Chemical and Pharmaceutical Bulletin
Past featured articles
Showing 1-20 articles out of 27 articles
  • Volume 65 (2017) Issue 11 Pages 1058-1077
    Discovery of a Novel Series of Pyrazolo[1,5-a]pyrimidine-Based Phosphodiesterase 2A Inhibitors Structurally Different from N-((1S)-1-(3-Fluoro-4-(trifluoromethoxy)phenyl)-2-methoxyethyl)-7-methoxy-2-oxo-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-carboxamide (TAK-915), for the Treatment of Cognitive Disorders

    It has been hypothesized that selective inhibition of phosphodiesterase (PDE) 2A could potentially be a novel approach to treat cognitive impairment in neuropsychiatric and neurodegenerative disorders through augmentation of cyclic nucleotide signaling pathways in brain regions associated with learning and memory. Following our earlier work, this article describes a drug design strategy for a new series of lead compounds structurally distinct from our clinical candidate 2 (TAK-915), and subsequent medicinal chemistry efforts to optimize potency, selectivity over other PDE families, and other preclinical properties including in vitro phototoxicity and in vivo rat plasma clearance. These efforts resulted in the discovery of N-((1S)-2-hydroxy-2-methyl-1-(4-(trifluoromethoxy)phenyl)propyl)-6-methyl-5-(3-methyl-1H-1,2,4-triazol-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (20), which robustly increased 3′,5′-cyclic guanosine monophosphate (cGMP) levels in the rat brain following an oral dose, and moreover, attenuated MK-801-induced episodic memory deficits in a passive avoidance task in rats. These data provide further support to the potential therapeutic utility of PDE2A inhibitors in enhancing cognitive performance.

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    This article describes the discovery of a new class of lead compound 5 by combining structural features from previously disclosed two chemotypes, represented by 3 and 4, and subsequent medicinal chemistry efforts to optimize potency, PDE selectivity, and other preclinical properties including in vitro phototoxicity and in vivo rat plasma clearance. These efforts culminated in the identification of 20, which demonstrated significant elevation of cGMP levels in rat brains, and moreover, attenuated MK-801-induced episodic memory deficits in a passive avoidance task in rats. These data provide further support to the potential therapeutic utility of PDE2A inhibitors in enhancing cognitive performance.

  • Volume 65 (2017) Issue 11 Pages 1051-1057
    Novel Non-steroidal Progesterone Receptor Ligands Based on m-Carborane Containing a Secondary Alcohol: Effect of Chirality on Ligand Activity

    The progesterone receptor (PR) controls various physiological processes, including the female reproductive system, and nonsteroidal PR ligands are considered to be drug candidates for treatment of various diseases without significant adverse effects. Here, we designed and synthesized m-carborane-based secondary alcohols and investigated their PR-ligand activity. All the synthesized alcohols exhibited PR-antagonistic activity at subnanomolar concentration. Among them, alcohols having a small alkyl side chain and a 4-cyanophenyl group also exhibited PR-agonistic activity in a relatively high concentration range. Optical resolution of secondary alcohols having a methyl side chain was performed, and the PR-ligand activity and PR-binding affinity of the purified enantiomers were examined. The chirality of the secondary alcohol appears to have a more significant influence on PR-agonistic activity than on antagonistic activity.

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    The authors designed and synthesized m-carborane-based secondary alcohols and investigated their PR-ligand activity. All the synthesized alcohols exhibited PR-antagonistic activity at subnanomolar concentration. Among them, alcohols having a small alkyl side chain and a 4-cyanophenyl group, such as 7a, also exhibited PR-agonistic activity in a relatively high concentration range. Optical resolution of secondary alcohols having a methyl side chain was performed, and the PR-ligand activity and PR-binding affinity of the purified enantiomers were examined. The chirality of the secondary alcohol appears to have a more significant influence on PR-agonistic activity than on antagonistic activity.

  • Volume 65 (2017) Issue 11 Pages 1035-1044
    Gelation Factors of Pectin for Development of a Powder Form of Gel, Dry Jelly, as a Novel Dosage Form

    Jellies for oral administration are dosage forms that contain water, as stipulated in the Japanese Pharmacopeia, and heat is generally applied to the jellies during the manufacturing process. Therefore, it is difficult to formulate drugs that may be affected adversely by water and/or heat. To solve this problem, we tried to develop a powder form of gel as a novel dosage form (dry jelly: jelly medicine extemporaneously prepared) that is converted to jelly after addition of water at the time of administration. For this purpose, a basic gel formulation consisting of pectin, glucono-δ-lactone, dibasic calcium phosphate hydrate, and sucrose was investigated to evaluate the critical factors affecting gelation phenomena. The gel form was developed by adjusting the amount of each component of the formulation and of water added. Gelation occurred even with hard water containing metal ions (hardness of approximately 304 mg/L), and no changes in gel hardness occurred. The desired gel hardness could be controlled by adjusting the amount of water. The gel hardness changed over time after the addition of water, but this change did not affect the dissolution behavior of drugs formulated in the dry jelly.

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    Jellies for oral administration are dosage forms that contain water and heat is generally applied to the jellies during the manufacturing process. Therefore, it is difficult to formulate drugs that may be affected adversely by water and/or heat. To solve this problem, the authors develop a powder form of gel as a novel dosage form (dry jelly) that is converted to gel after addition of water at the time of administration. The concept of dry jelly gelation by water addition is shown in graphical abstract. In the article, the critical factors affecting gelation phenomena as well as physical and drug dissolution properties of the gel prepared from drug-containing dry jelly are evaluated.

  • Volume 65 (2017) Issue 11 Pages 1028-1034
    Effect of Magnesium Stearate Mono- and Dihydrate Dispersibilities on Physical Properties of Tablets

    Magnesium stearate (MgSt), an essential lubricant in the manufacturing of tablets, is available in several hydrate forms with different qualities that affect the physical properties of tablets. This study examined MgSt mono- and dihydrates, and their effects on tablet dissolution, disintegration, and hardness. These effects were examined in terms of surface free energy and dispersibility. Dissolution, disintegration, and hardness were evaluated for tablets manufactured from powder mixtures of each MgSt hydrate form and other components, including ethenzamide as an active ingredient, using different mixing times. The surface energy was evaluated for MgSt mono- or dihydrate powder mixtures with a surface tensiometer. For dispersibility, the adhesion states of MgSt hydrates to other components were visually observed via near-infrared (NIR) chemical imaging. The dispersion behavior of MgSt hydrates was examined by quantitative evaluation of skewness and kurtosis of histograms, based on NIR images, and domain size estimated from their binary images. It was found that changes in those parameters related to dispersibility and dissolution differed between MgSt hydrates. This suggests that the quantitative determination of dispersibility of MgSt using NIR chemical imaging is a useful methodology for improving the understanding of tablet manufacturing blending processes.

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    Magnesium stearate (MgSt), an essential lubricant in the manufacturing of tablets, is available in several hydrate forms with different qualities that affect the physical properties of tablets. This article examined MgSt mono- and dihydrates, and their effects on tablet dissolution, disintegration, and hardness were examined in terms of surface free energy and dispersibility. It was found that changes in those parameters related to dispersibility and dissolution differed between MgSt hydrates. This suggests that the quantitative determination of dispersibility of MgSt using NIR-CI is a useful methodology for improving the understanding of tablet manufacturing blending processes.

  • Volume 65 (2017) Issue 11 Pages 1004-1010
    Protection of Tong-Qiao-Huo-Xue Decoction against Cerebral Ischemic Injury through Reduction Blood–Brain Barrier Permeability

    Tong-Qiao-Huo-Xue Decoction (TQHXD) is a classical prescription in traditional Chinese medicine treating blood stagnation in the head and facial channels, especially cerebral ischemia. We investigate the effect of TQHXD on the expressions of related proteins of the blood–brain barrier (BBB) and analysis of constituents in the cerebrospinal fluid (CSF) on cerebral ischemic model rats. Here, we demonstrate that TQHXD protected the hippocampus neurons, reduced the opening of tight junction (TJ) and decreased the permeability of BBB by up-regulating ZO-1, occludin, claudin-5 expressions, down-regulating aquaporin-4 (AQP-4) and matrix metalloproteinase-9 (MMP-9) expressions. Meanwhile, we detected Muscone, ligustilide and hydroxysafflor yellow A in CSF on cerebral ischemic model rats. These compounds could be identified as the main active ingredients of TQHXD on protecting the damaged BBB. These results suggest that TQHXD could act as a potential neuroprotective agent against BBB damage for cerebral ischemia.

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    The authors investigate the effect of TQHXD on the expressions of related proteins of the blood-brain barrier (BBB) and analysis of constituents in the cerebrospinal fluid (CSF) on cerebral ischemic rats. They found that TQHXD could up-regulate ZO-1, occludin, claudin-5 expressions and down-regulate AQP-4, MMP-9 expressions. Moreover, muscone, ligustilide and hydroxysafflor yellow A in CSF were also detected. These compounds could be identified as the main active ingredients of TQHXD on protecting the damaged BBB.

  • Volume 65 (2017) Issue 10 Pages 967-972
    Prediction of Dissolution Data Integrated in Tablet Database Using Four-Layered Artificial Neural Networks

    A large number of dissolution data were measured and integrated into a previously constructed tablet database composed of 14 kinds of compounds as model active pharmaceutical ingredients (APIs) with contents ranging from 10 to 80%. The database has contained physicochemical and powder properties of APIs, together with basic physical attributes of tablets such as the tensile strength and the disintegration time. In order to enhance the value of this database, drug dissolution data are essential to improving key information for designing tablet formulations. A four-layered artificial neural network (4LNN), newly implemented in commercially available software, was employed to predict dissolution data from physicochemical and powder properties of APIs. Our results showed that an excellent model for the prediction of dissolution data was achieved with 4LNN method. The function of 4LNN was appreciably better than that of conventional three-layered model, despite both models adopting the same number of nodes and algorithms for activation functions. Furthermore, linear regression models resulted in poor prediction of dissolution data.

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    A four-layered artificial neural network (4LNN) was employed to predict dissolution data from physicochemical and powder properties of active pharmaceutical ingredients (APIs) formulated in various kinds of tablets. Causal factors of APIs in the input layer were simplified into the nodes in the 1st hidden layer, properly integrated information would then be transferred to the nodes in the 2nd hidden layer, and finally the secured outcome was delivered in the output layer. An excellent model for the prediction of dissolution data was achieved with 4LNN method. The function of 4LNN was appreciably better than that of conventional three-layered model.



  • Volume 65 (2017) Issue 10 Pages 950-958
    Design, Synthesis and Antiproliferative Evaluation of Novel Disulfides Containing 1,3,4-Thiadiazole Moiety

    A series of novel disulfides containing 1,3,4-thiadiazole moiety were designed, synthesized, and the structures of all products were identified by spectral data (IR, NMR, and high resolution (HR)-MS). Their in vitro antiproliferative activities were evaluated using 2-(2-methoxy-4-nitro-phenyl)-3-(4-nitro-phenyl)-5-(2,4-disulfopheyl)-2H-tetrazolium monosodium salt (CCK-8) assay against human cancer cell lines, A549 (human lung cancer cell), HeLa (human cervical cancer cell), SMMC-7721 (human liver cancer cell) and normal cell lines L929. The bioassay results indicated that most of the tested compounds 6a–k, 7a–k and 8a–k exhibited antiproliferation with different degrees, and some compounds showed better effects than positive control 5-fluorouracil (5-FU) against various cancer cell lines. Among these compounds, compound 6e exhibited the most potent inhibitory activity against A549 cells with IC50 value of 3.62 µM. Compounds 6i, 7a, 7g, 8a and 8b showed significantly antiproliferative activities against HeLa cells with IC50 values of 3.88, 3.76, 3.59, 3.38 and 3.12 µM, respectively. Compounds 6a, 7a and 8a owned high antiproliferative activities against SMMC-7721 cells with IC50 values of 2.54, 2.69 and 2.31 µM, respectively. Furthermore, all of the tested compounds showed weak cytotoxic effect against the normal cell lines L929. Based on the preliminary results, the substituent groups are vital for improving the potency and selectivity of this class of compounds.

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    In the article, a series of novel disulfides containing 1,3,4-thiadiazole moiety were synthesized and evaluated for their in vitro antiproliferative activities using CCK-8 assay against human cancer cell lines A549, HeLa, SMMC-7721 and normal cell lines L929. The bioassay results indicated that most of the tested compounds exhibited antiproliferation with different degrees, and some compounds inhibited the proliferation better than positive control 5-fluorouracil against various cancer cell lines. Furthermore, all compounds showed weak cytotoxic effect against L929 cells. Therefore, the results suggest that the substituent groups are vital for improving the potency and selectivity of this class of compounds.



  • Volume 65 (2017) Issue 10 Pages 945-949
    Rapid Analysis of DOXIL Stability and Drug Release from DOXIL by HPLC Using a Glycidyl Methacrylate-Coated Monolithic Column

    In recent years, nanomedicines have received growing attention in a range of medical applications, including selective drug delivery technology. In this context, the analysis of liposome stability and drug release from liposomes is of particular importance, as the efficacy of a nanomedicine is determined by the release of the encapsulated drug. We investigated the influence of the surrounding environment on the stability and release of the encapsulated drug (i.e., doxorubicin) from DOXIL. Thus, for the purpose of this study, we selected the liposomal anticancer drug, DOXIL, as a typical nanomedicine, and investigated the influence of the surrounding environment on release of doxorubicin from DOXIL. We found that two pathways existed for doxorubicin release, namely the collapse of DOXIL, and an increase in the permeability of the lipid bilayer. DOXIL collapse occurred upon the addition of high concentrations (>60%) of a methanol solution, while an increase in permeability occurred at temperatures above the phase transition temperature of the DOXIL lipid bilayer, under basic conditions, and in the presence of membrane-permeable bases (e.g., Tris). As DOXIL is particularly stable and limited collapse of DOXIL occurred under physiological conditions, it is expected that doxorubicin release within the body took place through permeability changes in the lipid bilayer of the DOXIL structure.

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    The authors described that membrane-permeable bases accelerated the release of encapsulated drug, doxorubicin, from DOXIL by using a HPLC column for nanomedicine analysis.



  • Volume 65 (2017) Issue 10 Pages 940-944
    Versatile Amine-Promoted Mild Methanolysis of 3,5-Dinitrobenzoates and Its Application to the Synthesis of Colorado Potato Beetle Pheromone

    A mild deacylation method for 3,5-dinitrobenzoates using methanolic solutions of amines, such as dialkylamines, was developed. The method’s versatility was confirmed by applying it to synthesizing a key intermediate for Colorado potato beetle pheromone.

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    In the article, a mild deacylation method for 3,5-dinitrobenzoates, which are often used to improve their diastereomeric or enantiomeric purities by recrystallization and also widely used as a pro-nucleophile in the Mitsunobu reaction, has been developed by using methanolic solutions of amines, such as dialkylamines. Removal of dinitrobenzoyl groups undergoes without affecting existing acetyl groups and also without affecting stereochemistry in α-hydroxy ketone. Encouraged by the promising versatility, the authors successfully applied this method to the efficient asymmetric synthesis of Colorado potato beetle pheromone.



  • Volume 65 (2017) Issue 10 Pages 930-939
    Microtropins Q–W, ent-Labdane Glucosides: Microtropiosides G–I, Ursane-Type Triterpene Diglucoside and Flavonol Glycoside from the Leaves of Microtropis japonica

    Microtropins Q–W, (2S,3R)-2-ethyl-2,3-dihydroxybutyrate of various glucosides and glucose, as well as three ent-labdane diterpenoid glucosides, named microtropiosides G, H and I, an ursane-type triterpene diglucoside and a flavonoid glycoside were isolated from the MeOH extract of the leaves of Microtropis japonica. The structure of microtropioside A, also isolated from the branches of M. japonica, was elucidated spectroscopically in a previous experiment and was found to possess a rare seven-membered oxyrane ring. Its structure was confirmed by X-ray crystallographic analysis of its pentaacetate.

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    Since an antileukemic ansa macrolide, maytansine was first isolated from Maytenus ovata, plants belong to Celastraceae draw the attention of natural product chemists. The authors focused on the plants collected in Okinawa Islands, and Celastraceae plant, Microtropis japonica was chosen for the target material. ent-Labdane glycoside and 6'-O-(2"S,3R")-2"-ethyl-2",3"-dihydroxybutyrates of aliphatic alcohol β-D-glucosides branches have been isolated from leaves and branches respectively. Current investigation of leaves afforded further ent-labdane glucosides, 6'-O-2"-ethyl-2",3"-dihydroxybutyrates of aliphatic alcohol β-D-glucosides, ursane-type triterpene diglucoside, and flavonol glycoside.





  • Volume 65 (2017) Issue 9 Pages 862-868
    Ethereal C–O Bond Cleavage Mediated by Ni(0)-Ate Complex: A DFT Study

    Density functional theory calculations were performed to explore the mechanism of Ni-catalyzed cross-coupling reactions involving organo-lithium and -zinc reagents through ethereal C–O bond cleavage. Based on this work, together with our previous mechanistic study on etheric Kumada–Tamao reaction, we identify and characterize a novel catalytic cycle for cross-coupling mediated by Ni(0)-ate complex.

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    Density functional theory calculations were performed to explore the mechanism of Ni-catalyzed cross-coupling reactions involving organo-lithium and -zinc reagents though ethereal C–O bond cleavage. In comparison with our previous mechanistic study on etheric Kumada–Tamao reaction, it shows that the the Ni(0)-ate complex-mediated reaction pathway is a new and general mechanism for ethereal cross-coupling reactions, which can well explain the experimental findings for several ethereal C–O bond cleavage couplings.  The present work also suggests that the anionic character of organometallic nucleophiles can change oxidative addition mechanisms/pathways, which may provide new reactivity and selectivity.



  • Volume 65 (2017) Issue 9 Pages 848-853
    Effect of the External Lubrication Method for a Rotary Tablet Press on the Adhesion of the Film Coating Layer

    External lubrication is a useful method which reduces the adhesion of powder to punches and dies by spraying lubricants during the tableting process. However, no information is available on whether the tablets prepared using an external lubrication system can be applicable for a film coating process. In this study, we evaluated the adhesion force of the film coating layer to the surface of tablets prepared using an external lubrication method, compared with those prepared using internal lubrication method. We also evaluated wettability, roughness and lubricant distribution state on the tablet surface before film coating, and investigated the relationship between peeling of the film coating layer and these tablet surface properties. Increasing lubrication through the external lubrication method decreased wettability of the tablet surface. However, no change was observed in the adhesion force of the film coating layer. On the other hand, increasing lubrication through the internal lubrication method, decreased both wettability of the tablet surface and the adhesion force of the film coating layer. The magnesium stearate distribution state on the tablet surface was assessed using an X-ray fluorescent analyzer and lubricant agglomerates were observed in the case of the internal lubrication method. However, the lubricant was uniformly dispersed in the external lubrication samples. These results indicate that the distribution state of the lubricant affects the adhesion force of the film coating layer, and external lubrication maintained sufficient lubricity and adhesion force of the film coating layer with a small amount of lubricant.

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    We evaluated the adhesion force of the film coating layer to the surface of tablets prepared using an external lubrication method. Increasing lubrication decreased wettability of the tablet surface. However, no change was observed in the adhesion force of the film coating layer. The magnesium stearate distribution state on the tablet surface was assessed and the lubricant was uniformly dispersed in the external lubrication samples. The distribution state of the lubricant affects the adhesion force of the film coating layer, and external lubrication maintained sufficient lubricity and adhesion force of the film coating layer with a small amount of lubricant.



  • Volume 65 (2017) Issue 9 Pages 840-847
    Four New Lignans and IL-2 Inhibitors from Magnoliae Flos

    Four new lignans, a furofuran lignan medioresinol B (10) and three tetrahydrofuran lignans kobusinol C (16), 7′-methoxy magnostellin A (21), and mangnostellin D (23), along with 19 known lignans, were isolated from the flower buds of Magnolia biondii PAMP. The structures of the isolates were elucidated using spectroscopic analysis, mainly one- and two-dimensional NMR, high resolution-MS, and circular dichroism techniques as well as Mosher’s esterification method. The anti-allergic effects of the isolated compounds were evaluated by analyzing the inhibition of interleukin-2 (IL-2) expression in Jurkat T-cells. Compounds 1114 reduced IL-2 expression in a dose-dependent manner.

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    Four new lignans, a furofuran lignan medioresinol B (10) and three tetrahydrofuran lignans kobusinol C (16), 7'-methoxy magnostellin A (21), and mangnostellin D (23), along with 19 known lignans, were isolated from the flower buds of Magnolia biondii Pamp. The structures of the isolates were elucidated using spectroscopic analysis, mainly one- and two-dimensional NMR, high resolution mass spectrometry, and circular dichroism techniques as well as Mosher’s esterification method. The anti-allergic effects of the isolated compounds were evaluated by analyzing the inhibition of interleukin-2 (IL-2) expression in Jurkat T-cells. Compounds 1114 reduced IL-2 expression in a dose-dependent manner.



  • Volume 65 (2017) Issue 8 Pages 796-800
    7-Hydroxy-3-methyleneisoindolin-1-one as a New ESIPT-Fluorescent Probe to Monitor Aqueous Environments

    A 7-hydroxy derivative of 3-methyleneisoindolin-1-one 1 was synthesized and its properties as a new fluorophore undergoing excited-state intramolecular proton transfer (ESIPT) were investigated. In alcohols and dimethylsulfoxide, 1 exhibited dual emission at ca. 380 and 525−540 nm when excited at ca. 336 nm, which agreed well with the density functional theory (DFT) and time-dependent (TD)-DFT-calculated emission predictions of 1 and its ESIPT tautomer. In aqueous solutions at near neutral pH, 1 exhibited a broad emission band at ca. 497 nm, presumably caused by the overlap of emissions from 1 and the excited state phenolate species of 1. In binary mixtures of H2O and EtOH, the wavelength and intensity of fluorescence maxima were dependent on the dielectric constant of the solvent, suggesting that 1 could be applied as a fluorescent probe to monitor aqueous environments.

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    Fluorophores undergoing excited-state intramolecular proton transfer (ESIPT) exhibit several unique characteristics. In the paper, a range of 7-hydroxy-3-methyleneisoindolin-1-ones is investigated as new ESIPT fluorophores. In fact, dual emission is observed in alcohols and DMSO; ~380 and ~530 nm (exc. = ~336 nm), and a single emission is observed (~500 nm) in EtOH-H2O binary mixtures. Furthermore, the wavelength of fluorescence maxima is dependent on the dielectric constant of the solvent, suggesting their potential utility for monitoring aqueous environments.

  • Volume 65 (2017) Issue 8 Pages 784-795
    Efficient Synthesis of Heterocyclic Flavonoids with Hedgehog Signal Inhibitory Activity

    The hedgehog (Hh) signaling pathway performs important roles in embryonic development and cellular proliferation and differentiation. However, in many cancer cells Hh signaling is aberrantly activated, which has provided a strong impetus for the development of Hh pathway inhibitors. To address this, we synthesized a series of heterocyclic flavonoids and evaluated their Hh signaling inhibitory activity on cancer cell lines using our cell-based assay system. Of the synthetic flavonoids, compounds 4a and g showed good inhibitory activity (IC50 was 16.8 and 21.8 µM, respectively), and were cytotoxic toward human pancreatic (PANC1) and prostate (DU145) cancer cells in which Hh signaling was activated. Compounds 4a and g had moderate selectivity against PANC1 cells. Western blotting analyses revealed that PTCH and GLI1 expression was reduced after treatment with these compounds. Overall, these synthetic flavonoids represent promising new additions to our expanding panel of Hh pathway inhibitors, and with further development these molecules may ultimately be considered for clinical use.

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    The hedgehog (Hh) signaling pathway performs important roles in cellular process, however, in many cancer cells Hh signaling is aberrantly activated, which has provided a strong impetus for the development of Hh pathway inhibitors. In the paper, a series of heterocyclic flavonoids are prepared and evaluate their Hh signaling inhibitory activity. As a result, some of the synthetic flavonoids show good Hh inhibitory activity as well as cytotoxicity toward human cancer cells. Western blotting analyses also reveal that PTCH and GLI1 expression is reduced. 

  • Volume 65 (2017) Issue 8 Pages 726-731
    Melt Adsorption as a Manufacturing Method for Fine Particles of Wax Matrices without Any Agglomerates

    We have focused on melt adsorption as manufacture method of wax matrices to control particles size of granules more easily than melt granulation. The purpose of present study was to investigate the possibility of identifying a hydrophobic material with a low melting point, currently used as a meltable binder of melt granulation, to apply as a novel carrier in melt adsorption. Glyceryl monostearate (GM) and stearic acid (SA) were selected as candidate hydrophobic materials with low melting points. Neusilin US2 (US2), with a particle diameter of around 100 µm was selected as a surface adsorbent, while dibasic calcium phosphate dihydrate (DCPD), was used as a non-adsorbent control to prepare melting granules as a standard for comparison. We prepared granules containing ibuprofen (IBU) by melt adsorption or melt granulation and evaluated the particle size, physical properties and crystallinity of granules. Compared with melt granulation using DCPD, melt adsorption can be performed over a wide range of 14 to 70% for the ratio of molten components. Moreover, the particle size; d50 of obtained granules was 100–200 µm, and these physical properties showed good flowability and roundness. The process of melt adsorption did not affect the crystalline form of IBU. Therefore, the present study has demonstrated for the first time that melt adsorption using a hydrophobic material, GM or SA, has the potential capability to control the particle size of granules and offers the possibility of application as a novel controlled release technique.

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    This paper focuses on melt adsorption as manufacture method of wax matrices to control particles size of granules more easily than melt granulation, and demonstrated for the first time that melt adsorption using a hydrophobic material has the potential capability to control the particle size of granules and offers the possibility of application as a novel controlled release technique.

  • Volume 65 (2017) Issue 7 Pages 605-610
    Potential of Enzymomics Methodologies to Characterize Disease-Related Protein Functions

    Enzymatic functions are often altered during disease onset and progression, and therefore chemical–biological studies, which utilize chemical knowledge to discover novel protein functions, are often employed to find proteins with functions closely related to disease phenotypes. Such studies are known as forward chemical–biological approaches and form part of the emerging field of enzymomics (omics of enzymes). This review provides an overview of methodologies available for discovering and characterizing disease-related alterations of enzymatic functions and prospects for the future.

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    Cellular functions are mediated by a great variety of enzymes, and altered enzymatic functions are often observed during disease onset and progression. Therefore, discovering the novel connection between the functions of enzymes and specified diseases is the key to developing novel diagnostic methods, as well as therapeutic drugs.  In this review, we describe the recently advancing field of chemical biology that aims to discover and characterize disease-related alternation of enzymatic functions, which can be termed as “enzym-omics (omics of enzymes)”.  The review covers several key technologies that can be considered as the representative experimental systems used for this purpose.  

  • Volume 65 (2017) Issue 6 Pages 511-523
    Creation of Novel Cyclization Methods Using sp-Hybridized Carbon Units and Syntheses of Bioactive Compounds

    Some recent results on the development of new and reliable procedures for the construction of diverse ring systems based on the chemistry of sp-hybridized species, especially allene functionality, are described. This review includes: (i) synthesis of the multi-cyclic skeletons by combination of the π-component of allene with suitable other π-components such as alkyne, alkene, or additional allene under Rh-catalyzed conditions; (ii) synthesis of heterocycles as well as carbocycles by reaction of the sp-hybridized center of allene with some nucleophiles in an endo-mode manner; and (iii) total syntheses of natural products and related compounds from the sp-hybridized starting materials.

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    In this review, new and reliable procedures for the construction of diverse ring systems based on the chemistry of sp-hybridized species are described. The synthetic application includes (i) multi-cyclic skeletons by the Rh-catalyzed reaction of allenes with other π-components such as alkyne, alkene, and allene, (ii) hetero- and carbocycles from appropriate allenes and nucleophiles, and (iii) natural products and related compounds.

  • Volume 65 (2017) Issue 5 Pages 409-425
    Palladium(0)-Catalyzed Benzylic C(sp3)–H Functionalization for the Concise Synthesis of Heterocycles and Its Applications

    C–H functionalization reactions involve the activation of otherwise unreactive C–H bonds, and represent atom economical methods for the direct transformation of simple substrates to complex molecules. While transition metal-catalyzed C(sp2)–H functionalization reactions are regularly used in synthesis, C(sp3)–H functionalization is rarely applied to the synthesis of complex natural products because of the difficulties associated with controlling selectivity. With this in mind, we focused on the development of new palladium (Pd)(0)-catalyzed C(sp3)–H functionalization reactions for the synthesis of complex molecules, resulting in several new methods capable of solving these problems. We initially developed a concise synthetic method for the facile construction of oxindoles and spirooxindoles via a Pd-catalyzed benzylic C(sp3)–H functionalization reaction. This method was subsequently extended to the synthesis of various heterocycles, including 2-arylindoles, benzocarbazole, indolocarbazole, indoloquinazolinone, and indoloquinazolinedione, as well as the total synthesis of several pyrrolophenanthridine alkaloids without the need for any protecting groups. This method was also successfully applied to the synthesis of the right-hand fragment of benzohopane from tetrahydro-2H-fluorene, which was constructed by a Pd-catalyzed benzylic C(sp3)–H functionalization. In this review, we provide a detailed discussion of our most recent investigations pertaining to Pd(0)-catalyzed benzylic C(sp3)–H functionalization.

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    This review summarizes author’s recent reports on Pd(0)-catalyzed benzylic C(sp3)-H functionalization for the synthesis of various heterocycles including oxindoles, spirooxindoles, 2-arylindoles, benzocarbazoles, indolocarbazoles, and indoloquinazolinones. The key feature would be a chemoselective C(sp3)-H activation in the oxindole synthesis. The developed method was successfully applied to the total synthesis of several pyrrolophenanthridine alkaloids as well as a synthesis of the right-hand fragment of benzohopane.

  • Volume 65 (2017) Issue 4 Pages 356-358
    Alternative Formation of Red-Shifted Channelrhodopsins: Noncovalent Incorporation with Retinal-Based Enamine-Type Schiff Bases and Mutated Channelopsin

    Red-shifted channelrhodopsins (ChRs) are attractive for optogenetic tools. We developed a new type of red-shifted ChRs that utilized noncovalent incorporation of retinal and 3,4-dehydroretinal-based enamine-type Schiff bases and mutated channelopsin, C1C2-K296G. These ChRs exhibited absorption maxima that were shifted 10–30 nm toward longer wavelengths than that of C1C2-ChR regenerated with all-trans-retinal.

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    In this communication, development of a new type of red-shifted channelrhodopsins (ChRs) is described. Optogenetics is a powerful new technique which allows control of neuronal activity by light, and ChRs are now widely used in optogenetics due to their function of a light-gated cation channel. In neuroscience, ChRs responding to a long-wavelength light are eagerly required, because ChRs now used are maximally sensitive to green and blue light, and does not penetrate tissues. Here developed new type of ChRs model consisted of red-shifted chromophores (retinal-based enamine-type Schiff bases) and mutated channelopsin (C1C2-K296G), in which chromophores were incorporated noncovalently. Thus prepared new ChRs exhibited absorption maxima that were 10-30 nm red-shifted compared with the original C1C2.



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