Coumarin-Based Triapine Derivatives and Their Copper(II) Complexes: Synthesis, Cytotoxicity and mR2 RNR Inhibition Activity
Iryna Stepanenko,
Maria V. Babak,
Gabriella Spengler,
Marta Hammerstad,
Ana Popovic-Bijelic,
Sergiu Shova,
Gabriel E. Büchel,
Denisa Darvasiova,
Peter Rapta,
Vladimir B. Arion
Affiliations
Iryna Stepanenko
Institute of Inorganic Chemistry, University of Vienna, Währinger Strasse 42, A-1090 Vienna, Austria
Maria V. Babak
Drug Discovery Lab, Department of Chemistry, City University of Hong Kong, 83 Tat Chee Avenue, Hong Kong SAR 518057, China
Gabriella Spengler
Department of Medical Microbiology, Albert Szent-Györgyi Health Center and Faculty of Medicine, University of Szeged, Semmelweis utca 6, H-6725 Szeged, Hungary
Marta Hammerstad
Section for Biochemistry and Molecular Biology, Department of Biosciences, University of Oslo, P.O. Box 1066, Blindern, NO-0316 Oslo, Norway
Ana Popovic-Bijelic
Faculty of Physical Chemistry, University of Belgrade, Studentski trg 12–16, 11158 Belgrade, Serbia
Sergiu Shova
“Petru Poni” Institute of Macromolecular Chemistry, Aleea Gr. Ghica Voda 41A, 700487 Iasi, Romania
Faculty of Chemical and Food Technology, Institute of Physical Chemistry and Chemical Physics, Slovak University of Technology in Bratislava, Radlinského 9, SK-812 37 Bratislava, Slovakia
Peter Rapta
Faculty of Chemical and Food Technology, Institute of Physical Chemistry and Chemical Physics, Slovak University of Technology in Bratislava, Radlinského 9, SK-812 37 Bratislava, Slovakia
Vladimir B. Arion
Institute of Inorganic Chemistry, University of Vienna, Währinger Strasse 42, A-1090 Vienna, Austria
A series of thiosemicarbazone-coumarin hybrids (HL1-HL3 and H2L4) has been synthesised in 12 steps and used for the preparation of mono- and dinuclear copper(II) complexes, namely Cu(HL1)Cl2 (1), Cu(HL2)Cl2 (2), Cu(HL3)Cl2 (3) and Cu2(H2L4)Cl4 (4), isolated in hydrated or solvated forms. Both the organic hybrids and their copper(II) and dicopper(II) complexes were comprehensively characterised by analytical and spectroscopic techniques, i.e., elemental analysis, ESI mass spectrometry, 1D and 2D NMR, IR and UV–vis spectroscopies, cyclic voltammetry (CV) and spectroelectrochemistry (SEC). Re-crystallisation of 1 from methanol afforded single crystals of copper(II) complex with monoanionic ligand Cu(L1)Cl, which could be studied by single crystal X-ray diffraction (SC-XRD). The prepared copper(II) complexes and their metal-free ligands revealed antiproliferative activity against highly resistant cancer cell lines, including triple negative breast cancer cells MDA-MB-231, sensitive COLO-205 and multidrug resistant COLO-320 colorectal adenocarcinoma cell lines, as well as in healthy human lung fibroblasts MRC-5 and compared to those for triapine and doxorubicin. In addition, their ability to reduce the tyrosyl radical in mouse R2 protein of ribonucleotide reductase has been ascertained by EPR spectroscopy and the results were compared with those for triapine.
