Estrone-salicylaldehyde N-methylated thiosemicarbazone hybrids and their copper complexes: solution structure, stability and anticancer activity in tumour spheroids
- Author(s)
- Tatsiana V. Petrasheuskaya, Debora Wernitznig, Marton A. Kiss, Nora V. May, Dominik Wenisch, Bernhard K. Keppler, Eva Frank, Eva A. Enyedy
- 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 pK(a) 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 mu M). 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)
- Organisation(s)
- Department of Inorganic Chemistry
- External organisation(s)
- University of Szeged, Hungarian Academy of Sciences
- Journal
- Journal of Biological Inorganic Chemistry
- Volume
- 26
- Pages
- 775–791
- No. of pages
- 17
- ISSN
- 0949-8257
- DOI
- https://doi.org/10.1007/s00775-021-01891-7
- Publication date
- 10-2021
- Peer reviewed
- Yes
- Austrian Fields of Science 2012
- 104003 Inorganic chemistry, 104004 Chemical biology, 301904 Cancer research
- Keywords
- ASJC Scopus subject areas
- Biochemistry, Inorganic Chemistry
- Sustainable Development Goals
- SDG 3 - Good Health and Well-being
- Portal url
- https://ucrisportal.univie.ac.at/en/publications/1200e74e-b31e-40a4-84ac-e083390f4de4