Ruthenium-Cyclopentadienyl-Cycloparaphenylene Complexes: Sizable Multicharged Cations Exhibiting High DNA-Binding Affinity and Remarkable Cytotoxicity.

Two novel sizable multicharged cationic complexes, of the formulae [(η6--[12]CPP)[Ru(η5--Cp)]12]Χ12 and [(η6--[11]CPP)[Ru(η5--Cp)]11]Χ11, CPP = cycloparaphenylene, Cp = cyclopentadienyl, X = [PF6]-, (1), (3) and [Cl]-, (2), (4), were synthesized and characterized using NMR techniques, high-resolution mass spectrometry, and elemental analyses. Complexes (1) and (3) were stable in acetone and acetonitrile solutions over 48 h. In contrast, the water-soluble (2) and (4) begin to decompose in aqueous media after 1 h, due to the [Cl]- tendency for nucleophilic attack on ruthenium of the {Ru(η5--Cp)} units. Fluorescence quenching experiments conducted during the stability window of (2) with the d(5'-CGCGAATTCGCG-3')2-EtBr adducts revealed remarkably high values for Ksv = 1.185 × 104 ± 0.025 M-1 and Kb = 3.162 × 105 ± 0.001 M-1. Furthermore, the cytotoxic activity of (2) against A2780, A2780res, and MCF-7 cancer cell lines shows that it is highly cytotoxic with IC50 values in the range of 4.76 ± 1.85 to 16 ± 0.81 µΜ.

Dual-Emissive Rectangular Supramolecular Pt(II)-p-Biphenyl with 4,4'-Bipyridine Derivative Metallacycles: Stepwise Synthesis and Photophysical Properties.

Mixed-ligand tetranuclear supramolecular coordination complexes (SCCs) of Pt(II)-p-biphenyl and bridging ligands derivatives of 4,4'-bypiridine (8)-(10), were synthesized and characterized. The SCCs were synthesized stepwise, starting from the Pt-p-biphenyl -Pt core. The crystal structure of complex {[Pt(2,2'-bpy)]4(µ-bph)2(µ-(4,4'-bpy)2}{PF6}4 (2,2'-bpy = 2,2'-bipyridine, bph = p-biphenyl and 4,4'-bpy = 4,4' bipyridine), was determined using single-crystal diffraction methods. The emission profile of the tetranuclear complexes (8)-(10) was influenced by the length of the bridging ligands and was found to depend on solvent polarity. Dual-emission patterns in methanol-water mixtures were observed only in the cases of complexes (9) and (10), attributed to aggregation-induced emission phenomena.

Synthesis and Characterization of Ruthenium-Paraphenylene-Cyclopentadienyl Full-Sandwich Complexes: Cytotoxic Activity against A549 Lung Cancer Cell Line and DNA Binding Properties.

Novel full-sandwich (η5-Cp)-Ru-paraphenylene complexes with the general formula [(η5-Cp)nRu(η6-L)](PF6)n where n = 1-3 and L = biphenyl, p-terphenyl and p-quaterphenyl, were synthesized and characterized by means of spectroscopic and analytical techniques. The structures of the complexes [(η5-Cp)Ru(η6-biphenyl)](PF6) (1), [(η5-Cp)Ru(η6-terphenyl)](PF6) (3) and [(η5-Cp)2Ru(η6-terphenyl)](PF6)2 (4) was determined by X-ray single crystal methods. The interaction of the complexes [(η5-Cp)Ru(η6-quaterphenyl)]Cl, (6)Cl, and [(η5-Cp)2Ru(η6-quaterphenyl)]Cl2, (7)Cl2, with the DNA duplex d(5'-CGCGAATTCGCG-3')2 was studied using NMR techniques. The results showed that both complexes interacted non-specifically with both the minor and major grooves of the helix. Specifically, (6)Cl exhibited partial binding through intercalation between the T7 and T8 bases of the sequence without disrupting the C-G and A-T hydrogen bonds. Fluorometric determination of the complexes' binding constants revealed a significant influence of the number of connected phenyl rings in the paraphenylene ligand (L) on the binding affinity of their complexes with the d(5'-CGCGAATTCGCG-3')2. The complexes (6)Cl and (7)Cl2 were found to be highly cytotoxic against the A549 lung cancer cell line, with complex (6) being more effective than (7) (IC50 for (6)Cl: 17.45 ± 2.1 µΜ, IC50 for (7)Cl2: 65.83 ± 1.8 µΜ) and with a selectivity index (SI) (SI for (6)Cl: 1.1 and SI for (7)Cl2: 4.8).

Synthesis, characterization, interactions with the DNA duplex dodecamer d(5'-CGCGAATTCGCG-3')2 and cytotoxicity of binuclear η6-arene-Ru(II) complexes.

The novel binuclear η6-arene-Ru(II) complexes with the general formula {[(η6-cym)Ru(L)]2(µ-BL)}(PF6)4, and their corresponding water soluble {[(η6-cym)Ru(L)]2(µ-BL)}Cl4, where cym = p-cymene, L = 2,2'-bipyridine (bpy) and 1,10-phenanthroline (phen), BL = 4,4'-bipyridine (BL-1), 1,2-bis(4-pyridyl)ethane (BL-2) and 1,3-bis(4-pyridyl)propane (BL-3), were synthesized and characterized. The structure of {[(η6-cym)Ru(phen)]2(µ-BL-1)}(PF6)4 was determined by X-ray single crystal methods. The interaction of {[(η6-cym)Ru(phen)]2(µ-BL-i)}Cl4 (i = 1, 2, 3; (4), (5) and (6) correspondingly) with the DNA duplex d(5'-CGCGAATTCGCG-3')2 was studied by means of NMR techniques and fluorescence titrations. The results show that complex (4) binds with a Kb = 12.133 × 103 M-1 through both intercalation and groove binding, while (5) and (6) are groove binders (Kb = 2.333 × 103 M-1 and Kb = 3.336 × 103 M-1 correspondingly). Comparison with the mononuclear complex [(η6-cym)Ru(phen)(py)]2+ reveals that it binds to the d(5'-CGCGAATTCGCG-3')2 with a Kb value two orders of magnitude lower than (4) (Kb = 0.158 × 103 M-1), indicating that for the binuclear complexes both ruthenium moieties participate in the binding. The complexes were found to be cytotoxic against the A2780 and A2780 res. cancer cell line with a selectivity index (SI) in the range of 3.0-5.9.

Gut Barrier Disruption Secondary to Radiofrequency-Assisted Liver Parenchyma Resection in a Porcine Model.

BACKGROUND: Radiofrequency-assisted liver resection (RF-LR) techniques minimize intraoperative blood loss, while avoiding the Pringle maneuver. Both surgical excision and radiofrequency ablation of liver parenchyma compromise gut barrier function with subsequent bacterial translocation. The present study sought to investigate in a porcine model the impact of two RF-LR techniques on the integrity and inflammatory response of the gut barrier. METHODS: Twenty-four pigs were subjected to either (a) partial hepatectomy (PH) employing the "sequential coagulate-cut" technique using a monopolar electrode (SCC group), the one using the bipolar Habib-4X device (group H), or the "crush-clamp" technique (group CC) or (b) sham operation (group Sham). At 48-h post-operation, ileal tissue was excised to be subjected to histopathologic examination, histomorphometric analysis, and immunohistochemical assessment of the mitotic and apoptotic activities and the expression of interleukin-6 (IL-6), tumor necrosis factor-α (TNFα), and nuclear factor-κB (NFκΒ). RESULTS: Histopathologic score increased in all PH groups, being higher in group SCC, while lower in group H. Villous height decreased in group SCC only. Mitotic index decreased, while apoptotic index increased in all PH groups. An increase in tissue expression score was noted for IL-6 in group CC, for TNFα in all PH groups, being lower in group H compared to group CC, and for NFκB in all PH groups. CONCLUSIONS: The Habib-4X technique for liver resection proved to preserve the integrity of gut barrier, being less injurious in the intestinal mucosa compared to the SCC and CC techniques.

Synthesis, characterization, interactions with 9-MeG and cytotoxic activity of heterobimetallic RuII-PtII complexes bridged with 2, 2'-bipyrimidine.

The complexes [(η6-bz)Ru(bpm)Cl]PF6, (1)PF6, [(η6-bz)ClRu(µ-bpm)PtCl2]PF6, (2)PF6, [(η6-cym)ClRu(µ-bpm)PtCl2]PF6, (3)PF6, [(η6-cym)ClRu(µ-bpm)PdCl2]PF6, (4)PF6, [Pt(bpm)(cbdca)], (5) and [(η6-cym)ClRu(µ-bpm)Pt(cbdca)]PF6, (6)PF6, (bz = benzene, bpm = 2,2'-bipyrimidine, cym = p-cymene, cbdcaH2 = 1,1-cyclobutanedicarboxylic acid),were synthesized and characterized by means of 1H NMR and high-resolution ESI mass spectrometry. The complexes were transformed to the corresponding chloride salts to become soluble in aqueous media, and to be studied regarding their biological properties. However, while the heterobimetallic complexes (3)Cl and (6)Cl were almost stable, (2)Cl and (4)Cl were decomposed. The interaction of 9-MeG (9-MeG = 9-methylguanine) with (3)Cl and (6)Cl revealed that it coordinates only to the platinum center through N7. Decomposition of the heterobimetallic complexes takes place after the coordination of 9-MeG, mainly forming the complex [Pt(bpm)(9-MeG-N7)Cl]+. Notably, the cytotoxic activity of (6)Cl in cancer cells was found to be moderate when compared to cisplatin, but higher in comparison with its corresponding monomers.

Stepwise synthesis, characterization, DNA binding properties and cytotoxicity of diruthenium oligopyridine compounds conjugated with peptides.

Although the interactions of oligopyridine ruthenium complexes with DNA have been widely studied, the biological activity of similar diruthenium oligopyridine complexes conjugated with peptides has not been investigated. Herein, we report the stepwise synthesis and characterization of diruthenium complexes with the general formula [(La)Ru(tppz)Ru(Lb)]n+ (tppz = 2,3,5,6-tetra(2-pyridyl)pyrazine, La = 2,2':6',2''-terpyridine or 4-phenyl-2,2':6',2''-terpyridine and Lb = 2,2':6',2''-terpyridine-4'-CO(Gly1-Gly2-Gly3-LysCONH2) (5), (6), n = 5; 2,2':6',2''-terpyridine-4'-CO(Gly1-Gly2-Lys1-Lys2CONH2) (7), (8), n = 6; 2,2':6',2''-terpyridine-4'-CO(Ahx-Lys1Lys2CONH2) (9), (10), n = 5, Ahx = 6-aminohexanoic acid). The compounds [(trpy)Ru(tppz)Ru(trpy-CO2H)](PF6)4, (2)(PF6)4, [(ptrpy)Ru(tppz)Ru(trpy-CO2H)](PF6)4, (3)(PF6)4 and [(ptrpy)Ru(tppz)Ru(trpy)](PF6)4, (4)(PF6)4 were also characterized by single crystal X-ray methods. Moreover, the interactions of the chloride salts (5), (6) and (4) with the self-complementary dodecanucleotide duplex d(5'-CGCGAATTCGCG-3')2 were studied by NMR spectroscopic techniques. The results show that complex (4) binds in the central part of the oligonucleotide, from the minor groove through the ligand ptrpy, while the ligand trpy, which was located on the other side of the diruthenium core, does not contribute to the binding. Complex (5) binds similarly, through the ligand ptrpy. However, the induced upfield shifts of the ptrpy proton signals are significantly lower than the corresponding ones in the case of (4), indicating much lower binding affinity. This is clear evidence that the tethered peptide Gly1-Gly2-Gly3-Lys1CONH2 hinders the complex binding, even though it contains groups that are able to assist it (e.g., the positively charged amino group of lysine, the peptidic backbone, the terminal amide). Complex (6) shows a non-specific binding, interacting through electrostatic forces. The chloride salts of (4), (5) and (6) had insignificant effects on the cell cycle distribution and marginal cytotoxicity (IC50 > 750 µM) against human lung cancer cell lines H1299 and H1437, indicating that their binding to the oligonucleotide is not a sufficient condition for their cytotoxicity.

Chitosan encapsulation of essential oil "cocktails" with well-defined binary Zn(II)-Schiff base species targeting antibacterial medicinal nanotechnology.

The advent of biodegradable nanomaterials with enhanced antibacterial activity stands as a challenge to the global research community. In an attempt to pursue the development of novel antibacterial medicinal nanotechnology, we herein a) synthesized ionic-gelated chitosan nanoparticles, b) compared and evaluated the antibacterial activity of essential oils extracted from nine different herbs (Greek origin) and their combinations with a well-defined antibacterial Zn(II)-Schiff base compound, and c) encapsulated the most effective hybrid combination of Zn(II)-essential oils inside the chitosan matrix, thereby targeting well-formulated nanoparticles of distinct biological impact. The empty and loaded chitosan nanoparticles were physicochemically characterized by FT-IR, Thermogravimetric Analysis (TGA), Scanning Electron Microscopy (SEM), with the entrapment and drug release studies being conducted through UV-Visible and atomic absorption techniques. The antimicrobial properties of the novel hybrid materials were demonstrated against Gram positive (S. aureus, B. subtilis, and B. cereus) and Gram negative (E. coli and X. campestris) bacteria using modified agar diffusion methods. The collective physicochemical profile of the hybrid Zn(II)-essential oil cocktails, formulated so as to achieve optimal activity when loaded to chitosan nanoparticles, signifies the importance of design in the development of efficient nanomedicinal pharmaceuticals a) based on both natural products and biogenic metal ionic cofactors, and b) targeting bacterial infections and drug resistance.

Synthesis, reactivity and characterization of Pt(ii) complexes with N,N' chelating ligands; structure and dimethylsulfoxide reactivity relationship.

Platinum(ii) complexes of the formula PtLCl2 [L = 2-(2'-pyridyl)quinoxaline, (pqx) (1), 2,(2'-pyridyl)benzo[g]quinoxaline, (pbqx) (3) and 2,(2'-pyridyl)quinoline, (pqn) (5)] were synthesized and characterized by spectroscopic and X-ray diffraction methods. Also, monodentate coordination of the ligands pqx and pbqx formed the complexes trans-Pt(DMSO)pqxCl2 (2) and trans-Pt(DMSO)pbqxCl2 (4) as it is indicated from X-ray crystal structure and NMR studies. The reaction of the complexes (1), (3) and (5) with DMSO-d6 revealed a ligand-release solvolysis, which was studied by means of NMR techniques. Correlation between the crystal structures of (1), (3), and (5) and the kinetic or thermodynamic parameters of the solvolysis reactions showed that the tendency of the ligands pqx, pbqx, and pqn to return to the anti-configuration in addition to their ability to form non-classical H-bonds are crucial factors for the ligand-release solvolysis. Instantaneous DMSO-d6 solvolysis for the complexes (1) and (3) and slow kinetics solvolysis for (5) (k = 10-4 ± 6.4 × 10-6 s-1) reflect their structural differences in ligand planarity. Based on NMR techniques a two-step mechanism of the chelate ring opening was suggested with equilibrium constants of the overall reaction at 298 K, Keq = 4.1 ± 0.2 × 10-4 M-1 (1) and Keq = 1.7 ± 0.2 × 10-4 M-1 (2).

Synthesis and characterization of ruthenium(II)-oligopyridine-peptide conjugates. Interactions of the diasteromeres Δ- and Λ-[Ru(bpy)2(4-COY-4'-Mebpy)]Cl2 (Y=Gly-Lys(1)-Lys(2)CONH2, Lys(1)-Gly-Lys(2)CONH2, Lys(1)-Lys(2)-GlyCONH2) with the oligonucleotide d(5'-CGCGAATTCGCG-3')2.

Diastereomeric complexes of the general formulae Λ- and Δ-[Ru(bpy)2(4-COY-4'-Mebpy)]Cl2 where bpy=2,2'-bipyridine and Y=Gly-Lys(1)-Lys(2)CONH2, Lys(1)-Gly-Lys(2)CONH2, Lys(1)-Lys(2)-GlyCONH2, were synthesized and characterized. The ability of these compounds to bind to the oligonucleotide duplex d(5'-CGCGAATTCGCG-3') was studied with NMR techniques. Complex Λ-2, Λ-[Ru(bpy)2(4-COLys(1)-Gly-Lys(2)CONH2),4'-Mebpy)]Cl2 (Mebpy=methyl-2,2'-bipyridine), interacts non-specifically causing changes for both complex and oligonucleotide (1)H NMR signals. Both Λ-1, Λ-[Ru(bpy)2(4-COGly-Lys(1)-Lys(2)CONH2),4'-Mebpy)]Cl2 and Λ-3, Λ-[Ru(bpy)2(4-COLys(1)-Lys(2)-GlyCONH2),4'-Mebpy)]Cl2, were bound to the oligonucleotide through both lysine aliphatic chains, indicating that the side chains of the sequential lysines create a kind of "clamp" to connect the complex with the oligonucleotide. Complex Δ-1, Δ-[Ru(bpy)2(4-COGly-Lys(1)-Lys(2)CONH2),4'-Mebpy)]Cl2, interacts with the oligonucleotide duplex with both lysine side chains in a manner similar to Λ-1. Δ-2, Δ-[Ru(bpy)2(4-COLys(1)-Gly-Lys(2)CONH2),4'-Mebpy)]Cl2, interacts with the oligonucleotide with the bipyridine ligands. In addition, the formation of a hydrogen bond between the Gly-NH and the carbonyl groups of the oligonucleotide bases was detected. A completely different binding mode was observed for Δ-3 Δ-[Ru(bpy)2(4-COLys(1)-Lys(2)-GlyCONH2),4'-Mebpy)]Cl2, which at a ratio of 1:1 ([Ru]/[nucleotide]) opens the oligonucleotide strands. In addition, participation of all three peptidic NH of Δ-3 in hydrogen bonds was observed.