• Kateryna Ohui, Eleonora Afanasenko, Felix Bacher, Rachel Lim Xue Ting, Ayesha Zafar, Núria Blanco-Cabra, Eduard Torrents, Orsolya Dömötör, Nóra V May, Denisa Darvasiova, Éva A Enyedy, Ana Popović-Bijelić, Jóhannes Reynisson, Peter Rapta, Maria V Babak, Giorgia Pastorin, and Vladimir B Arion.
• Institute of Inorganic Chemistry , University of Vienna , Währinger Strasse 42 , A-1090 Vienna , Austria.
• J. Med. Chem. 2019 Jan 24; 62 (2): 512-530.

AbstractSix morpholine-(iso)thiosemicarbazone hybrids HL1-HL6 and their Cu(II) complexes with good-to-moderate solubility and stability in water were synthesized and characterized. Cu(II) complexes [Cu(L1-6)Cl] (1-6) formed weak dimeric associates in the solid state, which did not remain intact in solution as evidenced by ESI-MS. The lead proligands and Cu(II) complexes displayed higher antiproliferative activity in cancer cells than triapine. In addition, complexes 2-5 were found to specifically inhibit the growth of Gram-positive bacteria Staphylococcus aureus with MIC50 values at 2-5 μg/mL. Insights into the processes controlling intracellular accumulation and mechanism of action were investigated for 2 and 5, including the role of ribonucleotide reductase (RNR) inhibition, endoplasmic reticulum stress induction, and regulation of other cancer signaling pathways. Their ability to moderately inhibit R2 RNR protein in the presence of dithiothreitol is likely related to Fe chelating properties of the proligands liberated upon reduction.

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