title: Induction of Cytotoxicity in Pyridine Analogues of the Anti-metastatic Ru(III) Complex NAMI-A by Ferrocene Functionalization.
abstract: A series of novel ferrocene (Fc) functionalized Ru(III) complexes was synthesized and characterized. These compounds are derivatives of the anti-metastatic Ru(III) complex imidazolium [trans-RuCl4(1H-imidazole) (DMSO-S)] (NAMI-A) and are derived from its pyridine analogue (NAMI-Pyr), with direct coupling of Fc to pyridine at the 4 or 3 positions, or at the 4 position via a two-carbon linker, which is either unsaturated (vinyl) or saturated (ethyl). Electron paramagnetic resonance (EPR) and UV-vis spectroscopic studies of the ligand exchange processes of the compounds in phosphate buffered saline (PBS) report similar solution behavior to NAMI-Pyr. However, the complex with Fc substitution at the 3 position of the coordinated pyridine shows greater solution stability, through resistance to the formation of oligomeric species. Further EPR studies of the complexes with human serum albumin (hsA) indicate that the Fc groups enhance noncoordinate interactions with the protein and help to inhibit the formation of protein-coordinated species, suggesting the potential for enhanced bioavailability. Cyclic voltammetry measurements demonstrate that the Fc groups modestly reduce the reduction potential of the Ru(III) center as compared to NAMI-Pyr, while the reduction potentials of the Fc moieties of the four compounds vary by 217 mV, with the longer linkers giving significantly lower values of E1/2. EPR spectra of the compounds with 2-carbon linkers show the formation of a high-spin Fe(III) species (S = 5/2) in PBS with a distinctive signal at g = 4.3, demonstrating oxidation of the Fe(II) ferrocene center and likely reflecting degradation products. Density functional theory calculations and paramagnetic (1)H NMR describe delocalization of spin density onto the ligands and indicate that the vinyl linker could be a potential pathway for electron transfer between the Ru and Fe centers. In the case of the ethyl linker, electron transfer is suggested to occur via an indirect mechanism enabled by the greater flexibility of the ligand. In vitro assays with the SW480 cell line reveal cytotoxicity induced by the ruthenium ferrocenylpyridine complexes that is at least an order of magnitude higher than the unfunctionalized complex, NAMI-Pyr. Furthermore, migration studies with LNCaP cells reveal that Fc functionalization does not reduce the ability of the compounds to inhibit cell motility. Overall, these studies demonstrate that NAMI-A-type compounds can be functionalized with redox-active ligands to produce both cytotoxic and anti-metastatic activity.
authors.forename: Changhua
authors.initials: C
authors.lastname: Mu
authors.forename: Stephanie W
authors.initials: SW
authors.lastname: Chang
authors.forename: Kathleen E
authors.initials: KE
authors.lastname: Prosser
authors.affiliation: Department of Experimental Therapeutics, BC Cancer Agency , 675 West 10th Avenue, Vancouver, BC V5Z 4E6, Canada.
authors.forename: Ada W Y
authors.initials: AW
authors.lastname: Leung
authors.forename: Stephanie
authors.initials: S
authors.lastname: Santacruz
authors.forename: Thalia
authors.initials: T
authors.lastname: Jang
authors.forename: John R
authors.initials: JR
authors.lastname: Thompson
authors.affiliation: Department of Experimental Therapeutics, BC Cancer Agency , 675 West 10th Avenue, Vancouver, BC V5Z 4E6, Canada.
authors.forename: Donald T T
authors.initials: DT
authors.lastname: Yapp
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Warren
authors.affiliation: Department of Experimental Therapeutics, BC Cancer Agency , 675 West 10th Avenue, Vancouver, BC V5Z 4E6, Canada.
authors.forename: Marcel B
authors.initials: MB
authors.lastname: Bally
authors.forename: Timothy V
authors.initials: TV
authors.lastname: Beischlag
authors.forename: Charles J
authors.initials: CJ
authors.lastname: Walsby
mesh_terms: D018360:Crystallography, X-Ray; D004121:Dimethyl Sulfoxide / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D004578:Electron Spin Resonance Spectroscopy; D005296:Ferrous Compounds / Q000737:chemistry*; D000075163:Metallocenes; D015394:Molecular Structure; D009362:Neoplasm Metastasis / Q000517:prevention & control*; D009942:Organometallic Compounds / Q000737:chemistry* / Q000494:pharmacology; D011725:Pyridines / Q000737:chemistry*; D017975:Ruthenium Compounds
chemical_list: D005296:Ferrous Compounds; D000075163:Metallocenes; D009942:Organometallic Compounds; D011725:Pyridines; D017975:Ruthenium Compounds; C113661:imidazolium-bis(imidazole)dimethylsulfoxideimidazotetrachlororuthenate(III); C023666:pyridine; C004998:ferrocene; D004121:Dimethyl Sulfoxide