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Estrone–salicylaldehyde N-methylated thiosemicarbazone hybrids and their copper complexes: solution structure, stability and anticancer activity in tumour spheroids

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Abstract

The terminal N-mono- and dimethylated derivatives of an estrone–salicylaldehyde thiosemicarbazone hybrid and their highly cytotoxic Cu(II) complexes were synthesized and characterized in addition to their structurally related simpler bicyclic analogues. Solution stability and structure of the complexes were determined by UV–visible spectrophotometry and electron paramagnetic resonance spectroscopy. The monomethylation has a minor influence on the pKa values, while the dimethylation results in somewhat more acidic derivatives compared to the non-methylated derivatives, although all the compounds are neutral at physiological pH. Based on the speciation studies performed in a 30% (v/v) dimethyl sulfoxide/water mixture, the four novel ligands form fairly high-stability complexes with Cu(II) ions, in which they coordinate in mono-anionic (O‒,N,S) or di-anionic (O‒,N,S‒) binding modes. [CuLH‒1] species with (O‒,N,S‒)(H2O) coordination mode are present in solution at neutral pH, and these complexes were isolated and further studied. The Cu(II) complexes formed with the estrone hybrids were more stable in comparison with the bicyclic analogues. The terminal N-dimethylation results in the most stable complexes in a given ligand series. In vitro cytotoxicity of all the Cu(II) complexes was measured in 3D spheroids of HCT-116, A-549 and CH-1 human cancer cells which showed fairly low IC50 values (3.9‒17.1 μM). The Cu(II) complexes caused reduced tumour growth, and they activated the caspase-3 and caspase-7 endoproteases leading to apoptosis except the case of the complex formed with the monomethylated bicyclic derivative, where other type of mechanisms of action seems to induce the cell death.

Graphic abstract

Anticancer Cu(II) complexes of mono- and dimethylated salicylaldehyde thiosemicarbazone-estrone hybrids possessing high solution stability and strong cytotoxic effect against 3D spheroids of a series of human cancer cells. 398x273 mm (150 x 150 DPI)

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Acknowledgements

This work was supported by National Research, Development and Innovation Office-NKFIA (Hungary) through projects FK 124240, K124544, GINOP-2.3.2-15-2016-00038, Ministry of Human Capacities (Hungary) grant TKP-2020 and the Visegrad Scholarship 52010752 (T.V.P.).

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Authors and Affiliations

  1. Department of Inorganic and Analytical Chemistry, Interdisciplinary Excellence Centre, University of Szeged, Dóm tér 7, Szeged, 6720, Hungary

    Tatsiana V. Petrasheuskaya & Éva A. Enyedy

  2. MTA-SZTE Lendület Functional Metal Complexes Research Group, University of Szeged, Dóm tér 7, Szeged, 6720, Hungary

    Tatsiana V. Petrasheuskaya & Éva A. Enyedy

  3. Institute of Inorganic Chemistry and Research Cluster ‘Translational Cancer Therapy Research’, University of Vienna, Währinger Straße 42, Vienna, Austria

    Debora Wernitznig, Dominik Wenisch & Bernhard K. Keppler

  4. Department of Organic Chemistry, University of Szeged, Dóm tér 8, Szeged, 6720, Hungary

    Márton A. Kiss & Éva Frank

  5. Centre for Structural Science, Research Centre for Natural Sciences, Magyar tudósok körútja 2, Budapest, 1117, Hungary

    Nóra V. May

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  1. Tatsiana V. Petrasheuskaya
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Correspondence to Éva A. Enyedy.

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Petrasheuskaya, T.V., Wernitznig, D., Kiss, M.A. et al. Estrone–salicylaldehyde N-methylated thiosemicarbazone hybrids and their copper complexes: solution structure, stability and anticancer activity in tumour spheroids. J Biol Inorg Chem 26, 775–791 (2021). https://doi.org/10.1007/s00775-021-01891-7

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