Heterometallic titanium–gold complexes inhibit renal cancer cells in vitro and in vivo

Following recent work on heterometallic titanocene–gold complexes as potential chemotherapeutics for renal cancer, we report here on the synthesis, characterization and stability studies of new titanocene complexes containing a methyl group and a carboxylate ligand (mba = S–C₆H₄–COO^–) bound to gold(i)-phosphane fragments through a thiolate group [(η-C₅H₅)₂TiMe(μ-mba)Au(PR₃)]. The compounds are more stable in physiological media than those previously reported and are highly cytotoxic against human cancer renal cell lines. We describe here preliminary mechanistic data involving studies on the interaction of selected compounds with plasmid (pBR322) DNA used as a model nucleic acid, and with selected protein kinases from a panel of 35 protein kinases having oncological interest. Preliminary mechanistic studies in Caki-1 renal cells indicate that the cytotoxic and anti-migration effects of the most active compound 5 [(η-C₅H₅)₂TiMe(μ-mba)Au(PPh₃)] involve inhibition of thioredoxin reductase and loss of expression of protein kinases that drive cell migration (AKT, p90-RSK, and MAPKAPK3). The co-localization of both titanium and gold metals (1 : 1 ratio) in Caki-1 renal cells was demonstrated for 5 indicating the robustness of the heterometallic compound in vitro. Two compounds were selected for further in vivo studies on mice based on their selectivity in vitro against renal cancer cell lines when compared to non-tumorigenic human kidney cell lines (HEK-293T and RPTC) and the favourable preliminary toxicity profile in C57BL/6 mice. Evaluation of Caki-1 xenografts in NOD.CB17-Prkdc SCID/J mice showed an impressive tumor reduction (67%) after treatment for 28 days (3 mg per kg per every other day) with heterometallic compound 5 as compared with the previously described [(η-C₅H₅)₂Ti{OC(O)-4-C₆H₄-P(Ph₂)AuCl}₂] 3 which was non-inhibitory. These findings indicate that structural modifications on the ligand scaffold affect the in vivo efficacy of this class of compounds.     

Invar<Superscript>®</Superscript> oxidation in CO<Subscript>2</Subscript>

In this article, corrosion of Invar^® in a static carbon dioxide atmosphere \( 2\times 1 0^{4} \le P_{{{\text{CO}}_{ 2} }} \le 10^{5} \,{\text{Pa}} \) has been studied between 1163 and 1263 K. At the beginning, after a short initial deceleration for weight gains Δm/S <0.5 mg cm^?2, oxidation kinetics were linear up to weight gains of about 4.0 mg cm^?2, and only wüstite Fe_1?x O was formed with a constant rate r (mg cm^?2 s^?1) \( r = \frac{{{\text{d}}\left( {\frac{\Updelta m}{S}} \right)}}{{{\text{d}}t}} = 0.41 \times P_{{{\text{CO}}_{ 2} }} \exp \left( {\frac{ - 198000}{RT}} \right) \) where R is the gas constant and t the time (s). Reaction mechanism is similar to that of the pure iron in analogous conditions, with the same rate limiting step i.e. external reaction of CO₂ with wüstite and outward diffusion of ions Fe²⁺ (not limiting). For weight gains Δm/S higher than 4 mg cm^?2, the limiting step changes, with an increase of the reaction rate and an internal oxidation. The origin of this mechanism change lies in the microcracks appearing in the oxide during its growth. Then, wüstite is no longer bound to the substrate; outward diffusion of ions Fe²⁺ stops and a topotactic transformation converts wüstite into magnetite.     

Reactivity of the oxides in the ternary V<Subscript>2</Subscript>O<Subscript>5</Subscript>-CuO-α-Sb<Subscript>2</Subscript>O<Subscript>4</Subscript> system in air

In this work it has been established which compounds finally are formed in air in the two-component CuO-V₂O₅ and CuO-α-Sb₂O₄ systems. Unknown thermal properties of CuV₂O₆, Cu₂V₂O₇ and Cu₁₁V₆O₂₆ have been established. Reactivity of the oxides and phase relations in the ternary V₂O₅-CuO-α-Sb₂O₄ system in air have been studied by using XRD and DTA methods. The results have showed the reaction of V₂O₅, CuO with α-Sb₂O₄ does not produce any compound where all the three oxides would be involved. It has been established that the α-Sb₂O₄ reacts and forms binary phases independently with CuO or V₂O₅. On the base of these results the investigated system was divided into subsidiary subsystem in which CuSb₂O₆ remains at equilibrium in the solid state with other phases formed in corresponding binary systems.     

The sensor properties of SnO<Subscript>2</Subscript> · In<Subscript>2</Subscript>O<Subscript>3</Subscript> nanocomposite oxides in the detection of hydrogen in air

The sensor properties of In₂O₃ · SnO₂ polycrystalline films having different compositions were studied in the detection of 2% hydrogen in air over the temperature range 330–530°C. Films containing 19% In₂O₃ were most sensitive to hydrogen. The temperature dependence of the sensitivity of sensors passed a maximum, the position of which depended on the composition of the film. The temperature at which sensor sensitivity was maximum decreased as the content of indium oxide increased. This temperature was 485°C for the SnO₂ film and 425°C for the In₂O₃ film. The response and relaxation times of sensors also decreased as the amount of In₂O₃ in the composite metal oxide film increased. Possible mechanisms of the sensor sensitivity of the films are discussed.     

Induction of radiative forbidden transitions in an oxygen molecule in O<Subscript>2</Subscript>–H<Subscript>2</Subscript>O collision complexes

By the DFT/B3LYP method the equilibrium structures of oxygen complexes with water are calculated in various geometric conformations with symmetries C _2v and C _s . By the MRCI/CASSCF method potential energy surface cross-sections of the ^1.3[O₂–H₂O] complexation reaction are constructed. With taking into account the spin-orbit coupling, the forbidden transition moments a ¹Δ _g –X ³Σ _g ^?, b ¹Σ _g ⁺–a ¹Δ _g , c ¹Σ _u ^?–a ¹Δ _g , A ³Σ _u ⁺–X ³Σ _g ^? of the complexes are calculated and changes in their intensities at different geometric configurations of the complex are revealed.     

Electrochemistry of praseodymium in LiF–CaF<Subscript>2</Subscript>

The electrochemical behaviour of PrF₃ was studied in the LiF–CaF₂ (79/21 molar ratio) at 1,213 K. Inert (W) and reactive (Ni) electrodes were used. Pr(III) ions are reduced in a single, three electron exchange. The redox potential of the Pr(III)/Pr couple at the inert electrode was observed very close to the decomposition potential of the LiF–CaF₂ melt. Experiments using reactive working electrode were done. The results show the potential shift connected to the alloying reactions of Pr and Ni. Deposition of Pr–Ni layer was confirmed by SEM-EDX analysis. Conclusions for the Pr separation possibilities from spent nuclear fuel were done.     

Photochemistry of the IrCl<Subscript>6</Subscript><Superscript>2−</Superscript> complex in aqueous solutions in the presence of the bromide anions

Laser flash photolysis (308 nm) was applied to study photochemistry of the IrCl₆ ²⁻ complex in aqueous solutions in the presence of the Br⁻ anions. The formation of the Br₂ ^·− radical anions in the reaction between the Br⁻ ion and secondary radical pair formed after the photon absorption by the initial complex was observed. The Br₂ ^·− radical anions decay both in recombination and in the reaction with the initial IrCl₆ ²⁻ complex.     

Photochemistry of PtBr<Subscript>6</Subscript><Superscript>2−</Superscript> in aqueous solution

Photochemistry of the PtBr₆ ²⁻ complex in aqueous solution was studied by steady-state and laser flash photolysis (308 nm). The multistep photoaquation of the complex occurs in the nano-and microsecond time intervals without the formation of intermediate platinum(III) complexes. Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 12, pp. 2277–2283, December, 2007.     

Phase Transitions and Ionic Mobility in Solid Solutions in the System (NH<Subscript>4</Subscript>)<Subscript>2</Subscript>ZrF<Subscript>6</Subscript>–InF<Subscript>3</Subscript>

¹H and ¹⁹F NMR, XRD, and DTA methods are used to study thermal properties, ion mobility, and phase transitions (PT) in solid solutions obtained by doping anion-cationic conductor (NH₄)₂ZrF₆ with indium trifluoride. The types of ionic mobility are determined in the fluorine and ammonium sublattices of synthesized solid solutions at 150–450 K, their activation energies are estimated. A phase transition associated with formation of high-temperature modifications is registered at 400–413 K; ionic mobility in these modifications is mostly due to the diffusion of fluorine and ammonium ions.     

Nucleophilic Reactivity of Hydroxide and Hydroperoxide Ions in Aqueous-Alcoholic Media and of HCO<Stack><Subscript>4</Subscript><Superscript>−</Superscript></Stack> Ion in Water

Nucleophilic reactivity of hydroxide and hydroperoxide ions toward ethyl 4-nitrophenyl ethylphosphonate, diethyl 4-nitrophenyl phosphate, 4-nitrophenyl 4-toluenesulfonate, and 4-nitrophenyl dimethylcarbamate in the system H₂O₂-KOH was studied in aqueous-alcoholic solutions at 25°C. The rate of reactions of both anions with ethyl 4-nitrophenyl ethylphosphonate, diethyl 4-nitrophenyl phosphate, and 4-nitrophenyl dimethylcarbamate and of hydroxide ion with 4-nitrophenyl 4-toluenesulfonate increases with rise in the fraction of the alcohol in mixtures of water with isopropyl and tert-butyl alcohols, while the reaction rate of hydroperoxide ion with 4-nitrophenyl 4-toluenesulfonate decreases. The rate of reactions of both anions with all the above substrates in mixtures of water with ethylene glycol decreases as the fraction of the latter rises. The apparent rate of the reaction of ethyl 4-nitrophenyl ethylphosphonate with anionic nucleophiles in the system H₂O₂-HO^?-HCO ₃ ^? in water at pH 8.5 almost does not depend on the concentration of ammonium hydrogen carbonate up to a value of 1 M, and it increases when the NH₄HCO₃ concentration exceeds 1 M. Mixtures of water with the lower monohydric alcohols were recommended for use as components of H₂O₂-HO^?-HCO ₃ ^? systems for oxidative decomposition of ecotoxicants.     

Low-temperature phase formation in CaF<Subscript>2</Subscript>–HoF<Subscript>3</Subscript> system

Phase formation in CaF₂–HoF₃ system has been studied by coprecipitation followed by X-ray powder diffraction. Aqueous nitrate solutions have been used as initial substances, while hydrofluoric acid has been employed as fluorinating agent. Formation of hydrated nanophases: solid solution Ca_1–x Ho _x F_{2 + x} (х ≤ 0.1) and HoF3 has been revealed. Dehydration proceeds on heating to 600°C.     

Structure and conductivity in CeNb<Subscript>3</Subscript>O<Subscript>9-δ</Subscript>

Abstract  In the search of new materials for solid oxide fuel cells, a study of the structure and electrical conductivity of Mg-doped and nominally pure CeNb₃O_9-δ was undertaken. This material exhibits an orthorhombic crystal structure as determined by Rietveld refinement. Through a combined study of 4-point DC and AC impedance spectroscopy, it was determined that the material presents oxygen ion conductivity, electron conductivity and electron-hole conductivity according to the partial pressure of oxygen and temperature in agreement with a simple defect chemistry model. Finally, some experiments seem to indicate the presence of proton conduction. Graphical Abstract        

Properties of surface compounds in methanol conversion on γ-Al<Subscript>2</Subscript>O<Subscript>3</Subscript>: Data of in situ IR spectroscopy

In situ IR spectroscopic studies show that a formate, an aldehyde-like complex, and bridging and linear methoxy groups exist on the alumina surface involved in methanol conversion. In the absence of methanol in the gas phase, the interaction between two bridging methoxy groups yields dimethyl ether in the gas phase. When methanol is present in the gas phase, it interacts with methoxy groups on the surface. This reaction makes the main contribution to the formation of dimethyl ether. The linear methoxy group undergoes conversion via several routes. The main route is desorption with methanol formation in the gas phase, and no more than 10% of the linear methoxy groups are converted into formate and aldehyde, which are CO₂ sources in the gas phase. In the absence of methanol in the gas phase, the conversion rate of the methoxy groups is independent of the presence of water and oxygen. A scheme of the surface reactions is suggested to explain the conversion of the methoxy groups.     

Phase equilibria in the MgS–In<Subscript>2</Subscript>S<Subscript>3</Subscript> system

Phase equilibria in the MgS–In₂S₃ system were studied. This system is of the dystectic type with a limited region of a solid solution based on β-In₂S₃. In the MgS–In₂S₃ system, a compound of the composition MgIn₂S₄ forms, which forms congruently at 1180 K and crystallizes in the cubic system (space group Fd3m) with the unit cell parameter a = 1.0689 nm. Eutectics have the compositions 47 and 62 mol % In₂S₃ and the melting points 1150 and 1120 K, respectively. The MgS solubility in β-In₂S₃ at 1070 K reaches 9 mol % MgS.