Oxygen-to-Sulfur Coordination Switching in Kojic Acid Ligands Tunes the Electronics and Anticancer Activity of Ru(II)-Diphosphine Complexes against Glioblastoma Cells.

Two new ruthenium(II) diphosphine complexes with pyrone and thiopyrone-derived maltol/thiomaltol coordination, [Ru(dppe)2(koj)]PF6 (Ru1) and [Ru(dppe)2(thkoj)]PF6 (Ru2) (dppe = 1,2-bis(diphenylphosphino)ethane; kojH = kojic acid; thkojH = thiokojic acid), were synthesized and thoroughly characterized and found highly active against LN229 and LN18 GBM cancer cell lines by replacement of the coordinated O,O- donor site with an S,O- donor site. Surprisingly, through a series of systematic studies, it was demonstrated that a subtle change in coordination site can have a great impact on the overall electronics of the system, i.e., causing ∼100 nm red shift in MLCT band, ∼150 mV cathodic shift in RuII/RuIII redox potential, and lengthening of the bond length from Ru-O to Ru-S in their corresponding X-ray crystallographic structures, and the results were further validated by DFT studies. Further, such electronic changes of these redox-active compounds have a profound effect on their cytotoxicity against GBM cancer cells. To the best of our knowledge, the synthesis of mononuclear Ru(II)-diphosphine complexes with kojic/thiokojic acid-derived coordination has not been previously reported and tested under in vitro therapeutic activity against GBM cancer cells. This study is among the first to demonstrate that oxidation of the metal center represents the critical activation step that initiates redox homeostasis imbalance, occurring via the formation of a covalent adduct with glutathione. These complexes represent a new design motif for the selective binding of kojic and thiokojic acid in cis-{Ru(dppe)2}-core, and the findings provide the basis for coordination chemistry with this class of ruthenium diphosphine complexes in the realm of biological inorganic chemistry.