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Exploring pta Alternatives in the Development of Ruthenium-Arene Anticancer Compounds.

ABSTRACT: Organoruthenium pyrithione (1-hydroxypyridine-2-thione) complexes have been shown in our recent studies to be a promising family of compounds for development of new anticancer drugs. The complex [(η⁶-p-cymene)Ru(pyrithionato)(pta)]PF₆ contains phosphine ligand pta (1,3,5-triaza-7-phosphaadamantane) as a functionality that improves the stability of the complex and its aqueous solubility. Here, we report our efforts to find pta alternatives and discover new structural elements to improve the biological properties of ruthenium anticancer drugs. The pta ligand was replaced by a selection of phosphine, phosphite, and arsine ligands to identify new functionalities, leading to improvement in inhibitory potency towards enzyme glutathione S-transferase. In addition, cytotoxicity in breast, bone, and colon cancers was investigated.

SUBMITTER: Kljun J

PROVIDER: S-EPMC10058425 | biostudies-literature | 2023 Mar

REPOSITORIES: biostudies-literature

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Exploring pta Alternatives in the Development of Ruthenium-Arene Anticancer Compounds.

Kljun Jakob J Rebernik Mihaela M Balsa Lucía M LM Kladnik Jerneja J Rapuš Uroš U Trobec Tomaž T Sepčić Kristina K Frangež Robert R León Ignacio E IE Turel Iztok I

Molecules (Basel, Switzerland) 20230309 6

Organoruthenium pyrithione (1-hydroxypyridine-2-thione) complexes have been shown in our recent studies to be a promising family of compounds for development of new anticancer drugs. The complex [(η6-p-cymene)Ru(pyrithionato)(pta)]PF6 contains phosphine ligand pta (1,3,5-triaza-7-phosphaadamantane) as a functionality that improves the stability of the complex and its aqueous solubility. Here, we report our efforts to find pta alternatives and discover new structural ...[more]

PMID: 36985471

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Project description:The antibacterial activity of 22 thiolato-bridged dinuclear ruthenium(II)-arene compounds was assessed in vitro against Escherichia coli, Streptococcus pneumoniae, and Staphylococcus aureus. None of the compounds efficiently inhibited the growth of the three E. coli strains tested, and only compound 5 exhibited a medium activity against this bacterium [MIC (minimum inhibitory concentration) of 25 µM]. However, a significant antibacterial activity was observed against S. pneumoniae, with MIC values ranging from 1.3 to 2.6 µM for compounds 1-3, 5, and 6. Similarly, compounds 2, 5-7, and 20-22 had MIC values ranging from 2.5 to 5 µM against S. aureus. The tested diruthenium compounds have a bactericidal effect significantly faster than that of penicillin. Fluorescence microscopy assays performed on S. aureus using the BODIPY-tagged diruthenium complex 15 showed that this type of metal compound enters the bacteria and does not accumulate in the cell wall of gram-positive bacteria. Cellular internalization was further confirmed by inductively coupled plasma mass spectrometry experiments. The nature of the substituents anchored on the bridging thiols and the compounds molecular weight appears to significantly influence the antibacterial activity. Thus, if overall a decrease of the bactericidal effect with the increase of compounds' molecular weight is observed, however, the complexes bearing larger benzo-fused lactam substituents had low MIC values. This first antibacterial activity screening demonstrated that the thiolato-diruthenium compounds exhibit promising activity against S. aureus and S. pneumoniae and deserve to be considered for further studies. IMPORTANCE The in vitro assessment of diruthenium(II)-arene compounds against Escherichia coli, Streptococcus pneumoniae, and Staphylococcus aureus showed a significant antibacterial activity of some compounds against S. pneumoniae, with minimum inhibitory concentration (MIC) values ranging from 1.3 to 2.6 µM, and a medium activity against E. coli, with MIC of 25 µM. The nature of the substituents anchored on the bridging thiols and the compounds molecular weight appear to significantly influence the antibacterial activity. Fluorescence microscopy showed that these ruthenium compounds enter the bacteria and do not accumulate in the cell wall of gram-positive bacteria. These diruthenium(II)-arene compounds exhibit promising activity against S. aureus and S. pneumoniae and deserve to be considered for further studies, especially the compounds bearing larger benzo-fused lactam substituents.

Dataset Information

Exploring pta Alternatives in the Development of Ruthenium-Arene Anticancer Compounds.

Publications

Exploring pta Alternatives in the Development of Ruthenium-Arene Anticancer Compounds.

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