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

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