New Water-Soluble Copper(II) Complexes with Morpholine-Thiosemicarbazone Hybrids: Insights into the Anticancer and Antibacterial Mode of Action

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; Vladimir B Arion

doi:10.1021/acs.jmedchem.8b01031

New Water-Soluble Copper(II) Complexes with Morpholine-Thiosemicarbazone Hybrids: Insights into the Anticancer and Antibacterial Mode of Action

J Med Chem. 2019 Jan 24;62(2):512-530. doi: 10.1021/acs.jmedchem.8b01031. Epub 2018 Dec 18.

Authors

Kateryna Ohui¹, Eleonora Afanasenko¹, Felix Bacher¹, Rachel Lim Xue Ting², Ayesha Zafar³, Núria Blanco-Cabra⁴, Eduard Torrents⁴, Orsolya Dömötör⁵, Nóra V May⁶, Denisa Darvasiova⁷, Éva A Enyedy⁵, Ana Popović-Bijelić⁸, Jóhannes Reynisson³, Peter Rapta⁷, Maria V Babak^{9

10}, Giorgia Pastorin², Vladimir B Arion¹

Affiliations

¹ Institute of Inorganic Chemistry , University of Vienna , Währinger Strasse 42 , A-1090 Vienna , Austria.
² Department of Pharmacy , National University of Singapore , 3 Science Drive 2 , Singapore 117543 , Singapore.
³ School of Chemical Sciences , University of Auckland , Auckland 1010 , New Zealand.
⁴ Bacterial Infections: Antimicrobial Therapies, Institute for Bioengineering of Catalonia (IBEC) , The Barcelona Institute of Science and Technology , Barcelona 08036 , Spain.
⁵ Department of Inorganic and Analytical Chemistry , University of Szeged , Dóm tér 7. , H-6720 Szeged , Hungary.
⁶ Research Centre of Natural Sciences , Hungarian Academy of Sciences , Magyar tudósok körútja 2. , H-1117 Budapest , Hungary.
⁷ Institute of Physical Chemistry and Chemical Physics , Slovak Technical University of Technology , Radlinského 9 , 81237 Bratislava , Slovak Republic.
⁸ Faculty of Physical Chemistry , University of Belgrade , 11158 Belgrade , Serbia.
⁹ Department of Chemistry , National University of Singapore , 3 Science Drive 2 , 117543 , Singapore.
¹⁰ Drug Development Unit , National University of Singapore , 28 Medical Drive , 117546 , Singapore.

Abstract

Six 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(L^1-6)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.

Publication types

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

MeSH terms

Animals
Anti-Bacterial Agents / chemical synthesis
Anti-Bacterial Agents / chemistry
Anti-Bacterial Agents / pharmacology
Antineoplastic Agents / chemical synthesis*
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology
Binding Sites
Catalytic Domain
Cell Line, Tumor
Cell Proliferation / drug effects
Coordination Complexes / chemical synthesis
Coordination Complexes / chemistry*
Coordination Complexes / pharmacology
Copper / chemistry*
Crystallography, X-Ray
Humans
Mice
Molecular Conformation
Molecular Docking Simulation
Morpholines / chemistry*
Orphan Nuclear Receptors / antagonists & inhibitors
Orphan Nuclear Receptors / metabolism
Pseudomonas aeruginosa / drug effects
Solubility
Structure-Activity Relationship
Thiosemicarbazones / chemistry*

Substances

Anti-Bacterial Agents
Antineoplastic Agents
Coordination Complexes
Morpholines
Orphan Nuclear Receptors
Thiosemicarbazones
Copper