High-Throughput Analysis of Sofalcone in Human Plasma by Use of Automated 96-Well Protein Precipitation and LC-MS-MS

A sensitive and selective method for the determination of sofalcone in human plasma was established by use of protein precipitation and liquid chromatography-tandem mass spectrometry. Plasma samples were transferred into 96-well plate using an automated sample handling system and spiked with 10 L of 2 g mL^–1 internal standard solution (d₃-sofalcone). 0.5 mL of acetonitrile was added to the 96-well plate and the plasma samples were then vortexed for 30 sec. After centrifugation, the supernatant was transferred into another 96-well plate and completely evaporated at 40 °C under a stream of nitrogen. The dry residue was reconstituted with mobile phase. All sample transfer and protein precipitation was automated through the application of both the PerkinElmer MultiPROBE II HT and TOMTEC Quadra 96 workstation. The limit of quantitation of sofalcone was 2 ng mL^–1 using a sample volume of 0.2 mL for the analysis. The reproducibility of the method was evaluated by analyzing five samples at nine quality control (QC) levels over the nominal concentration range from 2 ng mL^–1 to 1000 ng mL^–1. Validation of the method showed that the assay has good precision and accuracy. Sofalcone and internal standard produced a protonated precursor ion ([M+H]⁺) at m/z 451 and 454, and both gave a corresponding product ion at m/z 315. The high sample throughput of the method has been successfully applied to a pharmacokinetic study of sofalcone in human plasma.     

Synthesis and Structures of Titanosiloxane Cage Compounds

Reaction of (triphenylmethyl)silanetriol (1) with cyclopentadienyltitanium trichloride (CpTiCl₃) in the presence of triethylamine as a HCl scavenger gave both compounds of a partial open-cage type {[Ph₃CSiO(OH)]₃(Ph₃CSiO_3/2)(CpTiO_3/2)₄} (2) and cube type (Ph₃CSiO_3/2CpTiO_3/2)₄ (3). The 1:1 reaction of 1 and CpTiCl₃ in toluene solvent at reflux temperature for 3 d afforded compounds 2 (22%) and 3 (36%). When 1 is reacted with a 1.5 fold excess of CpTiCl₃ under the same conditions, compound 3 was obtained in high yield (81%) along with 2 in trace quantities. Compounds 2 and 3 were fully characterized by the analyses of ¹H, ¹³C, ²⁹Si NMR, IR, and FAB MS data. The solid-state structure of 3 was determined by a single crystal X-ray diffraction study. Compound 3 had shown to have catalytic activity for the oxidation of alkenes such as 1-octene, cyclooctene, and norbornene with t-butyl hydrogen peroxide. The effect of solvent was observed in this epoxidation reaction. The order of reactivity were decreased as follows: CHCl₃ > hexane THF.     

Chemical lithography by Ag-nanoparticle-mediated photoreduction of aromatic nitro monolayers on Au

Patterned, amine-terminated monolayers can be fabricated from 4-nitrobenzenethiol (4-NBT) monolayers simply by irradiating under ambient conditions with visible laser after spreading Ag nanoparticles onto selected regions of the 4-NBT monolayers on Au. Au nanoparticles were adsorbed selectively onto the amine groups produced by photoreaction, and polyaniline was found to grow exclusively at the amine groups when electrochemical polymerization was conducted using the patterned substrate as the working electrode. These observations clearly support our previous contention that Ag nanoparticles can act as moderate photoelectron emitters.     

Photoactivation of pheophorbide a induces a mitochondrial-mediated apoptosis in Jurkat leukaemia cells

The mechanism of cell death by pheophorbide a (Pba) which has been established to be a potential photosensitizer was examined in experimental photodynamic therapy (PDT) on Jurkat cells, a human lymphoid tumor cell line. In 30-60 min after irradiation, Pba treated cells exhibited apoptotic features including membrane blebbing and DNA fragmentation. Pba/PDT caused a rapid release of cytochrome c from mitochondria into the cytosol. Sequentially, activation of caspase-3 and the cleavage of poly ADP-ribose polymerase (PARP) were followed. Meanwhile, no evidence of activation of caspase-8 was indicated in the cells. In experiments with caspase inhibitors, it was found that caspase-3 alone was sufficient initiator for the Pba-induced apoptosis of the cells. Pba specific emission spectra were confirmed in the mitochondrial fraction and the light irradiation caused a rapid change in its membrane potential. Thus, mitochondria were entailed as the crucial targets for Pba as well as a responsible component for the cytochrome c release to initiate apoptotic pathways. Taken together, it was concluded that the mode of Jurkat cell death by Pba/PDT is an apoptosis, which is initiated by mitochondrial cytochrome c release and caspase-3-pathways.     

Ab initio and DFT studies on hydrolyses of phosphorus halides

Hydrolyses of phosphorus halides, (RO)(2)POX where R = H or Me and X = F or Cl, in the gas phase and in the reaction field have been investigated theoretically with ab initio and the density functional theory (DFT). The free energy of activation in the reaction field was also estimated using the Onsager method with a correction of entropy change and basis set superposition error (BSSE). The reaction of (MeO)(2)POF proceeds through a path with bifunctional catalysis regardless of the medium, but the reaction of (MeO)(2)POCl proceeds through bifunctional and general base catalysis in the gas phase and in water, respectively. The estimated free energy barrier of 23 kcal/mol for the hydrolysis of (MeO)(2)POF is in good agreement with the experimental values of 24 kcal/mol, and relative barrier of 3 kcal/mol to the (MeO)(2)POCl is also in good agreement with the experimental values of 5 kcal/mol of diisopropyl phosphorus halides ((Pr(i)O)(2)POX, X = F and Cl).     

Dynamic pathway model for the formation of C(60)

We present a dynamic pathway model for the formation of C(60) using the action-derived molecular dynamics simulations. We propose candidate precursors for dynamic pathway models in which carbons spontaneously aggregate due to favorable energetics and kinetics. Various planar polycyclic models are in a disadvantageous state where they cannot be trapped in the forward reaction due to their high excess internal energies. Our simulation results show that precursors either in the shape of tangled polycyclics or in the shape of open cages are kinetically favored over precursors in the shape of planar hexagonal graphite fragments. Calculated activation energies for the probable precursor models are in good agreement with experiment. Existence of chains in the models of tangled polycyclics and open cages is beneficially for the formation of C(60) molecule. Chains attached to the precursor model are energetically favorable and display lithe movements along the dynamic pathway.     

Different adsorption structures of pyridine on Si(001) and Ge(001) surfaces

The adsorption and reaction of pyridine on the Si(001) and Ge(001) surfaces are investigated by first-principles density-functional calculations within the generalized gradient approximation. On both surfaces the N atom of pyridine initially reacts with the down atom of the dimer, forming a single bond between the N atom and the down atom. On Ge(001) such an adsorption configuration is most favorable, but on Si(001) a further reaction with a neighboring dimer occurs, resulting in formation of a bridge-type configuration. Especially we find that on Ge(001) the bridge-type configuration is less stable than the gas phase. Our results provide an explanation for a subtle difference in the adsorption structures of pyridine on Si(001) and Ge(001), which was observed from recent scanning tunneling microscopy experiments.     

Experimental and theoretical study on the olefin metathesis of alkenyl Baylis-Hillman adducts using second-generation Grubbs catalyst

[reaction: see text] We have investigated the olefin metathesis from alkenyl Baylis-Hillman adducts using second-generation Grubbs catalyst. In the experiment, the ring-closing metathesis (RCM) product could not be found, while the cross-metathesis (CM) products were found. The computational studies provided consistent explanations for the experimental result. The most limiting factor for the RCM process using second-generation Grubbs catalyst is caused by the high strain and steric effect in the metallacyclobutane intermediates.     

Aqua dissociation nature of cesium hydroxide

To understand the mechanism of aqueous base dissociation chemistry, the ionic dissociation of cesium-hydroxide in water clusters is examined using density functional theory and ab initio calculations. In this study, we report hydrated structures, stabilities, thermodynamic quantities, dissociation energies, infrared spectra, and electronic properties of CsOH(H(2)O)(n=0-4). With the addition of water molecules, the Cs-OH bond lengthened significantly from 2.46 A for n=1 to 3.08 A for n=4, which causes redshift in Cs-O stretching frequency. It is found that three water molecules are needed for the dissociation of Cs-OH, in contrast to the case of strong acid dissociation which requires at least four water molecules. However, the dissociation for n=3 could be considered as incomplete because a very weak CS em leader OH stretch mode is still present, while that for n=4 is complete since the Cs em leader OH mode no longer exists. This study can be related with hydration chemistry of cations and anions, and extended into the intra- and intercharge-transfer phenomena.     

Dynamic kinetic resolution of atropisomeric amides

[reaction: see text] Using L-proline as catalyst in the asymmetric aldol reaction and a series of benzamides and naphthamides, we have accomplished a dynamic kinetic resolution that simultaneously establishes the stereochemistry of the atropisomeric amide's chiral axis and a stereogenic center. The enantioselectivities ranged from 82% to 95% and the diastereoselectivities from 2.1:1 to 7.0:1.