Naphthalene Diimide-Functionalized Half-Sandwich Ru(II) Complexes as Mitochondria-Targeted Anticancer and Antimetastatic Agents

Anexample is presented herein for the rational design ofhalf-sandwich Ru(II) complexes with excellent emission performanceas mitochondria-targeted anticancer and antimetastatic agents by introducingthe NDI unit into the N,N-chelating ligand of these half-sandwichcomplexes. Because of the inherent emissive nature of the NDI moiety,these complexes, especially Ru4, are apt for intracellularvisualization and may have potential applications in the design ofmultifunctional theranostic agents and fluorescent biomarkers. In this work, four naphthalene diimide (NDI)-functionalizedhalf-sandwichRu(II) complexes Ru1-Ru4 bearingthe general formula [(eta(6)-arene)Ru-II(N<^>N)Cl]PF6, where arene = benzene (bn), p-cymene (p-cym), 1,3,5-trimethylbenzene (tmb), and hexamethylbenzene(hmb), have been synthesized and characterized. By introducing theNDI unit into the N,N-chelating ligand of these half-sandwich complexes,the poor luminescent half-sandwich complexes are endowed with excellentemission performance. Besides, modification on the arene ligand ofarene-Ru(II) complexes can influence the electron density of the metalcenter, resulting in great changes in the kinetic properties, catalyticactivities in the oxidative conversion of NADH to NAD(+),and biological activities of these compounds. Particularly, Ru4 exhibits the highest reactivity and the strongest inhibitoryactivity against the growth of three tested cancer cell lines. Furtherstudy revealed that Ru4 can enter cells quickly in anenergy-dependent manner and preferentially accumulate in the mitochondriaof MDA-MB-231 cells, inducing cell apoptosis via reactive oxygen speciesoverproduction and mitochondrial dysfunction. Significantly, Ru4 can effectively inhibit the cell migration and invasion.Overall, the complexation with NDI and modification on the arene ligandendowed the half-sandwich Ru(II) complexes with improved spectroscopicproperties and anticancer activities, highlighting their potentialapplications for cancer treatment.