Discovery of a novel acyl-CoA: cholesterol acyltransferase inhibitor: the synthesis, biological evaluation, and reduced adrenal toxicity of (4-phenylcoumarin)acetanilide derivatives with a carboxylic acid moiety

As a part of our research for novel potent and orally available acyl-CoA: cholesterol acyltransferase (ACAT) inhibitors that can be used as anti-atherosclerotic agents, we recently reported the discovery of the (4-phenylcoumarine)acetanilide derivative 1. However, compound 1 showed adrenal toxicity in animal models. In order to search for safer ACAT inhibitors that do not have adrenal toxicity, we examined the inhibitory activity of ACAT in human macrophage and adrenal cells. The introduction of a carboxylic acid moiety on the pendant phenyl ring and the adjustment of the lipophilicity led to the discovery of (2E)-3-[7-chloro-3-[2-[[4-fluoro-2-(trifluoromethyl)phenyl]amino]-2-oxoethyl]-6-methyl-2-oxo-2H-chromen-4-yl]phenyl]acrylic acid (21e), which showed potent ACAT inhibitory activity in macrophages and a selectivity of around 30-fold over adrenal cells. In addition, compound 21e showed high adrenal safety in guinea pigs.     

Microcapsules with macroholes prepared by the competitive adsorption of surfactants on emulsion droplet surfaces

We demonstrate a simple, unique method for preparing microcapsules with holes in their shells. Cross-linked polymelamine microcapsules are prepared by the phase-separation method. The holey shell of each microcapsule is synthesized on the surface of an oil-in-water (O/W) emulsion droplet where a water-soluble polymeric surfactant and an oil-soluble surfactant are competitively adsorbed. The water-soluble polymeric surfactant provides a reaction site for shell formation. The oil-soluble surfactant molecules seem to self-assemble while the shells are being formed, so holes appear where they assemble. The critical degree of surface coverage of an emulsion droplet by the water-soluble polymeric surfactant needed to form the holey shells is determined to be 0.90 from theoretical calculations in which competitive adsorption is considered. Theoretical consideration suggests that the size and quantity of the holes in the microcapsule shells are controlled by the composition of the surfactants adsorbed on the surface of an emulsion droplet. This theoretical consideration is confirmed by experiments. The prepared microcapsule with controllable macroholes in its shell has the potential to be used for controlled release applications and can be used to fabricate a microcapsule that encapsulates hydrophilic compounds.     

Highly phosphonated poly(N‐phenylacrylamide) for proton exchange membranes

A novel highly phosphonated poly(N‐phenylacrylamide) ( PDPAA ) with an ion‐exchange capacity (IEC) of 6.72 mequiv/g was synthesized by the radical polymerization of N‐[2,4‐bis(diethoxyphosphinoyl)phenyl]acrylamide ( DEPAA ), followed by the hydrolysis with trimethylsilyl bromide. Then, the crosslinked PDPAA membrane was successfully prepared by the electrophilic substitution reaction between the aromatic rings of PDPAA and the carbocation formed from hexamethoxymethylmelamine (CYMEL) as a crosslinker in the presence of methanesulfonic acid. The crosslinked PDPAA membrane had high oxidative stability against Fenton's reagent at room temperature. The proton conductivity of the crosslinked PDPAA membrane was 8.8 × 10^?2 S/cm at 95% relative humidity (RH) and 80 °C, which was comparable to Nafion 112. Under low RH, the crosslinked PDPAA membrane showed the proton conductivity of 1.9 × 10^?3 and 4.7 × 10^?5 S/cm at 50 and 30% RH, respectively. The proton conductivity of the crosslinked PDPAA membrane lied in the highest class among the reported phosphonated polymers, and, consequently, the very high local concentration of the acids of PDPAA (IEC = 6.72 mequiv/g) achieved high and effective proton conduction under high RH. © 2010 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2010     

Development and application of high‐performance affinity beads: Toward chemical biology and drug discovery

In drug development research, the elucidation and understanding of the interactions between physiologically active substances and proteins that numerous genes produce is important. Currently, most commercially available drugs and physiologically active substances have been brought to market without knowledge of factors interacting with the drugs and the substances. Affinity purification is a useful and powerful technique employed to understand factors that are targeted by drugs and physiologically active substances. However, use of conventional matrices for affinity chromatography often causes a decrease in efficiency of affinity purification and, as a result, more practical matrices for affinity purification have been developed for application in drug discovery research. In this paper, we describe the development of high‐performance affinity beads (SG beads and FG beads) that enable one‐step affinity purification of drug targets and the elucidation of the mechanism of the action of the drugs. We also describe a chemical screening system using our affinity beads. We hope that utilization of the affinity beads will contribute to the progress of research in chemical biology. © 2009 The Japan Chemical Journal Forum and Wiley Periodicals, Inc. Chem Rec 9: 66–85; 2009: Published online in Wiley InterScience ( www.interscience.wiley.com ) DOI 10.1002/tcr.20170     

Interactive Radical Dimers in Photoconductive Organic Thin Films

Fully interactive : Overlap between extended unoccupied molecular orbitals leads to the high photoconductivity of interactive radical dimers. Sandwich‐type cells (see picture; ITO=indium tin oxide) comprising highly oriented thin films of a disjoint diradical, 4,4′‐bis(1,2,3,5‐dithiadiazolyl) (BDTDA) exhibit a photocurrent with a high on/off ratio at reverse bias voltages and photovoltaic behavior at zero bias voltage.

     

Hydrogen Molecules Trapped in Interstitial Host Channels of α‐Hydroquinone

Easy come, easy go: Hydroquinone forms a channel structure of cages with hydrogen‐bonded hexagons. These may provide an ideal route for the fast inclusion and facile release of hydrogen molecules (see figure), which can lead to reversible hydrogen storage under mild conditions.

     

Calibration of force-field dependency in free energy landscapes of peptide conformations by quantum chemical calculations

The free energy landscapes of peptide conformations were calibrated by ab initio quantum chemical calculations, after the enhanced conformational diversity search using the multicanonical molecular dynamics simulations. Three different potentials of mean force for an isolated dipeptide were individually obtained by the multicanonical molecular dynamics simulations using the conventional force fields, AMBER parm94, AMBER parm96, and CHARMm22. Each potential of mean force was then calibrated based upon the umbrella sampling algorithm from the adiabatic energy map that was calculated separately by the ab initio molecular orbital method, and all of the calibrated potentials of mean force coincided well. The calibration method was also applied to the simulations of a peptide dimer in explicit water models, and it was shown that the calibrated free energy landscapes did not depend on the force field used in the classical simulations, as far as the conformational space was sampled well. The current calibration method fuses the classical free energy calculation with the quantum chemical calculation, and it should generally make simulations for biomolecular systems much more reliable when combining with enhanced conformational sampling.     

The first total synthesis of (+/-)-arisugacin A, a potent, orally bioavailable inhibitor of acetylcholinesterase

The first convergent total synthesis of (+/-)-arisugacin A was accomplished by stereoselective construction of the arisugacin skeleton via a Knoevenagel-type reaction of an alpha,beta-unsaturated aldehyde with a 4-hydroxy 2-pyrone and stereoselective dihydroxylation followed by deoxygenation.     

Validation of real-time PCR analyses for line-specific quantitation of genetically modified maize and soybean using new reference molecules

Novel analytical methods based on real-time quantitative polymerase chain reactions by use of new reference molecules were validated in interlaboratory studies for the quantitation of genetically modified (GM) maize and soy. More than 13 laboratories from Japan, Korea, and the United States participated in the studies. The interlaboratory studies included 2 separate stages: (1) measurement tests of coefficient values, the ratio of recombinant DNA (r-DNA) sequence, and endogenous DNA sequence in the seeds of GM maize and GM soy; and (2) blind tests with 6 pairs of maize and soy samples, including different levels of GM maize or GM soy. Test results showed that the methods are applicable to the specific quantitation of the 5 lines of GM maize and one line of GM soy. After statistical treatment to remove outliers, the repeatability and reproducibility of these methods at a level of 5.0% were <13.7 and 15.9%, respectively. The quantitation limits of the methods were 0.50% for Bt11, T25, and MON810, and 0.10% for GA21, Event176, and Roundup Ready soy. The results of blind tests showed that the numerical information obtained from these methods will contribute to practical analyses for labeling systems of GM crops.