chisinau, Moldova.
³ Petru Poni Institute of Macromolecular Chemistry, Laboratory of Inorganic Polymers, Aleea Grigore Ghica Voda, Nr. 41A, 700487 Iasi, Romania.
⁴ Elettra-Sincrotrone Trieste S.C.p.A, Strada Statale 14-km 163,5 in AREA Science Park, 34149 Basovizza, Trieste, Italy.
⁵ 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.
⁶ Department of Inorganic and Analytical Chemistry, Interdisciplinary Excellence Centre, University of Szeged, Dóm tér 7, H-6720 Szeged, Hungary.
⁷ MTA-SZTE Lendület Functional Metal Complexes Research Group, University of Szeged, Dóm tér 7, H-6720 Szeged, Hungary.
⁸ Department of Medical Microbiology and Immunobiology, University of Szeged, Dóm tér 10, H-6720 Szeged, Hungary.
⁹ Department of Pharmaceutical Chemistry, Faculty of Life Sciences, University of Vienna, A-1090 Vienna, Austria.
¹⁰ Institute of Pharmacology, Centre for Physiology and Pharmacology, Medical University of Vienna, A-1090 Vienna, Austria.
¹¹ Neuroproteomics, Paracelsus Private Medical University, 5020 Salzburg, Austria.

Abstract

A series of four water-soluble salicylaldehyde thiosemicarbazones with a positively charged trimethylammonium moiety ([H₂L^R]Cl, R = H, Me, Et, Ph) and four copper(II) complexes [Cu(HL^R)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 >>[H₂L^R]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.

Keywords: copper(II) complexes; cytotoxicity; organic cation transporters (OCT1–3), inhibitors; thiosemicarbazones.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Aldehydes / chemistry
Aldehydes / pharmacology*
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Cell Line
Cell Proliferation / drug effects
Coordination Complexes / chemical synthesis
Coordination Complexes / chemistry
Coordination Complexes / pharmacology*
Copper / chemistry
Copper / pharmacology*
Crystallography, X-Ray
Drug Screening Assays, Antitumor
Humans
Models, Molecular
Molecular Structure
Organic Cation Transport Proteins / antagonists & inhibitors*
Organic Cation Transport Proteins / metabolism
Thiosemicarbazones / chemistry
Thiosemicarbazones / pharmacology*

Substances

Aldehydes
Antineoplastic Agents
Coordination Complexes
Organic Cation Transport Proteins
Thiosemicarbazones
salicylaldehyde thiosemicarbazone
Copper

Grants and funding

(FWF grant no. P28223)/Austrian Science Fund/International