Enantioselective Cytotoxicity of Chiral Diphosphine Ruthenium(II) Complexes Against Cancer Cells
Denise Lovison, Dario Alessi, Lorenzo Allegri, Federica Baldan, Maurizio Ballico, Giuseppe Damante, Marilisa Galasso, Daniele Guardavaccaro, Silvia Ruggieri, Andrea Melchior, Daniele Veclani, Chiara Nardon, Walter Baratta
Abstract
Abstract The chiral cationic complex [Ru(η 1 ‐OAc)(CO)(( R,R )‐Skewphos)(phen)]OAc ( 2 R ), isolated from reaction of [Ru(η 1 ‐OAc)(η 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 NaPF 6 at pH=9 gives the diastereoisomers [Ru(( S )‐Cys)(CO)(PP)(phen)]PF 6 (PP=( R,R )‐Skewphos 2 R ‐Cys; ( S,S )‐Skewphos 2 S ‐Cys). The DFT energetic profile for 2 R with ( S )‐cysteine in H 2 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 EC 50 values of 2.8–0.04 μ M. The ( R , R )‐Skewphos derivatives show higher cytotoxicity compared to their enantiomers, 4 R (EC 50 =0.04 μ M) being 14 times more cytotoxic than 4 S against the anaplastic thyroid cancer 8505 C cell line.