Synthesis, characterization, and DNA binding, photocleavage, cytotoxicity, cellular uptake, apoptosis, and on-off light switching studies of Ru(II) mixed-ligand complexes containing 7-fluorodipyrido[3,2-a:2′,3′-c]phenazine

Four new ruthenium(II) polypyridyl complexes-[Ru(phen)(2)(7-F-dppz)](2+) (7-F-dppz is 7-fluorodipyrido[3,2-a:2',3'-c]phenazine, phen is 1,10-phenanthroline), [Ru(bpy)(2)(7-F-dppz)](2+)(2) (bpy is 2,2'-bipyridine), [Ru(dmb)(2)(7-F-dppz)](2+) (dmb is 4,4'-dimethyl-2,2'-bipyridine), and [Ru(hdpa)(2)(7-F-dppz)](2+) (hdpa is 2,2'-dipyridylamine)-have been synthesized and characterized. Their DNA binding behavior has been explored by various spectroscopic titrations and viscosity measurements, which indicated that all the complexes bind to calf thymus DNA by means of intercalation with different binding strengths. The light switching properties of these complexes have been evaluated, and their antimicrobial activities have been investigated. Photoinduced DNA cleavage studies have been performed. All the complexes exhibited efficient photocleavage of pBR322 DNA on irradiation. The cytotoxicity of these complexes has been evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay with various tumor cell lines. Cellular uptake was studied by flow cytometry and confocal microscopy. Flow cytometry experiments showed that these complexes induced apoptosis of HeLa cell lines. Cytotoxicity assays in vitro showed that the four complexes have antitumor activity but less than that of cisplatin. Complex 4 displays higher antitumor activity than the other three complexes. The antiproliferative effects on tumor cells exerted by 1-4 are consistent with their intracellular uptake properties, which are significantly enhanced by the increase of lipophilicity. Antiproliferative and cellular uptake studies revealed that all complexes show better cytotoxicity and uptake properties. The cellular uptake indicated that complexes 1-4 enter the cytoplasm and accumulate in the nuclei. The apoptosis studies showed that complexes 1-4 can induce apoptosis of HeLa cells. The difference in the efficiencies is due to the ancillary ligands. It is concluded from this study that 2,2'-dipyridylamine as an ancillary ligand with a hydrogen-bonding motif has a better binding constant and antitumor activity than the other ancillary ligands and so it has significant potential for the design of new metal-based drugs. The information obtained from this study will be helpful for designing new transition metal complexes used as potential antitumor drugs and as a practical probe of DNA sequence.