Mechanisms underlying the cytotoxic activity of syn/anti-isomers of dinuclear Au(I) NHC complexes
| Autor: | Jens Oberkofler, Pauline J. Fischer, Fritz E. Kühn, Teresa Pinheiro, Fernanda Marques, Christian H. G. Jakob, Eva‐Maria H. J. Esslinger, Robert M. Reich, João D. G. Correia, Bruno Dominelli |
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| Rok vydání: | 2020 |
| Předmět: |
Models
Molecular Steric effects Molecular Conformation Antineoplastic Agents Ligands 01 natural sciences Medicinal chemistry 03 medical and health sciences chemistry.chemical_compound Isomerism Nucleophile Coordination Complexes Cell Line Tumor Hexafluorophosphate Drug Discovery Humans Density Functional Theory 030304 developmental biology Membrane Potential Mitochondrial Pharmacology chemistry.chemical_classification 0303 health sciences 010405 organic chemistry Hydrogen bond Ligand Organic Chemistry Imidazoles Hydrogen Bonding General Medicine Nuclear magnetic resonance spectroscopy 0104 chemical sciences Solubility chemistry Thiol Gold Selectivity |
| Zdroj: | European Journal of Medicinal Chemistry. 203:112576 |
| ISSN: | 0223-5234 |
| Popis: | The syn- and anti-isomers of dinuclear Au(I) complexes of the type Au2(RLOH)(PF6)2 (R = isopropyl or mesityl) bearing 2-hydroxyethane-1,1-diyl-bridged bisimidazolylidene ligands were separated by reversed phase high performance liquid chromatography (HPLC) and characterized by NMR spectroscopy, elemental analysis, ESI mass spectrometry as well as single crystal X-ray diffraction analysis. Evaluation of the antiproliferative activity of the isolated isomers has shown very small difference in their cytotoxic behavior in various cancer cell lines. Additional counter-anion exchange (hexafluorophosphate to chloride) allows to increase the water solubility of synAu2(MesLOH)(PF6)2 and leads to higher antiproliferative activity when compared to the hexafluorophosphate-complex. Both isomers were treated with l -cysteine as nucleophilic thiol source and only the anti-isomer shows dissociation of one bisimidazolylidene ligand after 24 h. In the case of the syn-isomer, density functional theory calculations indicate a lower reactivity due to the higher steric hindrance of the N-substituents and additional hydrogen bond interaction, which prevents a nucleophilic attack. When the N-substituent is replaced by the bulkier mesityl group, both conformations remain unreactive and result to be the most cytotoxic complexes in the above-mentioned cancer cell lines. Interestingly, synAu2(MesLOH)(PF6)2 exhibits a high selectivity in the MCF-7 cell line with a selectivity index (SI) of 19, which is superior to auranofin (SI |
| Databáze: | OpenAIRE |
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