Supplementary material for: Nikolić, S., Arakelyan, J., Kushnarev, V., Mutasim Alfadul, S., Stanković, D., Kraynik, Y., Grgurić-Šipka, S.,& Babak, M.. (2023). Coordination of Ru(II)-Arene Fragments to Dipyridophenazine 2 Ligands Leads to the Modulation of Their In Vitro and In Vivo 3 Anticancer Activity. in Inorganic Chemistry Inorganic Chemistry., 62, 8188-8199. https://doi.org/10.1021/acs.inorgchem.3c00570
Authors
Nikolić, Stefan
Arakelyan, Jemma
Kushnarev, Vladimir
Mutasim Alfadul, Samah
Stanković, Dalibor

Kraynik, Yaroslav
Grgurić-Šipka, Sanja

Babak, Maria
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Despite extensive research on the anticancer properties of Rucomplexes with dipyrido[3,2-a:2′,3′-c]phenazine (dppz) ligands, their in vivoefficacy is rarely investigated. Aiming to understand whether the coordination ofcertain half-sandwich Ru(II)-arene fragments might improve the therapeuticpotential of dppz ligands, we prepared a series of Ru(II)-arene complexes withthe general formula [(η6-arene)Ru(dppz-R)Cl]PF6, where the arene fragmentwas benzene, toluene, or p-cymene and R was -NO2, -Me, or -COOMe. Allcompounds were fully characterized by 1H and 13C NMR spectroscopy and high-resolution ESI mass-spectrometry, and their purity was verified by elementalanalysis. The electrochemical activity was investigated using cyclic voltammetry. The anticancer activity of dppz ligands and their respective Ru complexes wasassessed against several cancer cell lines, and their selectivity toward cancer cellswas assessed using healthy MRC5 lung fibroblasts. The substitution of benzenewith a p-cymene... fragment resulted in a more than 17-fold increase of anticanceractivity and selectivity of Ru complexes and significantly enhanced DNA degradation in HCT116 cells. All Ru complexes were electrochemically active in the biologically accessible redox window and were shown to markedly induce the production of ROS in mitochondria. The lead Ru-dppz complex significantly reduced tumor burden in mice with colorectal cancers without inducing liver and kidney toxicity.
Keywords:
Ru(II)-arene / dppz / anticancer / structure-activity relationships / ROS / in vivoSource:
Inorganic Chemistry, 2023Publisher:
- Inorganic Chemistry
Funding / projects:
- City University of Hong Kong (project 9610518).
- City University of Hong Kong (project 7005614).
- Ministry of Education, Science and Technological Development, Republic of Serbia, Grant no. 200288 (Innovation Center of the Faculty of Chemistry) (RS-200288)
- Ministry of Education, Science and Technological Development, Republic of Serbia, Grant no. 200168 (University of Belgrade, Faculty of Chemistry) (RS-200168)
Note:
- Supplementary material for: https://doi.org/10.1021/acs.inorgchem.3c00570
- Related to published version: https://cherry.chem.bg.ac.rs/handle/123456789/5899
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- Referenced by
https://doi.org/10.1021/acs.inorgchem.3c00570 - Referenced by
https://cherry.chem.bg.ac.rs/handle/123456789/5899
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Hemijski fakultet / Faculty of ChemistryTY - DATA AU - Nikolić, Stefan AU - Arakelyan, Jemma AU - Kushnarev, Vladimir AU - Mutasim Alfadul, Samah AU - Stanković, Dalibor AU - Kraynik, Yaroslav AU - Grgurić-Šipka, Sanja AU - Babak, Maria PY - 2023 UR - http://cherry.chem.bg.ac.rs/handle/123456789/5900 AB - Despite extensive research on the anticancer properties of Rucomplexes with dipyrido[3,2-a:2′,3′-c]phenazine (dppz) ligands, their in vivoefficacy is rarely investigated. Aiming to understand whether the coordination ofcertain half-sandwich Ru(II)-arene fragments might improve the therapeuticpotential of dppz ligands, we prepared a series of Ru(II)-arene complexes withthe general formula [(η6-arene)Ru(dppz-R)Cl]PF6, where the arene fragmentwas benzene, toluene, or p-cymene and R was -NO2, -Me, or -COOMe. Allcompounds were fully characterized by 1H and 13C NMR spectroscopy and high-resolution ESI mass-spectrometry, and their purity was verified by elementalanalysis. The electrochemical activity was investigated using cyclic voltammetry. The anticancer activity of dppz ligands and their respective Ru complexes wasassessed against several cancer cell lines, and their selectivity toward cancer cellswas assessed using healthy MRC5 lung fibroblasts. The substitution of benzenewith a p-cymene fragment resulted in a more than 17-fold increase of anticanceractivity and selectivity of Ru complexes and significantly enhanced DNA degradation in HCT116 cells. All Ru complexes were electrochemically active in the biologically accessible redox window and were shown to markedly induce the production of ROS in mitochondria. The lead Ru-dppz complex significantly reduced tumor burden in mice with colorectal cancers without inducing liver and kidney toxicity. PB - Inorganic Chemistry T2 - Inorganic Chemistry T1 - Supplementary material for: Nikolić, S., Arakelyan, J., Kushnarev, V., Mutasim Alfadul, S., Stanković, D., Kraynik, Y., Grgurić-Šipka, S.,& Babak, M.. (2023). Coordination of Ru(II)-Arene Fragments to Dipyridophenazine 2 Ligands Leads to the Modulation of Their In Vitro and In Vivo 3 Anticancer Activity. in Inorganic Chemistry Inorganic Chemistry., 62, 8188-8199. https://doi.org/10.1021/acs.inorgchem.3c00570 UR - https://hdl.handle.net/21.15107/rcub_cherry_5900 ER -
@misc{ author = "Nikolić, Stefan and Arakelyan, Jemma and Kushnarev, Vladimir and Mutasim Alfadul, Samah and Stanković, Dalibor and Kraynik, Yaroslav and Grgurić-Šipka, Sanja and Babak, Maria", year = "2023", abstract = "Despite extensive research on the anticancer properties of Rucomplexes with dipyrido[3,2-a:2′,3′-c]phenazine (dppz) ligands, their in vivoefficacy is rarely investigated. Aiming to understand whether the coordination ofcertain half-sandwich Ru(II)-arene fragments might improve the therapeuticpotential of dppz ligands, we prepared a series of Ru(II)-arene complexes withthe general formula [(η6-arene)Ru(dppz-R)Cl]PF6, where the arene fragmentwas benzene, toluene, or p-cymene and R was -NO2, -Me, or -COOMe. Allcompounds were fully characterized by 1H and 13C NMR spectroscopy and high-resolution ESI mass-spectrometry, and their purity was verified by elementalanalysis. The electrochemical activity was investigated using cyclic voltammetry. The anticancer activity of dppz ligands and their respective Ru complexes wasassessed against several cancer cell lines, and their selectivity toward cancer cellswas assessed using healthy MRC5 lung fibroblasts. The substitution of benzenewith a p-cymene fragment resulted in a more than 17-fold increase of anticanceractivity and selectivity of Ru complexes and significantly enhanced DNA degradation in HCT116 cells. All Ru complexes were electrochemically active in the biologically accessible redox window and were shown to markedly induce the production of ROS in mitochondria. The lead Ru-dppz complex significantly reduced tumor burden in mice with colorectal cancers without inducing liver and kidney toxicity.", publisher = "Inorganic Chemistry", journal = "Inorganic Chemistry", title = "Supplementary material for: Nikolić, S., Arakelyan, J., Kushnarev, V., Mutasim Alfadul, S., Stanković, D., Kraynik, Y., Grgurić-Šipka, S.,& Babak, M.. (2023). Coordination of Ru(II)-Arene Fragments to Dipyridophenazine 2 Ligands Leads to the Modulation of Their In Vitro and In Vivo 3 Anticancer Activity. in Inorganic Chemistry Inorganic Chemistry., 62, 8188-8199. https://doi.org/10.1021/acs.inorgchem.3c00570", url = "https://hdl.handle.net/21.15107/rcub_cherry_5900" }
Nikolić, S., Arakelyan, J., Kushnarev, V., Mutasim Alfadul, S., Stanković, D., Kraynik, Y., Grgurić-Šipka, S.,& Babak, M.. (2023). Supplementary material for: Nikolić, S., Arakelyan, J., Kushnarev, V., Mutasim Alfadul, S., Stanković, D., Kraynik, Y., Grgurić-Šipka, S.,& Babak, M.. (2023). Coordination of Ru(II)-Arene Fragments to Dipyridophenazine 2 Ligands Leads to the Modulation of Their In Vitro and In Vivo 3 Anticancer Activity. in Inorganic Chemistry Inorganic Chemistry., 62, 8188-8199. https://doi.org/10.1021/acs.inorgchem.3c00570. in Inorganic Chemistry Inorganic Chemistry.. https://hdl.handle.net/21.15107/rcub_cherry_5900
Nikolić S, Arakelyan J, Kushnarev V, Mutasim Alfadul S, Stanković D, Kraynik Y, Grgurić-Šipka S, Babak M. Supplementary material for: Nikolić, S., Arakelyan, J., Kushnarev, V., Mutasim Alfadul, S., Stanković, D., Kraynik, Y., Grgurić-Šipka, S.,& Babak, M.. (2023). Coordination of Ru(II)-Arene Fragments to Dipyridophenazine 2 Ligands Leads to the Modulation of Their In Vitro and In Vivo 3 Anticancer Activity. in Inorganic Chemistry Inorganic Chemistry., 62, 8188-8199. https://doi.org/10.1021/acs.inorgchem.3c00570. in Inorganic Chemistry. 2023;. https://hdl.handle.net/21.15107/rcub_cherry_5900 .
Nikolić, Stefan, Arakelyan, Jemma, Kushnarev, Vladimir, Mutasim Alfadul, Samah, Stanković, Dalibor, Kraynik, Yaroslav, Grgurić-Šipka, Sanja, Babak, Maria, "Supplementary material for: Nikolić, S., Arakelyan, J., Kushnarev, V., Mutasim Alfadul, S., Stanković, D., Kraynik, Y., Grgurić-Šipka, S.,& Babak, M.. (2023). Coordination of Ru(II)-Arene Fragments to Dipyridophenazine 2 Ligands Leads to the Modulation of Their In Vitro and In Vivo 3 Anticancer Activity. in Inorganic Chemistry Inorganic Chemistry., 62, 8188-8199. https://doi.org/10.1021/acs.inorgchem.3c00570" in Inorganic Chemistry (2023), https://hdl.handle.net/21.15107/rcub_cherry_5900 .