N-Heterocyclic Carbene (NHC)-Stabilized Ru0 Nanoparticles: In Situ Generation of an Efficient Transfer Hydrogenation Catalyst.

Tethered and untethered ruthenium half-sandwich complexes were synthesized and characterized spectroscopically. X-ray crystallographic analysis of three untethered and two tethered Ru N-heterocyclic carbene (NHC) complexes were also carried out. These RuNHC complexes catalyze transfer hydrogenation of aromatic ketones in 2-propanol under reflux, optimally in the presence of (25 mol %) KOH. Under these conditions, the formation of 2-3 nm-sized Ru0 nanoparticles was detected by TEM measurements. A solid-state NMR investigation of the nanoparticles suggested that the NHC ligands were bound to the surface of the Ru nanoparticles (NPs). This base-promoted route to NHC-stabilized ruthenium nanoparticles directly from arene-tethered ruthenium-NHC complexes and from untethered ruthenium-NHC complexes is more convenient than previously known routes to NHC-stabilized Ru nanocatalysts. Similar catalytically active RuNPs were also generated from the reaction of a mixture of [RuCl2 (p-cymene)]2 and the NHC precursor with KOH in isopropanol under reflux. The transfer hydrogenation catalyzed by these NHC-stabilized RuNPs possess a high turnover number. The catalytic efficiency was significantly reduced if nanoparticles were exposed to air or allowed to aggregate and precipitate by cooling the reaction mixtures during the reaction.

Biotin Decorated Gold Nanoparticles for Targeted Delivery of a Smart-Linked Anticancer Active Copper Complex: In Vitro and In Vivo Studies.

The synthesis and anticancer activity of a copper(II) diacetyl-bis(N4-methylthiosemicarbazone) complex and its nanoconjugates are reported. The copper(II) complex is connected to a carboxylic acid group through a cleavable disulfide link to enable smart delivery. The copper complex is tethered to highly water-soluble 20 nm gold nanoparticles (AuNPs), stabilized by amine terminated lipoic acid-polyethylene glycol (PEG). The gold nanoparticle carrier was further decorated with biotin to achieve targeted action. The copper complex and the conjugates with and without biotin, were tested against HeLa and HaCaT cells. They show very good anticancer activity against HeLa cells, a cell line derived from cervical cancer and are less active against HaCaT cells. Slow and sustained release of the complex from conjugates is demonstrated through cleavage of disulfide linker in the presence of glutathione (GSH), a reducing agent intrinsically present in high concentrations within cancer cells. Biotin appended conjugates do not show greater activity than conjugates without biotin against HeLa cells. This is consistent with drug uptake studies, which suggests similar uptake profiles for both conjugates in vitro. However, in vivo studies using a HeLa cell xenograft tumor model shows 3.8-fold reduction in tumor volume for the biotin conjugated nanoparticle compared to the control whereas the conjugate without biotin shows only 2.3-fold reduction in the tumor volume suggesting significant targeting.

Contrasting electronic requirements for C-H binding and C-H activation in d(6) half-sandwich complexes of rhenium and tungsten.

A computational study of the interaction half-sandwich metal fragments (metal = Re/W, electron count = d(6)), containing linear nitrosyl (NO(+) ), carbon monoxide (CO), trifluorophosphine (PF3 ), N-heterocyclic carbene (NHC) ligands with alkanes are conducted using density functional theory employing the hybrid meta-GGA functional (M06). Electron deficiency on the metal increases with the ligand in the order NHC < CO < PF3 < NO(+). Electron-withdrawing ligands like NO(+) lead to more stable alkane complexes than NHC, a strong electron donor. Energy decomposition analysis shows that stabilization is due to orbital interaction involving charge transfer from the alkane to the metal. Reactivity and dynamics of the alkane fragment are facilitated by electron donors on the metal. These results match most of the experimental results known for CO and PF3 complexes. The study suggests activation of alkane in metal complexes to be facile with strong donor ligands like NHC.

The nature of bond critical points in dinuclear copper(I) complexes.

Closed-shell contacts between two copper(I) ions are expected to be repulsive. However, such contacts are quite frequent and are well documented. Crystallographic characterization of such contacts in unsupported and bridged multinuclear copper(I) complexes has repeatedly invited debates on the existence of cuprophilicity. Recent developments in the application of Bader's theory of atoms-in-molecules (AIM) to systems in which weak hydrogen bonds are involved suggests that the copper(I)-copper(I) contacts would benefit from a similar analysis. Thus the nature of electron-density distributions in copper(I) dimers that are unsupported, and those that are bridged, have been examined. A comparison of complexes that are dimers of symmetrical monomers and those that are dimers of two copper(I) monomers with different coordination spheres has also been made. AIM analysis shows that a bond critical point (BCP) between two Cu atoms is present in most cases. The nature of the BCP in terms of the electron density, ρ, and its Laplacian is quite similar to the nature of critical points observed in hydrogen bonds in the same systems. The ρ is inversely correlated to Cu-Cu distance. It is higher in asymmetrical systems than what is observed in corresponding symmetrical systems. By examining the ratio of the local electron potential-energy density (V(c)) to the kinetic energy density (G(c)), |V(c)|/G(c) at the critical point suggests that these interactions are not perfectly ionic but have some shared nature. Thus an analysis of critical points by using AIM theory points to the presence of an attractive metallophilic interaction similar to other well-documented weak interactions like hydrogen bonding.

Anticancer activity of hydrogen-bond-stabilized half-sandwich Ru(II) complexes with heterocycles.

Neutral half-sandwich organometallic ruthenium(II) complexes of the type [(η(6)-cymene)RuCl(2)(L)] (H1-H10), where L represents a heterocyclic ligand, have been synthesized and characterized spectroscopically. The structures of five complexes were also established by single-crystal X-ray diffraction confirming a piano-stool geometry with η(6) coordination of the arene ligand. Hydrogen bonding between the N-H group of the heterocycle and a chlorine atom attached to Ru stabilizes the metal-ligand interaction. Complexes coordinated to a mercaptobenzothiazole framework (H1) or mercaptobenzoxazole (H6) showed high cytotoxicity against several cancer cells but not against normal cells. In vitro studies have shown that the inhibition of cancer cell growth involves primarily G1-phase arrest as well as the generation of reactive oxygen species (ROS). The complexes are found to bind DNA in a non-intercalative fashion and cause unwinding of plasmid DNA in a cell-free medium. Surprisingly, the cytotoxic complexes H1 and H6 differ in their interaction with DNA, as observed by biophysical studies, they either cause a biphasic melting of the DNA or the inhibition of topoisomerase IIα activity, respectively. Substitution of the aromatic ring of the heterocycle or adding a second hydrogen-bond donor on the heterocycle reduces the cytotoxicity.

A novel zinc bis(thiosemicarbazone) complex for live cell imaging.

Fluorescent zinc complexes have recently attracted a lot of interest owing to their vast applications in cellular imaging. We report the synthesis as well as physical, chemical and biological studies of a novel zinc glyoxalbis(4-methyl-4-phenyl-3-thiosemicarbazone), [Zn(GTSC)]3, complex. As compared with the well-studied zinc biacetylbis(4-methyl-3-thiosemicarbazone), Zn(ATSM), complex, which was used as a reference, [Zn(GTSC)]3 had 2.5-fold higher fluorescence. When cellular fluorescence was measured using flow cytometry, we observed that [Zn(GTSC)]3 had 3.4-fold to 12-fold higher fluorescence than Zn(ATSM) in various cell lines (n = 9) of different tissue origin. Confocal fluorescence microscopy results showed that [Zn(GTSC)]3 appeared to have a nuclear localization within 30 min of addition to MCF7 cells. Moreover, [Zn(GTSC)]3 showed minimal cytotoxicity compared with Zn(ATSM), suggesting that [Zn(GTSC)]3 may be less deleterious to cells when used as an imaging agent. Our data suggest that the novel [Zn(GTSC)]3 complex can potentially serve as a biocompatible fluorescent imaging agent for live cells.

Enhancement of quadratic nonlinearity via multiple hydrogen-bonded supramolecular complex formation.

The formation and quadratic nonlinearity of a multiple hydrogen-bonded 1:1 supramolecular complex 1.2 between the 2,6-diaminopyridine-based Lambda-shaped molecule, 1, and ferrocenyl barbituric acid, 2, in solution have been investigated by the hyper-Rayleigh scattering (HRS) and NMR techniques. A 6-fold increase in the molecular hyperpolarizability (beta) of the complex 1.2 over the sum of the molecular hyperpolarizabilities of the components 1 and 2 is seen. Such a significant enhancement in beta is attributed to the alignment of the molecular dipoles of 1 and 2 in the 2D plane leading to the creation of a large dipole moment in the plane of the supramolecular complex. Depolarized HRS experiments led to the determination of the in-plane polarization components of beta of the supramolecular complex 1.2. The component of beta in the direction of the dipole moment is large. This investigation exemplifies the role of multiple hydrogen bonds in stabilizing a 2D supramolecular architecture leading to a large enhancement of molecular nonlinearity.

Mechanism of cytotoxicity of copper(I) complexes of 1,2-bis(diphenylphosphino)ethane.

The cytotoxic properties of arylphosphines are regulated by metals. We have synthesized a series of copper(I) complexes of 1,2-bis(diphenylphosphino)ethane (DPPE) and tested their in vitro cytotoxicity in a human lung carcinoma cell line H460. One of the complexes [Cu(2)(DPPE)(3)(CH(3)CN)(2)](ClO(4))(2) (C1), showed maximum cytotoxicity comparable to that of adriamycin. Treatment of cells with C1 caused DNA damage in vitro and activated the p53 pathway. Flow cytometry revealed that growth inhibition by C1 was due to a combination of cell cycle arrest and apoptosis. Simultaneous addition of C1 and adriamycin increased the cytotoxicity of either compound, suggesting the potential use of adriamycin in combination with C1. DNA binding and simulation studies suggest that adriamycin binds to DNA synergistically in the presence of C1. Thus, we have identified C1, a copper(I) complex of DPPE, as a potential chemotherapeutic drug for further testing, which could be used either alone or in combination with other chemotherapeutic drugs.

Catalytic metathesis of carbon dioxide with heterocumulenes mediated by titanium isopropoxide.

The insertion of an isopropoxide ligand of titanium isopropoxide into heterocumulenes gives a product that carries out metathesis at elevated temperatures by undergoing insertion of a second heterocumulene in a head to head fashion, followed by an extrusion reaction.

On the water promoted reaction of titanium isopropoxide with carbon dioxide.

Insertion of carbon dioxide into titanium isopropoxide takes place only in the presence of trace quantities of water to give an isopropyl carbonato cluster which has been crystallographically characterised.

Reversible Insertion of Methyl Isothiocyanate into Copper(I) Aryloxides.

MeNCS undergoes insertion into the copper(I)-aryloxide bond to form [N-methylimino(aryloxy)methanethiolato]copper(I) complexes. This insertion occurs in the absence of ancillary ligands unlike the analogous insertion of PhNCS. The reaction with 4-methylphenoxide results in the formation of hexakis[[N-methylimino(4-methylphenoxy)methanethiolato]copper(I)] (1), which has been characterized by X-ray crystallography. Crystal data for 1: hexagonal R&thremacr;, a = 12.365(3) Å, c = 36.734(16) Å, gamma = 120 degrees, Z = 3, V = 4863(3) Å(3), R = 0.0306. Reactions of 2,6-dimethyl- and 4-chlorophenoxides also result in analogous copper(I) complexes 2 and 3. Addition of stochiometric amounts of PPh(3) to the oligomeric complexes typically results in the extrusion of MeNCS. The ease of extrusion is dependent on the substituents on the aryloxide, and this deinsertion is accelerated by water. However, the extrusion reaction is slow enough in the case of the N-methylimino(2,6-dimethylphenoxy)methanethiolate complex and the isolation of an intermediate monomeric product bis(triphenylphosphine)[N-methylimino(2,6-dimethylphenoxy)methanethiolato]copper(I) (4) is possible. Crystal data for 4: triclinic P&onemacr;, a = 10.088(2) Å, b = 11.302(1) Å, c = 17.990(2) Å, alpha = 94.06(1) degrees, beta = 95.22(2) degrees, gamma = 103.94(1) degrees, Z = 2, V = 1974.4(7) Å(3), R = 0.0361. In the presence of of PPh(3), the insertion reaction becomes reversible. This allows the exchange of the heterocumulene MeNCS or the aryloxy group in these molecules with another heterocumulene or a phenol, respectively, when catalytic amounts of PPh(3) are added. Oligomers with exchanged heterocumulmes and phenols could be characterized by independent synthesis.

Synthesis and Structures of Oxyanion Encapsulated Copper(I)-dppm Complexes (dppm = Bis(diphenylphosphino)methane).

Copper(I)-dppm complexes encapsulating the oxyanions ClO(4)(-), NO(3)(-), CH(3)C(6)H(4)CO(2)(-), SO(4)(2-), and WO(4)(2-) have been synthesized either by reduction of the corresponding Cu(II) salts and treatment with dppm, or by treating the complex [Cu(2)(dppm)(2)(dmcn)(3)](BF(4))(2) (1) (dmcn = dimethyl cyanamide) with the respective anion. The isolated complexes [Cu(2)(dppm)(2)(dmcn)(2)(ClO(4))] (ClO(4)) (2), [Cu(2)(dppm)(2)(dmcn)(2)(NO(3))] (NO(3)) (3), Cu(2)(dppm)(2)(NO(3))(2) (4), [Cu(2)(dppm)(2)(CH(3)C(6)H(4)CO(2))(2)]dmcn.2THF (5), Cu(2)(dppm)(2)(SO(4)) (6), and [Cu(3)(dppm)(3)(Cl)(WO(4))] 0.5H(2)O (7) have been characterized by IR, (1)H and (31)P{(1)H} NMR, UV-vis, and emission spectroscopy. The solid-state molecular structure of complexes 1, 2, 4, and 7 were determined by single-crystal X-ray diffraction. Pertinent crystal data are as follows: for 1, monoclinic P2(1)/c, a = 11.376(10) Å, b = 42.503(7) Å, c = 13.530(6) Å, beta = 108.08(2) degrees, V = 6219(3) Å(3), Z = 4; for 2, monoclinic P2(1)/n, a = 21.600(3) Å, b = 12.968(3) Å, c = 23.050(3) Å, beta = 115.97(2) degrees, V = 5804(17) Å(3), Z = 4; for 4, triclinic P&onemacr;, a = 10.560(4) Å, b = 10.553(3) Å, c = 22.698(3) Å, alpha = 96.08(2) degrees, beta = 96.03(2) degrees, gamma = 108.31(2) degrees, V = 2362(12) Å(3), Z = 2; and for 7, orthorhombic P2(1)2(1)2(1), a = 14.407(4) Å, b = 20.573(7) Å, c = 24.176(6) Å, V = 7166(4) Å(3), Z = 4. Analyses of the crystallographic and spectroscopic data of these complexes reveal the nature of interactions between the Cu(I)-dppm core and oxyanion. The anchoring of the oxyanion to the Cu(n)()(dppm)(n)() unit is primarily through coordination to the metal, but the noncovalent C-H.O interactions between the methylene and phenyl protons of the dppm and oxygen atoms of the oxyanion play a significant role. The solid-state emission spectra for complexes 1-6 are very similar but different from 7. In CDCl(3) solution, addition of ClO(4)(-) or NO(3)(-) (as their tetrabutylammonium salts) to 1 establishes a rapid equilibrium between the anion-complexed and uncomplexed forms. The association constant values for ClO(4)(-) and NO(3)(-) have been estimated from the (31)P{(1)H} NMR spectra.

In vitro and in vivo anticancer activity of copper bis(thiosemicarbazone) complexes.

Neutral and cationic copper bis(thiosemicarbazone) complexes bearing methyl, phenyl, and hydrogen, on the diketo-backbone of the ligand have been synthesized. All of them were characterized by spectroscopic methods and in three cases by X-ray crystallography. In vitro cytotoxicity studies revealed that they are cytotoxic unlike the corresponding zinc complexes. Copper complexes Cu(GTSC) and Cu(GTSCHCl) derived from glyoxal-bis(4-methyl-4-phenyl-3-thiosemicarbazone) (GTSCH(2)) are the most cytotoxic complexes against various human cancer cell lines, with a potency similar to that of the anticancer drug adriamycin and up to 1000 fold higher than that of the corresponding zinc complex. Tritiated thymidine incorporation assay revealed that Cu(GTSC) and Cu(GTSCHCl) inhibit DNA synthesis substantially. Cell cycle analyses showed that Cu(GTSC) and Cu(GTSCHCl) induce apoptosis in HCT116 cells. The Cu(GTSCHCl) complex caused distinct DNA cleavage and Topo IIα inhibition unlike that for Cu(GTSC). In vivo administration of Cu(GTSC) significantly inhibits tumor growth in HCT116 xenografts in nude mice.

Catalytic reactions of titanium alkoxides with Grignard reagents and imines: a mechanistic study.

The reactivity of Grignard reagents towards imines in the presence of catalytic and stoichiometric amounts of titanium alkoxides is reported. Alkylation, reduction, and coupling of imines take place. Whereas reductive coupling is the major reaction in stoichiometric reactions, alkylation is favored in catalytic reactions. Mechanistic studies clearly indicate that intermediates involved in the two reactions are different. Catalytic reactions involve a metal-alkyl complex. This has been confirmed by reactions of deuterium-labeled substrates and different alkylating agents. Under the stoichiometric conditions, however, titanium olefin complexes are formed through reductive elimination, probably through a multinuclear intermediate.

Cytotoxicity of half sandwich ruthenium(II) complexes with strong hydrogen bond acceptor ligands and their mechanism of action.

Neutral and cationic organometallic ruthenium(II) piano stool complexes of the type [(eta(6)-cymene)RuCl(X)(Y)] (complexes R1-R8) has been synthesized and characterized. In cationic complexes, X, Y is either a eta(2) phosphorus ligand such as 1,1-bis(diphenylphosphino)methane (DPPM) and 1,2-bis(diphenylphosphino)ethane (DPPE) or partially oxidized ligands such as 1,2-bis(diphenylphosphino)methane monooxide (DPPMO) and 1,2-bis(diphenylphosphino)ethane monooxide (DPPEO) which are strong hydrogen bond acceptors. In neutral complexes, X is chloride and Y is a monodentate phosphorous donor. Complexes with DPPM and DPPMO ligands ([(eta(6)-cymene)Ru(eta(2)-DPPM)Cl]PF(6) (R2), [(eta(6)-cymene)Ru(eta(2)-DPPMO)Cl]PF(6) (R3), [(eta(6)-cymene)Ru(eta(1)-DPPM)Cl(2)] (R5) and [(eta(6)-cymene)Ru(eta(1)-DPPMO)Cl(2)] (R6) show good cytotoxicity. Growth inhibition study of several human cancer cell lines by these complexes has been carried out. Mechanistic studies for R5 and R6 show that inhibition of cancer cell growth involves both cell cycle arrest and apoptosis induction. Using an apoptosis PCR array, we identified the sets of anti-apoptotic genes that were down regulated and pro-apoptotic genes that were up regulated. These complexes were also found to be potent metastasis inhibitors as they prevented cell invasion through matrigel. The complexes were shown to bind DNA in a non intercalative fashion and cause unwinding of plasmid DNA in cell-free medium by competitive ethidium bromide binding, viscosity measurements, thermal denaturation and gel mobility shift assays.