Enantioselective Cytotoxicity of Chiral Diphosphine Ruthenium(II) Complexes Against Cancer Cells

The chiral cationic complex [Ru(η1-OAc)(CO)((R,R)-Skewphos)(phen)]OAc (2R), isolated from [Ru(η1-OAc)(η2-OAc)(R,R)-Skewphos)(CO)] (1R) and phen, reacts with NaOPiv and KSAc affording [RuX(CO)((R,R)-Skewphos)(phen)]Y (X = Y = OPiv 3R; X = SAc, Y = OAc 4R). The corresponding enantiomers 2S-4S have been obtained from 1S containing (S,S)-Skewphos. Reaction of 2R and 2S with (S)-cysteine and NaPF6 at pH = 9 gives the diastereoisomers [Ru((S)-Cys)(CO)(PP)(phen)]PF6 (PP = (R,R)-Skewphos 2R-Cys; (S,S)-Skewphos 2S-Cys). The DFT energetic profile for 2R with (S)-cysteine in H2O indicates that aquo and hydroxo species are involved in formation of 2R-Cys. The stability of the ruthenium complexes in 0.9% NaCl solution, PBS and complete DMEM medium, as well as the n-octanol/water partition coefficient, have been evaluated. The chiral complexes show high cytotoxic activity against SW1736, 8505C, HCT-116 and A549 cell lines with EC50 values of 2.8-0.04 µM. The (R,R)-Skewphos derivatives show higher cytotoxicity compared to their enantiomers, 4R (EC50 = 0.04 µM) being 14 times more cytotoxic than 4S against the anaplastic thyroid 8505C line.