Pernar, Margareta/MP; Kokan, Zoran; Kralj, Juran; Glasovac, Zoran; Tumir, Lidija-Marija; Piantanida, Ivo; Eljuga, Domagoj; Turel, Iztok; Brozović, Anamaria; Kirin, Srećko (2019) Organometallic ruthenium(II)-arene complexes with triphenylphosphine amino acid bioconjugates: Synthesis, characterization and biological properties. Bioorganic Chemistry, 87 . pp. 432-446. ISSN 0045-2068
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Abstract
(p-Cymene)-ruthenium bioconjugates ML (1) and ML2 (2), bearing phosphane ligands substituted with chiral or non-chiral amino acid esters, L, were synthetized and characterized by instrumental methods (NMR, CD, MS) and DFT calculations (using the wB97xD functional). Cytotoxic activity of complexes 1 and 2 was investigated by using human cervical carcinoma cell line (HeLa) and MTT assay. Four (2pG, 2pA, 2mG and 2mA) out of ten synthesized ruthenium complexes showed significant toxicity, with IC50 values of 5-30 μM. Evaluation of the potential biomolecular targets of bioconjugates 2 by UV-Vis, fluorescence and CD spectroscopy revealed no measurable interaction with DNA, but micromolar affinity for proteins. The cytotoxicity of bioconjugates 2 is in correlation with their BSA binding constants, i. e. bioconjugates with lower IC50 values show higher binding affinities towards BSA. Compound 2mG with value of IC50 16 μM was selected for further biological characterization. The higher level of toxicity towards tumor compared to normal cell lines indicates its selective activity, important characteristic for potential medical use. It was detected 2mG caused increase of cells in the S phase of cell cycle and consequential decrease of cells in G0/G1 phase. Additionally, 2mG caused dose- and time-dependent increase of SubG0/G1 cell population, suggesting its ability to induce programmed cell death. Further investigation determined autophagy as the mode of cell death. The role of GSH in HeLa cells response to investigated organometallic ruthenium complexes was confirmed using specific regulators of GSH synthesis, buthionine sulfoximine and N-acetyl-cysteine. Pre-treatment of cells with ethacrynic acid and probenecid emphasized the role of GSH in detoxification of 2mG compound. The amount of total ruthenium accumulation in the cell did not correlate with toxicity of 2pG, 2pA, 2mG and 2mA, suggesting structure dependent differences in either cell uptake or kinetics of ruthenium complexes detoxification. We speculate that ruthenium complexes bind protein-based biomolecules further triggering cell death. Based on the gained knowledge, the synthesis and development of more tumor-specific ruthenium-based complexes as potential anticancer drugs can be expected.
| Item Type: | Article | ||||||||||||||||
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| Uncontrolled Keywords: | Cell death; Cytotoxicity; P-Cymene; Phosphine ligands; Ruthenium | ||||||||||||||||
| Subjects: | NATURAL SCIENCES NATURAL SCIENCES > Chemistry NATURAL SCIENCES > Chemistry > Organic Chemistry NATURAL SCIENCES > Biology BIOMEDICINE AND HEALTHCARE BIOMEDICINE AND HEALTHCARE > Basic Medical Sciences INTERDISCIPLINARY FIELDS OF ART |
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| Divisions: | Division of Materials Chemistry Division of Molecular Biology Division of Organic Chemistry and Biochemistry |
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| Depositing User: | Anamaria Brozović | ||||||||||||||||
| Date Deposited: | 08 Dec 2020 12:05 | ||||||||||||||||
| URI: | http://fulir.irb.hr/id/eprint/6065 | ||||||||||||||||
| DOI: | 10.1016/j.bioorg.2019.03.048 |
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