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

Abstract

The chiral cationic complex [Ru(η¹ -OAc)(CO)((R,R)-Skewphos)(phen)]OAc (2^R ), isolated from reaction of [Ru(η¹ -OAc)(η² -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 H₂ O 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 μM. The (R,R)-Skewphos derivatives show higher cytotoxicity compared to their enantiomers, 4^R (EC₅₀ =0.04 μM) being 14 times more cytotoxic than 4^S against the anaplastic thyroid cancer 8505 C cell line.

Keywords: N Ligands; P Ligands; antitumor agents; chirality; cytotoxicity; ruthenium.