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

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.