Chemical and Pharmaceutical Bulletin
Online ISSN : 1347-5223
Print ISSN : 0009-2363
ISSN-L : 0009-2363
Volume 64 , Issue 9
Showing 1-25 articles out of 25 articles from the selected issue
Review
  • Hidehiko Nakagawa
    2016 Volume 64 Issue 9 Pages 1249-1255
    Published: September 01, 2016
    Released: September 01, 2016
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    Nitric oxide (NO) is a gas that plays various roles in physiological signal transduction, for example, in vasodilation, neural transmission, and biodefence. Recently, other gaseous signal mediators such as carbon monoxide (CO) and hydrogen sulfide (H2S) have also been found to have important biological activities. Since experimental studies with gaseous mediators are difficult, chemicals that enable controlled release of these gases are indispensable. We have developed a range of photocontrollable releasers that generate NO, H2S, and related species with fine spatiotemporal control, and we have also employed these caged compounds in various applications. This paper briefly reviews our work on photocontrollable NO, H2S, and HNO releasers, and presents some typical applications illustrating the suitability of our compounds for controlled release of these biologically active species in cellular and tissue systems. These compounds also appear to have potential for future therapeutic applications.

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    Editor’s picks

    This review summarizes the authors’ recent work on photocontrolable releases, or caged compounds, which can release specific biological mediators such as NO, HNO, and H2S, upon photoirradiation, and a wide range of colors (wavelengths), from ultraviolet to near infrared, are available depending on the properties of the compounds. These photocontrollable compounds realized the spatiotemporal control of the release, and the manipulation of biological responses specific for the mediators. One of our photocontrollable NO releasers with the near infrared two photon excitation succeeded to control vasodilation in the anesthetized mouse brain with spatiotemporal resolution, and the ex vivo rat aorta relaxation was also achieved with another controllable NO releaser by the visible light irradiation.

Regular Articles
  • Takatoshi Sakamoto, Shigeto Kachi, Shohei Nakamura, Shinsuke Miki, Hid ...
    2016 Volume 64 Issue 9 Pages 1256-1261
    Published: September 01, 2016
    Released: September 01, 2016
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    This study investigated how the inclusion of magnesium oxide (MgO) maintained tablet hardness during storage in an unpackaged state. Tablets were prepared with a range of MgO levels and stored at 40°C with 75% relative humidity for up to 14 d. The hardness of tablets prepared without MgO decreased over time. The amount of added MgO was positively associated with tablet hardness and mass from an early stage during storage. Investigation of the water sorption properties of the tablet components showed that carmellose water sorption correlated positively with the relative humidity, while MgO absorbed and retained moisture, even when the relative humidity was reduced. In tablets prepared using only MgO, a petal- or plate-like material was observed during storage. Fourier transform infrared spectrophotometry showed that this material was hydromagnesite, produced when MgO reacts with water and CO2. The estimated level of hydromagnesite at each time-point showed a significant negative correlation with tablet porosity. These results suggested that MgO suppressed storage-associated softening by absorbing moisture from the environment. The conversion of MgO to hydromagnesite results in solid bridge formation between the powder particles comprising the tablets, suppressing the storage-related increase in volume and increasing tablet hardness.

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  • Eiko Yasui, Jyunpei Tsuda, Satoshi Ohnuki, Shinji Nagumo
    2016 Volume 64 Issue 9 Pages 1262-1267
    Published: September 01, 2016
    Released: September 01, 2016
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    Pyrrole-2,5-dicarboxylates were rapidly and selectively reduced to the corresponding mono-alcohol using 3 eq of diisobutylaluminum hydride at 0°C. Pyrrole-2,4-dicarboxylate showed the same reactivity; however, the selectivity decreased with pyrrole-3,4-dicarboxylate. When the nitrogen atom of the pyrrole-2,5-dicarboxylate is protected with a benzyl group, selective mono-reduction does not occur. Considering that furan-2,5-dicarboxylates did not give the corresponding mono-alcohol under the same conditions, the unprotected nitrogen atom of pyrrole apparently plays an important role in this selective mono-reduction.

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  • Martha Moheb Morcoss, Nada Sayed Abdelwahab, Nouruddin Wagieh Ali, Moh ...
    2016 Volume 64 Issue 9 Pages 1268-1274
    Published: September 01, 2016
    Released: September 01, 2016
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    Two selective spectrophotometric and TLC-densitometric methods were developed for determination of mesalazine (ME) and its two toxic impurities, 4-amino phenol (4AP) and salicylic acid (SA) without preliminary separation. The proposed methods are: ratio difference in the subtracted spectra (RDSS) {Method 1}, area under the curve (AUC) {Method 2} and TLC-densitometric {Method 3}. In method {1} combination of measuring the amplitude of the constant at 350 nm (using standard spectrum of 10 µg/mL ME as a divisor) and ratio difference in the subtracted ratio spectrum for determination of 4AP and SA using the ratio difference at 221.4 and 242.2 nm, 230 and 241.2 nm, respectively. In method {2} ME was determined by direct measuring the AUC in the wavelength range of 350–370 nm while the impurities could be determined by dividing their spectra by standard spectrum of 10 µg/mL ME then interference from ME was eliminated by subtracting the amplitude of the constant at 350 nm then multiplying by the divisor. AUC in the range of 220–230 and 235–245 nm was used for measuring concentrations of 4AP and SA. On the other hand, the third method {3} is TLC–densitometric method at which chromatographic separation was achieved using ethyl acetate–methanol–triethylamine (8.5 : 2 : 0.7, v/v/v) as a developing system with UV scanning at 230 nm. The validation of the proposed methods was performed according to International Conference on Harmonization (ICH) guidelines. No significant difference was found when these methods were compared to the reported one.

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  • Sayaka Masada, Yutaka Takahashi, Yukihiro Goda, Takashi Hakamatsuka
    2016 Volume 64 Issue 9 Pages 1275-1280
    Published: September 01, 2016
    Released: September 01, 2016
    [Advance publication] Released: June 25, 2016
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    Red vine leaf extracts (RVLEs) have traditionally been used for leg wellness and are now standardized to be used as OTC drugs in Europe. In Japan, one brand of RVLE products was recently approved as a direct OTC drug, and RVLEs are still used as ingredients in health food products. Since there is no mandated criterion for the quality of health food products in Japan, the consistent quality and composition of these products are not assured. Here we analyzed OTC drug and health food products containing RVLEs with different lot numbers by LC/MS. Subsequent multivariate analyses clearly indicated that the quality of the health food products was highly variable compared to that of the drug products. Surprisingly, the component contents in the health foods were different even within a same lot in a same brand. The quantitative analyses of flavonols and stilbene derivatives in the drugs and health foods indicated that the concentration of each substance was kept constant in the drugs but not in the health foods. These results strongly indicated that the quality of RVLEs as a whole was not properly controlled in the manufacturing process of health foods. Since RVLE is an active ingredient with pharmaceutical evidences and is used for drugs, the proper regulation for ensuring the consistent quality of RVLEs from product to product would be recommended even in the health foods.

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  • Sulunay Parlar, Gulsah Bayraktar, Ayse Hande Tarikogullari, Vildan Alp ...
    2016 Volume 64 Issue 9 Pages 1281-1287
    Published: September 01, 2016
    Released: September 01, 2016
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    Supplementary material

    A series of pyridinium salts bearing alkylphenyl groups at 1 position and hydrazone structure at 4 position of the pyridinium ring were synthesized and evaluated for the inhibition of both acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) enzymes. The cholinesterase (ChE) inhibitory activity studies were carried out by using the Ellman’s colorimetric method. All compounds displayed considerable AChE and BuChE inhibitory activity and some of the compounds manifested remarkable anti-AChE activity compared to the reference compound, galantamine. Among the title compounds, the series including benzofuran aromatic ring exhibited the best inhibitory activity both on AChE and BuChE enzymes. Compound 3b, 4-[2-(1-(benzofuran-2-yl)ethylidene)hydrazinyl]-1-(3-phenylpropyl)pyridinium bromide, was the most active compound with IC50 value of 0.23 (0.24) µM against enantiomeric excess (ee)AChE (human (h)AChE) while compound 3a, 4-[2-(1-(benzofuran-2-yl)ethylidene)hydrazinyl]-1-phenethylpyridinium bromide, was the most active compound with IC50 value of 0.95 µM against BuChE. Moreover, 3a and b exhibited higher activity than the reference compound galantamine (eeAChE (hAChE) IC50 0.43 (0.52) µM; BuChE IC50 14.92 µM). Molecular docking studies were carried out on 3b having highest inhibitory activity against AChE.

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  • Hironori Tanaka, Yasunori Iwao, Masahiro Izumikawa, Syusuke Sano, Hito ...
    2016 Volume 64 Issue 9 Pages 1288-1297
    Published: September 01, 2016
    Released: September 01, 2016
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    In the present study, a microwave treatment process has been applied to prepare orally disintegrating tablets (ODTs) containing powdered tea leaves with enriched levels of the anti-inflammatory compounds such as chafuroside A (CFA) and chafuroside B (CFB). The use of distilled water as the adsorbed and granulation solvents in this preparation process afforded tablets with a long disintegration time (more than 120 s). The CFA and CFB contents of these tablets did not also change after 4 min of microwave irradiation due to the tablet temperature, which only increased to 100°C. In contrast, the tablet temperature increased up to 140°C after 3 min of microwave irradiation when a 1.68 M Na2HPO4 solution instead of distilled water. Notably, the disintegration time of these tablets was considerably improved (less than 20 s) compared with the microwave-untreated tablets, and there were 7- and 11-fold increases in their CFA and CFB contents. In addition, the operational conditions for the preparation of the tablets were optimized by face-centered composite design based on the following criteria: tablet hardness greater than 13 N, disintegration time less than 30 s and friability less than 0.5%. The requirements translated into X1 (the amount of granulation solvent), X2 (tableting pressure) and X3 (content of the powdered tea leaves) values of 45%, 0.43 kN and 32%, respectively, and the ODTs containing powdered tea leaves prepared under these optimized conditions were found to show excellent tablet properties and contain enriched levels of CFA and CFB.

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  • Jung-Sub Shin, Hee-Won Park, Gyo In, Hyun Kyu Seo, Tae Hyung Won, Kyou ...
    2016 Volume 64 Issue 9 Pages 1298-1303
    Published: September 01, 2016
    Released: September 01, 2016
    [Advance publication] Released: July 05, 2016
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    Supplementary material

    Panax ginseng C.A. MEYER is one of the most popular medicinal herbs in Asia and the chemical constituents are changed by processing methods such as steaming or sun drying. Metabolomic analysis was performed to distinguish age discrimination of four- and six-year-old red ginseng using ultra-performance liquid chromatography quadruple time of flight mass spectrometry (UPLC-QToF-MS) with multivariate statistical analysis. Principal component analysis (PCA) showed clear discrimination between extracts of red ginseng of different ages and suggest totally six discrimination markers (two for four-year-old and four for six-year-old red ginseng). Among these, one marker was isolated and the structure determined by NMR spectroscopic analysis was 13-cis-docosenamide (marker 6-1) from six-year-old red ginseng. This is the first report of a metabolomic study regarding the age differentiation of red ginseng using UPLC-QToF-MS and determination of the structure of the marker. These results will contribute to the quality control and standardization as well as provide a scientific basis for pharmacological research on red ginseng.

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  • Yuuki Kasashima, Keiichi Yoshihara, Takehiko Yasuji, Kazuhiro Sako, Sh ...
    2016 Volume 64 Issue 9 Pages 1304-1309
    Published: September 01, 2016
    Released: September 01, 2016
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    The objective of this study was to establish the key factor of the lauryl sulfate (LS) salt/complex for sustained release of a hydrophilic drug at various physiological pH levels. Mirabegron is a hydrophilic drug that exhibits pH-dependent solubility. Sodium lauryl sulfate (SLS) bound to mirabegron in a stoichiometric manner. The formation of the LS salt/complex significantly reduced mirabegron solubility and helped achieve sustained release of mirabegron over a wide range of pH levels. In addition to SLS, other additives containing a sulfate group formed salts/complexes with mirabegron and reduced its solubility at different pH levels. Furthermore, octyl sulfate (OS), myristyl sulfate (MS), and cetyl sulfate (CS) salts/complexes, which contain alkyl chains of different lengths, showed a lower solubility than mirabegron and promoted sustained release of mirabegron. The rank order of solubility and dissolution rate were as follows: OS salt/complex>LS salt/complex>MS salt/complex>CS salt/complex, which corresponded to the rank of alkyl chain lengths. We conclude that the presence of a sulfate group and the length of the alkyl chain are key factors of the LS salt/complex for sustained release of a hydrophilic drug at various physiological pH levels.

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  • Gu-Liang Yang, Sheng-Fang Zhao, Nian-You Chen, Shiming Li
    2016 Volume 64 Issue 9 Pages 1310-1314
    Published: September 01, 2016
    Released: September 01, 2016
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    A novel fluoroporphyrin–anthraquinone hybrid with dipeptide link and its metal complexes were synthesized and evaluated for anti-proliferation activity in human cancer cell line HeLa. The preliminary results demonstrated that all the compounds showed moderate to excellent antitumor activities. Among the active compounds, compound 3 which contains fluorinated porphyrin–anthraquinone and zinc ion exhibited the highest potency with IC50 value of 8.83 µM, indicating that it was a promising antitumor candidate.

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  • Takamasa Nishioka, Ikuya Oshiro, Kazumitsu Onizuka, Yosuke Taniguchi, ...
    2016 Volume 64 Issue 9 Pages 1315-1320
    Published: September 01, 2016
    Released: September 01, 2016
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    Cross-linking is a widely-used technology in the studies of DNA, RNA and their complexes with proteins. Intrinsically active alkylating moieties and photo-activated agents are chemically or enzymatically incorporated into nucleic acids. Thionucleobases resemble the corresponding natural bases, and form cross-links by UVA irradiation. They form cross-links only with a site in close contact, thereby allowing identification of the contacts within the nucleic acids and/or between the nucleic acids and proteins in complex nucleoprotein assemblies. On the other hand, the thionucleobase forms a cross-link less efficiently for the reaction with the opposite natural base in the DNA duplex. In this study, 6-thioguanine was connected to 2′-deoxyribose through an ethylene linker at the 1′-position (Et-thioG). The linker was expected to bring the 6-thio group close to the nucleobase in the opposite strand. In a duplex in which the 2′-deoxy-6-thioguanosine (6-thio-dG) did not form a crosslink, Et-thioG efficiently formed crosslink with a high selectivity for T by UVA irradiation, but with a much lower efficiency for dA, dG, dC, 5-methyl-dC or dU. Interestingly, the yield of the photo-crosslinked product with dT was effectively improved in the presence of dithiothreitol or sodium hydrosulfide (NaSH) at a low UVA irradiation dose. The efficient and selective cross-link formation at a low UVA dose may be beneficial for the biological application of Et-thioG.

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  • Shuji Yamamoto, Tsuyoshi Shibata, Kumi Abe, Koji Oda, Takeshi Aoki, Ya ...
    2016 Volume 64 Issue 9 Pages 1321-1337
    Published: September 01, 2016
    Released: September 01, 2016
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    A novel glycine transporter 1 (GlyT1) inhibitor was designed by the superposition of different chemotypes to enhance its inhibitory activity. Starting from 2-chloro-N-{(S)-phenyl[(2S)-piperidin-2-yl]methyl}-3-(trifluoromethyl)benzamide (2, SSR504734), the introduction of heteroaromatic rings enabled an increase in the GlyT1 inhibitory activity. Subsequent optimization led to the identification of 3-chloro-N-{(S)-[3-(1-ethyl-1H-pyrazol-4-yl)phenyl][(2S)-piperidine-2-yl]methyl}-4-(trifluoromethyl)pyridine-2-carboxamide (7w), which showed a powerful GlyT1 inhibitory activity (IC50=1.8 nM), good plasma exposure and a plasma to brain penetration in rats that was sufficient to evaluate the compound’s pharmacological properties. Compound 7w showed significant effects in several rodent models for schizophrenia without causing any undesirable central nervous system side effects.

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  • Takashi Uchida, Masafumi Yakumaru, Keisuke Nishioka, Yoshihiro Higashi ...
    2016 Volume 64 Issue 9 Pages 1338-1346
    Published: September 01, 2016
    Released: September 01, 2016
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    We evaluated the effectiveness of a silicone membrane as an alternative to human skin using the skin permeation parameters of chemical compounds. An in vitro permeation study using 15 model compounds was conducted, and permeation parameters comprising permeability coefficient (P), diffusion parameter (DL−2), and partition parameter (KL) were calculated from each permeation profile. Significant correlations were obtained in log P, log DL−2, and log KL values between the silicone membrane and human skin. DL−2 values of model compounds, except flurbiprofen, in the silicone membrane were independent of the lipophilicity of the model compounds and were 100-fold higher than those in human skin. For antipyrine and caffeine, which are hydrophilic, KL values in the silicone membrane were 100-fold lower than those in human skin, and P values, calculated as the product of a DL−2 and KL, were similar. For lipophilic compounds, such as n-butyl paraben and flurbiprofen, KL values for silicone were similar to or 10-fold higher than those in human skin, and P values for silicone were 100-fold higher than those in human skin. Furthermore, for amphiphilic compounds with log Ko/w values from 0.5 to 3.5, KL values in the silicone membrane were 10-fold lower than those in human skin, and P values for silicone were 10-fold higher than those in human skin. The silicone membrane was useful as a human skin alternative in an in vitro skin permeation study. However, depending on the lipophilicity of the model compounds, some parameters may be over- or underestimated.

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  • Rémy Bertrand Teponno, Chiaki Tanaka, Bai Jie, Léon Azefack Tapondjou, ...
    2016 Volume 64 Issue 9 Pages 1347-1355
    Published: September 01, 2016
    Released: September 01, 2016
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    Four previously unreported steroidal saponins, trifasciatosides A–D (14), three pairs of previously undescribed steroidal saponins, trifasciatosides E–J (5a, b7a, b) including acetylated ones, together with twelve known compounds were isolated from the n-butanol soluble fraction of the methanol extract of Sansevieria trifasciata. Their structures were elucidated on the basis of detailed spectroscopic analysis, including 1H-NMR, 13C-NMR, 1H–1H correlated spectroscopy (COSY), heteronuclear single quantum coherence (HSQC), heteronuclear multiple bond connectivity (HMBC), total correlated spectroscopy (TOCSY), nuclear Overhauser enhancement and exchange spectroscopy (NOESY), electrospray ionization-time of flight (ESI-TOF)-MS and chemical methods. Compounds 2, 4, and 7a, b exhibited moderate antiproliferative activity against HeLa cells.

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  • Sobhi Mohamed Gomha, Hassan Mohamed Abdel-aziz, Khaled Dessouky Khalil
    2016 Volume 64 Issue 9 Pages 1356-1363
    Published: September 01, 2016
    Released: September 01, 2016
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    In the present study, a novel series of 2-(2-(3-aryl-5-substituted-1,3,4-thiadiazol-2(3H)-ylidene)hydrazinyl)-4,4-diphenyl-1H-imidazol-5(4H)-one derivatives were designed and prepared via the reaction of the most versatile, hitherto unreported 2-(5-oxo-4,4-diphenyl-4,5-dihydro-1H-imidazol-2-yl)-N-phenylhydrazinecarbothioamide with the appropriate hydrazonoyl halides. In addition, some thiazole derivatives were prepared. The structures of the newly synthesized compounds were established based on spectroscopic evidences and their alternative syntheses. Some of the newly synthesized compounds have been evaluated for their anticancer activity against a liver carcinoma cell line HEPG2-1. Moreover, their structure–activity relationship (SAR) was explored for further development in this area. The results indicated that many of the tested compounds showed moderate to high anticancer activity with respective to doxorubicin as a reference drug. Consequently, the new synthesized series of thiadiazole–imidazole derivatives are considered as powerful anticancer agents.

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  • Noriki Kutsumura, Yasuaki Koyama, Kotaro Tateno, Naoshi Yamamoto, Hiro ...
    2016 Volume 64 Issue 9 Pages 1364-1369
    Published: September 01, 2016
    Released: September 01, 2016
    [Advance publication] Released: June 16, 2016
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    The ZnCl2-promoted intramolecular hetero-Diels–Alder reaction of N-(ortho-propargylphenyl)-N′-arylcarbodiimides, in which the aryl-N=C moiety functioned as a 2-azabuta-1,3-diene, 4π component, has been achieved. By this method, very rare 5,12-dihydrodibenzo[b,g][1,8]naphthyridines and fully aromatized dibenzo[b,g][1,8]naphthyridines were successfully synthesized.

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  • Masaki Ohtawa, Yusuke Hishinuma, Eiji Takagi, Takafumi Yamada, Fumihir ...
    2016 Volume 64 Issue 9 Pages 1370-1377
    Published: September 01, 2016
    Released: September 01, 2016
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    Supplementary material

    Cyslabdan was isolated from the culture broth of Streptomyces sp. K04-0144 as a new potentiator of imipenem activity against methicillin-resistant Staphylococcus aureus. We accomplished the synthesis of cyslabdan according to a previously reported structure. However, we subsequently found that this structure was incorrect; our analysis of natural cyslabdan showed that it possessed R stereochemistry at the C8 position, not S, as had previously been reported. Thus, we completed the protecting-group-free synthesis of the correct structure of cyslabdan, which is described herein.

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  • Seika Amemiya, Takao Yamaguchi, Taki Sakai, Yuichi Hashimoto, Tomomi N ...
    2016 Volume 64 Issue 9 Pages 1378-1383
    Published: September 01, 2016
    Released: September 01, 2016
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    Bromodomains are epigenetic ‘readers’ of histone acetylation. The first potent bromodomain and extra-terminal domain (BET) inhibitors, (+)-JQ1 and I-BET762 (also known as GSK525762), were reported in 2010. Some BET inhibitors are already under clinical trial for the treatment of cancers, but so far, only a few chemical scaffolds are available. We have reported potent N6-benzoyladenine-based inhibitors of BRD4, a BET family member that serves as a key mediator of transcriptional elongation. Here we present an analysis of the structure–activity relationships of these inhibitors. Among the compounds examined, 20, 28 and 29 enhanced all-trans retinoic acid (ATRA)-induced HL-60 cell differentiation and inhibited tumor necrosis factor (TNF)-α production by THP-1 cells.

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  • Takeshi Nanjo, Chihiro Tsukano, Yoshiji Takemoto
    2016 Volume 64 Issue 9 Pages 1384-1392
    Published: September 01, 2016
    Released: September 01, 2016
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    Supplementary material

    The synthesis of benzocyclobutenes from simple arenes bearing a directing group was investigated via the palladium-catalyzed cyclization of norbornene derivatives. This approach allowed for the facile construction of benzocyclobutenes along with the double functionalization of the C–H bonds at the positions ortho and meta to the directing group. This result shows that the key palladacyclopentene intermediate in the Catellani reaction can be prepared by the directed double ortho C–H activation of the substrate. The results of this study also revealed that the combination of an N-protected amino acid with benzoquinone (BQ) was effective for this transformation.

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Notes
  • Go Watanabe, Shunsuke Sato, Mitsuo Iwadate, Hideaki Umeyama, Michiyo H ...
    2016 Volume 64 Issue 9 Pages 1393-1396
    Published: September 01, 2016
    Released: September 01, 2016
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    Supplementary material

    Hepatitis B virus (HBV) chronically infects millions of people worldwide and is a major cause of serious liver diseases, including liver cirrhosis and liver cancer. In our previous study, in silico screening was used to isolate new anti-viral compounds predicted to bind to the HBV capsid. Four of the isolated compounds have been reported to suppress the cellular multiplication of HBV experimentally. In the present study, molecular dynamics simulations of the HBV capsid were performed under rotational symmetry boundary conditions, to clarify how the structure and dynamics of the capsid are affected at the atomic level by the binding of one of the isolated compounds, C13. Two simulations of the free HBV capsid, two further simulations of the capsid-C13 complex, and one simulation of the capsid-AT-130 complex were performed. For statistical confidence, each set of simulations was repeated by five times, changing the simulation conditions. C13 continued to bind at the predicted binding site during the simulations, supporting the hypothesis that C13 is a capsid-binding compound. The structure and dynamics of the HBV capsid were greatly influenced by the binding and release of C13, and these effects were essentially identical to those seen for AT-130, indicating that C13 likely inhibits the function of the HBV capsid.

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  • Takashi Iida, Kazunari Namegawa, Naoya Nakane, Kyoko Iida, Alan Freder ...
    2016 Volume 64 Issue 9 Pages 1397-1402
    Published: September 01, 2016
    Released: September 01, 2016
    [Advance publication] Released: June 18, 2016
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    The chemical synthesis of the 9α-hydroxy derivatives of chenodeoxycholic and lithocholic acids is reported. For initiating the synthesis of the 9α-hydroxy derivative of chenodeoxycholic acid, cholic acid was used; for the synthesis of the 9α-hydroxy derivative of lithocholic acid, deoxycholic acid was used. The principal reactions involved were (1) decarbonylation of conjugated 12-oxo-Δ9(11)-derivatives using in situ generated monochloroalane (AlH2Cl) prepared from LiAlH4 and AlCl3, (2) epoxidation of the deoxygenated Δ9(11)-enes using m-chloroperbenzoic acid catalyzed by 4,4′-thiobis-(6-tert-butyl-3-methylphenol), (3) subsequent Markovnikov 9α-hydroxylation of the Δ9(11)-enes with AlH2Cl, and (4) selective oxidation of the primary hydroxyl group at C-24 in the resulting 3α,9α,24-triol and 3α,7α,9α,24-tetrol to the corresponding C-24 carboxylic acids using sodium chlorite (NaClO2) in the presence of a catalytic amount of 2,2,6,6-tetramethylpiperidine 1-oxyl free radical (TEMPO) and sodium hypochlorite (NaOCl). The 1H- and 13C-NMR spectra are reported. The 3α,7α,9α-trihydroxy-5β-cholan-24-oic acid has been reported to be present in the bile of the Asian bear, and its 7-deoxy derivative is likely to be a bacterial metabolite. These bile acids are now available as authentic reference standards, permitting their identification in vertebrate bile acids.

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  • Yuka Kariya, Yuta Asanuma, Makoto Inai, Tomohiro Asakawa, Kyoko Ohashi ...
    2016 Volume 64 Issue 9 Pages 1403-1407
    Published: September 01, 2016
    Released: September 01, 2016
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    Polyamines, such as spermine (1), thermospermine (2) and norspermine (3), are widely distributed in nature, and have multiple biological activities. In addition, many of their conjugates have potential for pharmacological use. Here, we present a solid-phase synthesis using our nitrobenzenesulfonyl (Ns) strategy, which can provide 1, 2 and 3 on a gram scale. This approach should be suitable for facile construction of a diverse library of polyamines.

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  • Masateru Ono, Saki Taketomi, Yuichi Kakiki, Shin Yasuda, Masafumi Okaw ...
    2016 Volume 64 Issue 9 Pages 1408-1410
    Published: September 01, 2016
    Released: September 01, 2016
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    A new resin glycoside, named muricatin IX (1), was isolated from the seeds of Ipomoea muricata (L.) JACQ. (Convolvulaceae). The structure of 1 was determined on the basis of spectroscopic data as well as chemical evidence. Compound 1 is the first representative of resin glycosides in which an organic acid connects the sugar moiety and the aglycone moiety to form macrocyclic ester ring.

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  • Xiao-Yan Han, Yi-Fan Zhong, Sheng-Bin Li, Guo-Chao Liang, Guan Zhou, X ...
    2016 Volume 64 Issue 9 Pages 1411-1416
    Published: September 01, 2016
    Released: September 01, 2016
    [Advance publication] Released: July 02, 2016
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    Supplementary material

    Invasive fungal disease constitutes a growing health problem and development of novel antifungal drugs with high potency and selectivity against new fungal molecular targets are urgently needed. In order to develop potent antifungal agents, a novel series of 6-alkyl-indolo[3,2-c]-2H-thiochroman derivatives were synthesized. Microdilution broth method was used to investigate antifungal activity of these compounds. Most of them showed good antifungal activity in vitro. Compound 4o showed the best antifungal activity, which (inhibition of Candida albicans and Cryptococcus neoformans) can be achieved at the concentration of 4 µg/mL. Compounds 4b (inhibition of Cryptococcus neoformans), 4j (inhibition of Cryptococcus neoformans), 4d (inhibition of Candida albicans) and 4h (inhibition of Candida albicans) also showed the best antifungal activity at the concentrations of 4 µg/mL. The molecular interactions between 4o and the N-myristoyltransferase of Candida albicans (PDB ID: 1IYL) were finally investigated through molecular docking. The results indicated that these thiochromanone derivatives containing indole skeleton could serve as promising leads for further optimization as novel antifungal agents.

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  • Ninh Thi Ngoc, Pham Thi Mai Huong, Nguyen Van Thanh, Nguyen Xuan Cuong ...
    2016 Volume 64 Issue 9 Pages 1417-1419
    Published: September 01, 2016
    Released: September 01, 2016
    [Advance publication] Released: June 17, 2016
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    Supplementary material

    Six steroids (16), including the two new compounds 3β,4α-dihydroxyergosta-5,24(28)-diene (1) and 24(S),28-epoxyergost-5-ene-3β,4α-diol (2), were isolated from the methanol extract of the Vietnamese soft coral Sinularia nanolobata. Their structures were elucidated by spectroscopic methods including one and two dimensional (1D- and 2D)-NMR, Fourier transform ion cyclotron resonance (FT-ICR)-MS, and circular dichroism (CD). Compound 2 exhibited moderate cytotoxicity against the acute leukemia (HL-60) cell line with IC50 value of 33.53±4.25 µM and weak effect on the hepatoma cancer (HepG2) and colon adenocarcinoma (SW480) cell lines with IC50 values of 64.35±7.00 and 71.02±4.00 µM, respectively.

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