Ti(II)-mediated domino cyclization of 2-functionalized 1-halo-2,n-enynes (n = 7, 8) to bicyclic compounds

The reaction of 2-functionalized 1-halo-2,n-enynes (n = 7 or 8) with a divalent titanium reagent, Ti(O-i-Pr)₄/2i-PrMgCl, proceeded in a domino fashion to afford bicyclic compounds in good yields.     

Open-loop and closed-loop control of dissociative ionization of ethanol in intense laser fields

The relative yield of the C-O bond breaking with respect to the C-C bond breaking in ethanol cation C2H5OH+ is maximized in intense laser fields (10(13)-10(15) Wcm2) by open-loop and closed-loop optimization procedures. In the open-loop optimization, a train of intense laser pulses are synthesized so that the temporal separation between the first and last pulses becomes 800 fs, and the number and width of the pulses within a train are systematically varied. When the duration of 800 fs is filled with laser fields by increasing the number of pulses or by stretching all pulses in a triple pulse train, the relative yield of the C-O bond breaking becomes significantly large. In the closed-loop optimization using a self-learning algorithm, the four dispersion coefficients or the phases of 128 frequency components of an intense laser pulse are adopted as optimized parameters. From these optimization experiments it is revealed that the yield ratio of the C-O bond breaking is maximized as far as the total duration of the intense laser field reaches as long as approximately 1 ps and that the intermittent disappearance of the laser field within a pulse does not affect the relative yields of the bond breaking pathways.     

Particle design of three-component system for sustained release using a 4-fluid nozzle spray-drying technique

We prepared composite particles of acetaminophen (Act) with chitosan (Cht) and hydroxypropylmethylcellulose phthalate (HPMCP) as a carrier using a newly developed 4-fluid nozzle spray-dryer. Cht dissolves in acid solutions and forms a gel, but it is insoluble in alkaline solutions. On the other hand, HPMCP is insoluble in acid solutions, but it dissolves in alkaline solutions. Therefore, we tested a preparation of controlled release composite particles using the characteristics of these carriers. Act and Cht mixtures in prescribed ratios were dissolved in an acid solution. Composite particles of Act and HPMCP in prescribed ratios were dissolved in alkaline solutions. We evaluated the composite particles of the three components (Act, Cht, and HPMCP) by preparing solid dispersions using a 4-fluid nozzle spray-dryer. Observation of particle morphology by scanning electron microscopy (SEM) revealed that the particles from the spray-drying process had atomized to several microns and had all become spherical. We investigated the physical properties of the composite particles by powder X-ray diffraction, differential scanning calorimetry, and dissolution rate analysis to clarify the effects of crystallinity on the dissolution rate. Powder X-ray diffraction peaks and the heat of fusion of Act in the spray-dried samples decreased in proportion to the carrier content, indicating that the drug was amorphous. These results indicate that the Act-Cht-HPMCP system formed a solid dispersion. Furthermore, we investigated the interaction between the drug and the carrier using FT-IR analysis. FT-IR spectroscopy of the Act solid dispersions suggested that the Act carbonyl and Cht amino groups formed a hydrogen bond. On the other hand, interaction by hydrogen bond was observed between the carbonyl group of HPMCP with the amino group of Act. In the three-component Act-Cht-HPMCP system, the 4-fluid nozzle spray-dried preparation with a mixing ratio of 1 : 2.5 : 2.5 obtained sustained release preparation in all pH test solutions.     

Heterocyclic quinol-type fluorophores: synthesis, X-ray crystal structures, and solid-state photophysical properties of novel 5-hydroxy-5-substituent-benzo[b]naphtho[1,2-d]furan-6-one and 3-hydroxy-3-substituent-benzo[kl]xanthen-2-one derivatives

Novel heterocyclic quinol-type fluorophores (4 a-c) and (5 a-c) that contain substituents (R = Me, Bu, Ph) with nonconjugated linkages to the chromophore skeleton have been synthesized and their photophysical properties have been investigated in solution and in the solid state. Considerable differences in the absorption and fluorescence spectra were observed between the two states. Quinols 4 a-c and 5 a-c exhibited almost the same absorption and fluorescence spectra in solution; however, their solid-state fluorescence excitation and emission spectra in the crystalline state were quite different. We performed X-ray crystallographic analyses to elucidate the dramatic effect of the substituents of the nonconjugated linkage on the solid-state fluorescence excitation and emission spectra. The relationships between the solid-state photophysical properties and the chemical and crystal structures of 4 a-c and 5 a-c are discussed on the basis of the X-ray crystal structures.     

Dependency of ligand free energy landscapes on charge parameters and solvent models

We performed replica-exchange molecular dynamics (REMD) simulations of six ligands to examine the dependency of their free energy landscapes on charge parameters and solvent models. Six different charge parameter sets for each ligand were first generated by RESP and AM1-BCC methods using three different conformations independently. RESP charges showed some conformational dependency. On the other hand, AM1-BCC charges did not show conformational dependency and well reproduced the overall trend of RESP charges. The free energy landscapes obtained from the REMD simulations of ligands in vacuum, Generalized-Born (GB), and TIP3P solutions were then analyzed. We found that even small charge differences can produce qualitatively different landscapes in vacuum condition, but the differences tend to be much smaller under GB and TIP3P conditions. The simulations in the GB model well reproduced the landscapes in the TIP3P model using only a fraction of the computational cost. The protein-bound ligand conformations were rarely the global minimum states, but similar conformations were found to exist in aqueous solution without proteins in regions close to the global minimum, local minimum or intermediate states.     

A clinical trial for therapeutic drug monitoring using microchip-based fluorescence polarization immunoassay

Microchip analysis is a promising method for therapeutic drug monitoring. This led us to evaluate a microchip-based fluorescence polarization immunoassay (FPIA) system for point-of-care testing on patients being treated with theophylline. The sera were collected from 20 patients being treated with theophylline. Fluorescence polarization was measured on the microchip and theophylline concentrations in serum were obtained. Regression analysis of the correlations was done between the results given by the microchip-based FPIA and the conventional cloned enzyme donor immunoassay (CEDIA), and between the results given by the microchip-based FPIA and the conventional particle-enhanced turbidimetric inhibition immunoassay (PETINIA). We successfully carried out a quantitative analysis of theophylline in serum at values near its therapeutic range in 65 s. The results obtained by the microchip-based FPIA correlated well with CEDIA and PETINIA results; the correlation coefficients (R ²) were 0.986 and 0.989, respectively. The FPIA system is a simple and rapid method for point-of-care testing of drugs in serum, and its accuracy is the same as the conventional CEDIA and PETINIA. It is essential to use real samples from patients and to confirm good correlations with conventional methods for a study on the realization of microchip.     

Emission control by binary energy transfer processes on oligouridine

Fluorescent oligonucleotides have been designed on which two different energy transfer processes were mounted together: excitonic interaction and FRET. The fluorescence emission of the oligonucleotides was controlled well by the two different energy transfer processes, in response to their hybridization to the complementary RNA both in vitro and in cells.     

Synthesis of the proposed structure of phaeosphaeride A

The first total synthesis of the proposed structure of phaeosphaeride A has been achieved via six-membered-ring formation by means of an intramolecular vinyl-anion aldol reaction as the key step. This synthesis suggests a revised configurational assignment for phaeosphaeride A.