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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
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SYSNO ASEP 0554906 Document Type J - Journal Article R&D Document Type Journal Article Subsidiary J Článek ve WOS Title Hetero-Bis-Conjugation of Bioactive Molecules to Half-Sandwich Ruthenium(II) and Iridium(III) Complexes Provides Synergic Effects in Cancer Cell Cytotoxicity Author(s) Biancalana, L. (IT)
Kostrhunová, Hana (BFU-R) RID, ORCID
Batchelor, L. (CH)
Hadiji, M. (CH)
Degano, I. (IT)
Pampaloni, G. (IT)
Zacchini, S. (IT)
Dyson, P.J. (CH)
Brabec, Viktor (BFU-R) RID, ORCID
Marchetti, F. (IT)Number of authors 10 Source Title Inorganic Chemistry. - : American Chemical Society - ISSN 0020-1669
Roč. 60, č. 13 (2021), s. 9529-9541Number of pages 13 s. Publication form Print - P Language eng - English Country US - United States Keywords anticancer agents ; platinum(iv) prodrug ; crystal-structure ; rational design ; acid ; derivatives OECD category Organic chemistry R&D Projects GC20-14082J GA ČR - Czech Science Foundation (CSF) Method of publishing Limited access Institutional support BFU-R - RVO:68081707 UT WOS 000671099600035 EID SCOPUS 85110193018 DOI 10.1021/acs.inorgchem.1c00641 Annotation 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. Workplace Institute of Biophysics Contact Jana Poláková, polakova@ibp.cz, Tel.: 541 517 244 Year of Publishing 2022 Electronic address https://pubs.acs.org/doi/10.1021/acs.inorgchem.1c00641
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