title: Correlation of [RuCl3(dppb)(VPy)] cytotoxicity with its effects on the cell membranes: an investigation using Langmuir monolayers as membrane models.
abstract: One of the major challenges in drug design is to identify compounds with potential toxicity toward target cells, preferably with molecular-level understanding of their mode of action. In this study, the antitumor property of a ruthenium complex, mer-[RuCl3(dppb)(VPy)] (dppb = 1,4-bis(diphenylphosphine)butane and VPy = 4-vinylpyridine) (RuVPy), was analyzed. Results showed that this compound led to a mortality rate of 50% of HEp-2 cell with 120 ± 10 μmol L(-1), indicating its high toxicity. Then, to prove if its mode of action is associated with its interaction with cell membranes, Langmuir monolayers were used as a membrane model. RuVPy had a strong effect on the surface pressure isotherms, especially on the elastic properties of both the zwitterionic dipalmitoylphosphatidylcholine (DPPC) and the negatively charged dipalmitoylphosphatidylglycerol (DPPG) phospholipids. These data were confirmed by polarization-modulated infrared reflection-absorption spectroscopy (PM-IRRAS). In addition, interactions between the positive group from RuVPy and the phosphate group from the phospholipids were corroborated by density functional theory (DFT) calculations, allowing the determination of the Ru complex orientation at the air-water interface. Although possible contributions from receptors or other cell components cannot be discarded, the results reported here represent evidence for significant effects on the cell membranes which are probably associated with the high toxicity of RuVPy.
authors.affiliation: Departamento de Química, Universidade Estadual de Ponta Grossa , 84035-900, Ponta Grossa, PR, Brasil.
authors.forename: B
authors.initials: B
authors.lastname: Sandrino
authors.forename: T T
authors.initials: TT
authors.lastname: Tominaga
authors.forename: T M
authors.initials: TM
authors.lastname: Nobre
authors.forename: L
authors.initials: L
authors.lastname: Scorsin
authors.forename: E C
authors.initials: EC
authors.lastname: Wrobel
authors.forename: B C
authors.initials: BC
authors.lastname: Fiorin
authors.forename: M P
authors.initials: MP
authors.lastname: de Araujo
authors.forename: L
authors.initials: L
authors.lastname: Caseli
authors.forename: O N
authors.initials: ON
authors.lastname: Oliveira
authors.forename: K
authors.initials: K
authors.lastname: Wohnrath
mesh_terms: D015060:1,2-Dipalmitoylphosphatidylcholine / Q000737:chemistry; D000388:Air; D000818:Animals; D002460:Cell Line; D002462:Cell Membrane / Q000187:drug effects* / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002522:Chlorocebus aethiops; D004548:Elasticity; D006801:Humans; D008567:Membranes, Artificial; D008954:Models, Biological; D008956:Models, Chemical; D010715:Phosphatidylglycerols / Q000737:chemistry; D011312:Pressure; D011725:Pyridines / Q000633:toxicity; D017975:Ruthenium Compounds / Q000633:toxicity*; D013055:Spectrophotometry, Infrared; D014867:Water / Q000737:chemistry
chemical_list: D008567:Membranes, Artificial; D010715:Phosphatidylglycerols; D011725:Pyridines; D017975:Ruthenium Compounds; D014867:Water; D015060:1,2-Dipalmitoylphosphatidylcholine; C029351:4-vinylpyridine; C030345:1,2-dipalmitoylphosphatidylglycerol