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Hetero-Bis-Conjugation of Bioactive Molecules to Half-Sandwich Ruthenium(II) and Iridium(III) Complexes Provides Synergic Effects in Cancer Cell Cytotoxicity
L. Biancalana, H. Kostrhunova, LK. Batchelor, M. Hadiji, I. Degano, G. Pampaloni, S. Zacchini, PJ. Dyson, V. Brabec, F. Marchetti
Language English Country United States
Document type Journal Article
- MeSH
- Iridium chemistry pharmacology MeSH
- Coordination Complexes chemical synthesis chemistry pharmacology MeSH
- Humans MeSH
- Ligands MeSH
- Molecular Structure MeSH
- Tumor Cells, Cultured MeSH
- DNA Damage MeSH
- Cell Proliferation drug effects MeSH
- Antineoplastic Agents chemical synthesis chemistry pharmacology MeSH
- Pyridines chemistry pharmacology MeSH
- Ruthenium chemistry pharmacology MeSH
- Drug Screening Assays, Antitumor MeSH
- Cell Survival drug effects MeSH
- Dose-Response Relationship, Drug MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
Four bipyridine-type ligands variably derivatized with two bioactive groups (taken from ethacrynic acid, flurbiprofen, biotin, and benzylpenicillin) were prepared via sequential esterification steps from commercial 2,2'-bipyridine-4,4'-dicarboxylic acid and subsequently coordinated to ruthenium(II) p-cymene and iridium(III) pentamethylcyclopentadienyl scaffolds. The resulting complexes were isolated as nitrate salts in high yields and fully characterized by analytical and spectroscopic methods. NMR and MS studies in aqueous solution and in cell culture medium highlighted a substantial stability of ligand coordination and a slow release of the bioactive fragments in the latter case. The complexes were assessed for their antiproliferative activity on four cancer cell lines, showing cytotoxicity to the low micromolar level (equipotent with cisplatin). Additional biological experiments revealed a multimodal mechanism of action of the investigated compounds, involving DNA metalation and enzyme inhibition. Synergic effects provided by specific combinations of metal and bioactive fragments were identified, pointing toward an optimal ethacrynic acid/flurbiprofen combination for both Ru(II) and Ir(III) complexes.
Czech Academy of Sciences Institute of Biophysics Kralovopolska 135 CZ 61265 Brno Czech Republic
Dipartimento di Chimica e Chimica Industriale Università di Pisa Via G Moruzzi 13 1 56124 Pisa Italy
References provided by Crossref.org
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