Coordination of Ru(II)-Arene Fragments to Dipyridophenazine Ligands Leads to the Modulation of Their In Vitro and In Vivo Anticancer Activity

Astable half-sandwich Ru-dipyridophenazine complex causedthe significant reduction of tumor burden in mouse xenografts withoutinducing kidney and liver toxicity. The mechanism of action was linkedto DNA degradation and ROS induction. Despiteextensive research on the anticancer properties of Ru complexeswith dipyrido-[3,2-a:2 ',3 '-c]-phenazine (dppz) ligands, their in vivo efficacy is rarely investigated.Aiming to understand whether the coordination of certain half-sandwichRu-(II)-arene fragments might improve the therapeutic potential ofdppz ligands, we prepared a series of Ru-(II)-arene complexes withthe general formula [(eta(6)-arene)-Ru-(dppz-R)-Cl]-PF6, where the arene fragment was benzene, toluene, or p-cymene and R was -NO2, -Me, or -COOMe. Allcompounds were fully characterized by H-1 and C-13 NMR spectroscopy and high-resolution ESI mass-spectrometry, andtheir purity was verified by elemental analysis. The electrochemicalactivity was investigated using cyclic voltammetry. The anticanceractivity of dppz ligands and their respective Ru complexes was assessedagainst several cancer cell lines, and their selectivity toward cancercells was assessed using healthy MRC5 lung fibroblasts. The substitutionof benzene with a p-cymene fragment resulted in amore than 17-fold increase of anticancer activity and selectivityof Ru complexes and significantly enhanced DNA degradation in HCT116cells. All Ru complexes were electrochemically active in the biologicallyaccessible redox window and were shown to markedly induce the productionof ROS in mitochondria. The lead Ru-dppz complex significantly reducedtumor burden in mice with colorectal cancers without inducing liverand kidney toxicity.