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Enantioselective Cytotoxicity of Chiral Diphosphine Ruthenium(II) Complexes Against Cancer Cells
Author(s) -
Lovison Denise,
Alessi Dario,
Allegri Lorenzo,
Baldan Federica,
Ballico Maurizio,
Damante Giuseppe,
Galasso Marilisa,
Guardavaccaro Daniele,
Ruggieri Silvia,
Melchior Andrea,
Veclani Daniele,
Nardon Chiara,
Baratta Walter
Publication year - 2022
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.202200200
Subject(s) - ruthenium , chemistry , diastereomer , enantiomer , stereochemistry , enantioselective synthesis , cationic polymerization , cytotoxicity , medicinal chemistry , cysteine , catalysis , organic chemistry , in vitro , enzyme , biochemistry
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.