Discovery of a potent and orally available acyl-CoA: cholesterol acyltransferase inhibitor as an anti-atherosclerotic agent: (4-phenylcoumarin)acetanilide derivatives

Acyl-CoA: cholesterol acyltransferase (ACAT) is an intracellular enzyme that catalyzes cholesterol esterification. ACAT inhibitors are expected to be potent therapeutic agents for the treatment of atherosclerosis. A series of potent ACAT inhibitors based on an (4-phenylcoumarin)acetanilide scaffold was identified. Evaluation of the structure-activity relationships of a substituent on this scaffold, with an emphasis on improving the pharmacokinetic profile led to the discovery of 2-[7-chloro-4-(3-chlorophenyl)-6-methyl-2-oxo-2H-chromen-3-yl]-N-[4-chloro-2-(trifluoromethyl)phenyl]acetamide (23), which exhibited potent ACAT inhibitory activity (IC50=12 nM) and good pharmacokinetic profile in mice. Compound 23 also showed regressive effects on atherosclerotic plaques in apolipoprotein (apo)E knock out (KO) mice at a dose of 0.3 mg/kg per os (p.o.).     

Ab initio molecular dynamics of protonated water clusters by integrated multicenter molecular-orbital method

To analyze large-scale cluster systems theoretically, we recently developed an "integrated multicenter molecular-orbital" (IMiC-MO) method. This method calculates the force of an entire system by dividing the system into small regions. We used the method to analyze the effect of cluster size and the process of hydrogen bond network (HBN) growth to form H(+)(H(2)O)(n) (n = 9, 17, and 33) clusters. Our simulations reveal that H(3)O(+) and water molecules in the first solvation shell function take an important role to grow the HBN. In addition, the number of hydrogen donors in each water molecule is strongly related to the shape of the HBN.     

Theoretical studies on [2 + 2 + 2] reaction mechanisms of three ethynes. More accurate estimation of activation energy

The mechanisms of the [2 + 2 + 2] cycloaddition reaction of three ethyne molecules were studied by ab initio molecular orbital and density functional methods. The transition states range from that of the concerted mechanism with D_3h symmetry to that of the stepwise mechanism with C₂ symmetry. The transition state structure and the activation energy depend on the basis set and computational method employed in the analysis. The activation energy barrier was determined to be in the range of 36–44 kcal/mol. The activation energy determined by various methods corresponds to the interaction energy, which is related to the electron correlation energy. The best estimation of the activation energy barrier is 41.6 kcal/mol, achieved from the relation between the interaction energy and the activation energy. Copyright © 2013 John Wiley & Sons, Ltd.     

Ruthenium- and Copper-Catalyzed Propargylic Substitution Reactions of Propargylic Alcohol Derivatives with Hydrazones

Ruthenium- and copper-catalyzed propargylic substitution reactions of propargylic alcohol derivatives with N-monosubstituted hydrazones as ambident nucleophiles are achieved in which N-monosubstituted hydrazones exhibit impressive different reactivities depending on different catalytic systems, behaving as carbon-centered nucleophiles to give the corresponding propargylic alkylated products in ruthenium catalysis, or as nitrogen-centered nucleophiles to afford the corresponding propargylic aminated products in copper catalysis. DFT calculations were carried out to investigate the detailed reaction pathways of these two systems. Further transformation of propargylic substituted products affords the corresponding multisubstituted pyrazoles as cyclization products in good to high yields.     

Magnetic Correlation Engineering in Spin-Sandwiched Layered Magnetic Frameworks

The insertion of “sandwiched spins” between magnetic layers could efficiently affect the interlayer magnetic correlations, but doing so increases the complexity in the interlayer spin alignment because of competition between the inserted spin-layer interaction J_NNI and the interlayer through-space interaction J_NNNI if the magnitude of J_NNI is of the same order as J_NNNI with reciprocal signs of the respective interactions. Herein, systematic tuning of the magnetic phase variations by J_NNI and J_NNNI in two kinds of metal-variable isostructural series of supramolecular pillared layer magnets [MCp*₂][{Ru₂^II,II(2,3,5,6-F₄CO₂)₄}₂(TCNQ)] ⋅ 2 DCE (M=Co, Fe, Cr; 2,3,5,6-F₄PhCO₂⁻=2,3,5,6-tetrafluorobenzoate; TCNQ=7,7,8,8-tetracyano-p-quinodimethane; DCE=1,2-dichloroethane) and their DCE-free series, in which [MCp*₂]⁺ (Cp*=η⁵-C₅Me₅) species with S=0, 1/2, and 3/2 for M=Co, Fe, Cr, respectively, are sandwiched between ferrimagnetic layers of [{Ru₂}₂(TCNQ)]⁻, is demonstrated. The results showed that the flexible magnetic natures of these magnets are changeable in dependence on J_NNI and J_NNNI, as well as on interlayer inserted spins M.     

Total Syntheses of Juglorescein and Juglocombins A and B

Total syntheses of juglorescein and juglocombins A and B are reported. The highly oxygenated 6/6/5/6/6‐fused pentacyclic ring system of these natural products was constructed through a bioinspired dimerization of 1,4‐naphthoquinone. Notably, five new stereogenic centers were constructed in a single step by the dimerization reaction. The epoxide intermediate obtained from the dimerization was successfully converted into juglocombins A and B through photoinduced reduction of the epoxide, dehydration, and conversion of the resultant quinone into a hydroquinone derivative. The same epoxide intermediate was also converted into a dicarboxylic acid, which was transformed into juglorescein through intramolecular lactonization, hydrolysis of the resulting lactone, and removal of the protecting groups. Furthermore, the relative and absolute configurations of juglorescein and juglocombins A and B were determined.     

Synthesis and specific solvatochromism of D–π–A type pyridinium dye

Donor–π–acceptor (D–π–A) type pyridinium dye bearing an iodide ion as the counter anion that has been newly synthesized showed specific solvatochromism, leading to large bathochromic shift of absorption band in halogenated solvents: the bathochromic shifts of the D–π–A type pyridinium dye in halogenated solvents are larger than those of the non-halogenated solvents of low ?_r values. Investigation of absorption spectral measurement, ¹H NMR measurements, and semi-empirical molecular calculations (AM1 and INDO/S using the SCRF Onsager Model) revealed that the intramolecular charge transfer (ICT) characteristics of the D–π–A type pyridinium dye became stronger in the halogenated solvents. On the basis of the experimental results and the theoretical calculations, the influences of halogenated solvent on the large bathochromic shift of D–π–A type pyridinium dye are discussed. ^©2012 Elsevier Science. All rights reserved.     

Sugar nanowires based on cyclodextrin prepared by single particle nanofabrication technique

The direct formation of nanowires consisting of cyclodextrins by single particle nanofabrication technique (SPNT) is investigated in the present paper. Substittuted cyclodextrin (CD) derivatives and their composite with poly(4-bromostyrene) caused efficient cross-linking reaction upon irradiation, and gave nanostructures by SPNT. Successful visualization of the nanostructures by atomic force microscopy suggested drastic increase in the surface area of the materials based on CDs, leading to considerable increase in the selective adsorption efficiency of the molecules fit to the size of the hydrophobic holes of CDs.     

Analysis of MS/MS fragmentation of taxoids

The fragmentation pathways of seven types of taxoids were investigated by using a LC-MS/MS method, namely: (1) neutral taxoids with a C-4(20) double bond; (2) taxoids with a C-4(20) double bond and oxygenation at C-14; (3) 5-cinnamoyl taxoids with a C-4(20) double bond; (4) a basic taxoid with a C-4(20) double bond; (5) a taxoid with a C-4(20) epoxide; (6) taxoids with an oxetane ring; and (7) taxoids with an oxetane ring and a phenylisoserine C-13 side chain. Depending on the class of core structure and the substitution pattern, each taxoid gave either the molecular adduct ion [M+NH4]+ or [M+H]+. In the MS/MS, the molecular adduct ion gave characteristic product ions corresponding to the loss of water, acetic acid, benzoic acid, and cinnamic acid or the phenylisoserine group. These could reflect the difference of the substitutions and structural modifications and should be utilized for the structure elucidation oftaxoids by LC-MS.