Chemical and Pharmaceutical Bulletin
Online ISSN : 1347-5223
Print ISSN : 0009-2363
ISSN-L : 0009-2363
Volume 64 , Issue 6
Showing 1-17 articles out of 17 articles from the selected issue
Reviews
  • Takashi Ohshima
    2016 Volume 64 Issue 6 Pages 523-539
    Published: June 01, 2016
    Released: June 01, 2016
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    Our studies on tetranuclear zinc cluster-catalyzed environmentally friendly reactions are presented here. The newly developed μ-oxo-tetranuclear zinc cluster is a highly efficient catalyst for the direct formation of oxazolines from esters, carboxylic acids, lactones, and nitriles; for the transesterification of various methyl esters including α-amino esters and β-keto esters; for the acetylation of alcohols in EtOAc; and for the deacylation of esters in MeOH. A unique hydroxy group-selective acylation in the presence of inherently much more nucleophilic amino groups was also achieved by this zinc cluster. Zinc cluster-catalyzed transesterification, in particular, was drastically accelerated by the addition of alkyl amine and N-heteroaromatic ligands, which coordinate with the metals, stabilize the clusters with lower nuclearities, and enhance catalytic activity for the transesterification. We also performed several mechanistic studies which revealed that alkoxide metal complexes are the active species in this catalytic cycle, and that the Michaelis−Menten behavior of the complexes through an ordered ternary complex mechanism is similar to that of dinuclear metalloenzymes. The deprotonation of nucleophiles was the most important step in this process, not only for achieving high catalytic activity but also for determining chemoselectivity, resulting in the chemical differentiation of alcohols and amines.
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  • Tomomi Noguchi-Yachide
    2016 Volume 64 Issue 6 Pages 540-547
    Published: June 01, 2016
    Released: June 01, 2016
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    Acetylation of histone is a key epigenetic modification, and contributes to many DNA-dependent cellular processes. The bromodomain structure, which consists of approximately 110 amino acid residues, serves as a ‘reader’ that recognizes acetylated lysine in histones, leading to recruitment of positive transcriptional elongation factor b (P-TEFb), and thereby promoting transcriptional activity and chromatin remodeling. Among bromodomain-containing proteins, members of the bromodomain and extra-terminal domain (BET) family contain tandem N-terminal bromodomains. BET proteins, especially BRD4, have attracted interest as candidate therapeutic targets due to their putative involvement in the pathogenesis of various diseases, including cancer and inflammatory diseases. Several BET inhibitors are under clinical trial for treatment of various cancers. Furthermore, polypharmacological agents such as dual kinase/BET inhibitors and dual histone deacetylase (HDAC)/BET inhibitors have recently been developed, in addition to agents that degrade BET family proteins, such as proteolysis-targeting chimeras (PROTACs). This paper reviews recent progress in epigenetic therapy targeting the BET bromodomain.
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Regular Articles
  • Jie Hao, Wei-Wei Li, Hong Du, Zhi-Fang Zhao, Fan Liu, Jing-Chao Lu, Xi ...
    2016 Volume 64 Issue 6 Pages 548-557
    Published: June 01, 2016
    Released: June 01, 2016
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    How to provide effective prevention and treatment of myocardial ischemia/reperfusion (I/R) injury and study of the mechanism underlying I/R injury are hotspots of current research. This study aimed to elucidate the effect and cardioprotective mechanism of vitamin C (VC) on myocardial I/R injury. Our study introduced two different I/R models: I/R in vitro and oxygen–glucose deprivation/recovery (OGD/R) in primary neonatal rat cardiac myocytes. We used the mitochondrial permeability transition pore (mPTP) opener lonidamine (LND) and the mitochondrial KATP (mitoKATP) channel inhibitor 5-hydroxydecanoate (5-HD) to analyze the underlying mechanisms. We found that post-treatment with VC decreased I/R injury in our models. Post-treatment with VC significantly decreased I/R-induced injury, attenuated apoptosis, and maintained the functional integrity of mitochondria via alleviation of Ca2+ overload, reactive oxygen species burst, inhibition of the opening of mPTP, and prevention of mitochondrial membrane potential (ΔΨm) depolarization. VC post-treatment increased the phosphorylation of Akt and glycogen synthase kinase (GSK)-3β. The present results demonstrate that VC might protect the myocardium from I/R-induced injury by inhibiting the mPTP opening via activation of mitoKATP channels. VC mediates cardioprotection via activation of the phosphatidyl inositol 3-kinase (PI3K)-Akt signaling pathway. These findings may contribute toward the development of novel strategies for clinical cardioprotection against I/R injury.
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  • Ekhlass Nassar, Yaser Abdel-Moemen El-Badry, Hagar El Kazaz
    2016 Volume 64 Issue 6 Pages 558-563
    Published: June 01, 2016
    Released: June 01, 2016
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    Chalcone (3) has been synthesized as a new chalcone derivative bearing benzofuran moiety at 1 position. Such chalcone was used as a model dielectrophile applied to react with some nucleophiles such as 5-amino pyrazoles, 5-amino-1,2,4-triazole, 2-aminobenzimidazole, and 6-uraciles under Michael reaction conditions and resulted in a new series of fused pyrimidines such as pyrazolo[1,5-a]pyrimidines 7ae, [1,2,4]-triazolo[1,5-a]pyrimidine 9, pyrimido[1,2-a]benzimidazole 11, and synthesis of pyrido[2,3-d]pyrimidinones 13a and b. The structures of the synthesized target heterocyclic compounds were confirmed by microanalytical and spectral data such as Fourier transform (FT)-IR, 1H-NMR, and MS spectra. The newly synthesized compounds were evaluated for their anti-inflammatory and antimicrobial activities; most showed significant activities.
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  • Yayoi Kawano, Masanaho Sasatsu, Ayako Mizutani, Kaoru Hirose, Takehisa ...
    2016 Volume 64 Issue 6 Pages 564-569
    Published: June 01, 2016
    Released: June 01, 2016
    [Advance publication] Released: March 10, 2016
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    Stomatitis induced by radiation therapy or cancer chemotherapy is a factor in sleep disorders and/or eating disorders, markedly decreasing patient quality of life. In recent years, disintegrating oral films that are easy to handle have been developed; therefore, we focused on the formulation of these films. We prepared an adhesive film for the oral cavity using xyloglucan (Xylo), which is a water-soluble macromolecule. We used loperamide, which has been reported to relieve pain caused by stomatitis effectively, as a model drug in this study. Films were prepared from Xylo solutions (3% (w/w)) and hypromellose (HPMC) solutions (1% (w/w)). Xylo and HPMC solutions were mixed at ratios of 1 : 1, 2 : 1, or 3 : 1 for each film, and films 2×2 cm weighing 3 g were prepared and dried at 37°C for 24 h. Physicochemical properties such as strength, adhesiveness, disintegration behavior, and dissolution of loperamide from films were evaluated. Films prepared from Xylo solution alone had sufficient strength and mucosal adhesion. On the other hand, films prepared from a mixture of Xylo and HPMC were inferior to those made from Xylo, but showed sufficient strength and mucosal adhesion and were flexible and easy to handle. The films prepared in this study are useful as adhesion films in the oral cavity.
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  • Satyanarayana Reddy Julakanti, Manimala Patel, Venkateswarlu Ponneri
    2016 Volume 64 Issue 6 Pages 570-576
    Published: June 01, 2016
    Released: June 01, 2016
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    A new, simple, highly efficient method for the synthesis of different types of carbonyl chalcones through a regioselective condensation reaction of appropriate 5-acetyl-2-hydroxybenzaldehyde with various substituted acetophenones and 4-hydroxyisothalaldehyde with various substituted aldehydes using BF3–Et2O as a reagent is described.
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  • Md Ashraf Ali, Shuji Noguchi, Yasunori Iwao, Toshihiko Oka, Shigeru It ...
    2016 Volume 64 Issue 6 Pages 577-584
    Published: June 01, 2016
    Released: June 01, 2016
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    SN-38 is a potent active metabolite of irinotecan that has been considered as an anticancer candidate. However, the clinical development of this compound has been hampered by its poor aqueous solubility and chemical instability. In this study, we developed SN-38-encapsulated cubosomes to resolve these problems. Six α-monoglyceride additives, comprising monocaprylin, monocaprin, monolaurin, monomyristin, monopalmitin, and monostearin, were used to prepare phytantriol (PHYT) cubosomes by probe sonication. The mean particle size, polydispersity index, and zeta potential values of these systems were around 190–230 nm, 0.19–0.25 and −17 to −22 mV, respectively. Small-angle X-ray scattering analyses confirmed that the SN-38-encapsulated cubosomes existed in the Pn̄3m space group both with and without the additives. The monoglyceride additives led to around a two-fold increase in the solubility of SN-38 compared with the PHYT cubosome. The drug entrapment efficiency of PHYT cubosomes with additives was greater than 97%. The results of a stability study at 25°C showed no dramatic changes in the particle size or polydispersity index characteristics, with at least 85% of the SN-38 existing in its active lactone form after 10 d, demonstrating the high stability of the cubosome nanoparticles. Furthermore, approximately 55% of SN-38 was slowly released from the cubosomes with additives over 96 h in vitro under physiological conditions. Taken together, these results show that the SN-38-encapsulated PHYT cubosome particles are promising drug carriers that should be considered for further in vivo experiments, including drug delivery to tumor cells using the enhanced permeability and retention effect.
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  • Shizuyo Horiyama, Mayuko Hatai, Yuta Takahashi, Sachiko Date, Tsutomu ...
    2016 Volume 64 Issue 6 Pages 585-593
    Published: June 01, 2016
    Released: June 01, 2016
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    The major toxicants in cigarette smoke, α,β-unsaturated aldehydes, such as acrolein (ACR) and crotonaldehyde (CA), and α,β-unsaturated ketone, methyl vinyl ketone (MVK), are known to form Michael-type adducts with glutathione (GSH) and consequently cause intracellular GSH depletion, which is involved in cigarette smoke-induced cytotoxicity. We have previously clarified that exposure to cigarette smoke extract (CSE) of a mouse melanoma cell culture medium causes rapid reduction of intracellular GSH levels, and that the GSH–MVK adduct can be detected by LC/MS analysis while the GSH–CA adduct is hardly detected. In the present study, to clarify why the GSH–CA adduct is difficult to detect in the cell medium, we conducted detailed investigation of the structures of the reaction products of ACR, CA, MVK and CSE in the GSH solution or the cell culture medium. The mass spectra indicated that in the presence of the cells, the GSH–CA and GSH–ACR adducts were almost not detected while their corresponding alcohols were detected. On the other hand, both the GSH–MVK adducts and their reduced products were detected. In the absence of the cells, the reaction of GSH with all α,β-unsaturated carbonyls produced only their corresponding adducts. These results show that the GSH adducts of α,β-unsaturated aldehydes, CA and ACR, are quickly reduced by certain intracellular carbonyl reductase(s) and excreted from the cells, unlike the GSH adduct of α,β-unsaturated ketone, MVK. Such a difference in reactivity to the carbonyl reductase might be related to differences in the cytotoxicity of α,β-unsaturated aldehydes and ketones.
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  • Ana Carolina Corrêa de Sousa, Gil Mendes Viana, Nuria Cirauqui Diaz, M ...
    2016 Volume 64 Issue 6 Pages 594-601
    Published: June 01, 2016
    Released: June 01, 2016
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    Malaria is one of the most important tropical diseases; the use of amodiaquine as a current chemotherapy in the treatment of malaria has shown some problems such as hepatotoxicity and agranulocytosis. In this work we present the rational design, synthesis, and biological evaluation (antimalarial activity, cytotoxicity and genotoxicity) of four new fluoroamodiaquine analogues. The results showed significant correlation between MolDock score and IC50 values. The molecules 7b and c were the most active of the planned compounds, with lower IC50 against Plasmodium falciparum W2 strain (0.9 and 0.8 µM, respectively) and an excellent cytotoxicity profile. The present study revealed no mutagenicity or genotoxicity for the analogues. Confirming our docking results, the molecular dynamics showed that compound 7b remains stably bound to the heme group by means of π–stacking interactions between quinoline and the porphyrin ring. Based on these findings, this study may prove to be an efficient approach for the rational design of hemozoin inhibiting compounds to treat malaria.
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  • Masanori Matsuura, Suguru Kato, Yoko Saikawa, Masaya Nakata, Kimiko Ha ...
    2016 Volume 64 Issue 6 Pages 602-608
    Published: June 01, 2016
    Released: June 01, 2016
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    A toxic mushroom, Russula subnigricans, causes fatal poisoning by mistaken ingestion. In spite of the potent bioactivity, the responsible toxin had not been identified for about 50 years since its first documentation. Recently, we isolated an unstable toxin and determined the structure. The slow elucidation was partly due to the instability of the toxin and also due to misidentification of R. subnigricans for similar mushrooms. To discriminate genuine Russula subnigricans from similar unidentified Russula species, we searched for a unique chemical marker contained in the mushroom. Cyclopropylacetyl-(R)-carnitine specific to R. subnigricans was identified as a novel compound whose 1H-NMR signals appearing in the upfield region were easily recognizable among the complicated signals of the crude extract.
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  • Wei Peng, Yan-Yan Ma, Kun Zhang, Ai-Yu Zhou, Yu Zhang, Huaqian Wang, Z ...
    2016 Volume 64 Issue 6 Pages 609-615
    Published: June 01, 2016
    Released: June 01, 2016
    [Advance publication] Released: March 24, 2016
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    Long-term use of nonsteroidal antiinflammatory drugs (NSAIDs) may cause serious side effects such as gastric mucosal damage. Resveratrol, a naturally dietary polyphenol, exhibited anti-inflammatory activity and a protective effect against gastric mucosa damage induced by NSAIDs. In this regard, we synthesized a series of resveratrol-based NSAIDs derivatives and evaluated their anti-inflammatory activity against nitric oxide (NO) overproduction in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages. We identified mono-substituted resveratrol–ibuprofen combination 21 as the most potent anti-inflammatory agent, which is more active than a physical mixture of ibuprofen and resveratrol, individual ibuprofen, or individual resveratrol. In addition, compound 21 exerted potent inhibitory effects on the LPS-induced expression of tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β). Furthermore, compound 21 significantly increased the survival rate in an LPS-induced acute inflammatory model and produced markedly less gastric damage than ibuprofen. It was found that compound 21 may be a potent anti-inflammatory agent for the treatment of inflammation-related diseases.
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  • Wen Zhang, Guoqing Sui, Yulin Li, Mei Fang, Xinjuan Yang, Xihan Ma, We ...
    2016 Volume 64 Issue 6 Pages 616-624
    Published: June 01, 2016
    Released: June 01, 2016
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    The study reported the synthesis and antifungal activities in vitro against six phytopathogenic fungi of 17 novel N-[2-hydroxy-3,3-dimethyl-2-[(1H-1,2,4-triazol-1-yl)methyl]butyl]benzamide derivatives. All the target compounds were synthesized and elucidated by means of MS, high resolution (HR)-MS, IR, 1H- and 13C-NMR analysis. The results showed that almost all the derivatives exhibited good activities against each of the tested fungi at the concentration of 50 µg/mL. Among them, 6h displayed excellent activity against Alternaria alternata with the median effective concentration value (EC50) of 1.77 µg/mL, superior to myclobutanil (EC50=6.23 µg/mL), a commercial fungicide with broad-spectrum bioactivities for plant protection and high-efficiency. Compound 6k showed the broadest antifungal spectrum, demonstrating positive activities against the corresponding fungi with EC50 values ranging from 0.98 to 6.71 µg/mL. Furthermore, 6e to 6i revealed good activities against Alternaria solani with EC50 values of 1.90, 4.51, 7.07, 2.00 and 5.44 µg/mL, respectively. The preliminary analysis of structure–activity relationship (SAR) demonstrated that the presence of F or Cl on the benzene ring remarkably improved the activity, while the introduction of 4-OMe or CF3 group decreased the activity in varying degrees. Thus, the present results strongly suggest that N-[2-hydroxy-3,3-dimethyl-2-[(1H-1,2,4-triazol-1-yl)methyl]butyl]benzamide derivatives should be promising candidates for the development of novel antifungal agents in the effective control of phytopathogenic fungi.
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  • Kazuichi Hayakawa, Fumiya Makino, Mari Yasuma, Shota Yoshida, Yvonne C ...
    2016 Volume 64 Issue 6 Pages 625-631
    Published: June 01, 2016
    Released: June 01, 2016
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    Surface water samples were collected at 15 sampling sites in the southeastern Japan Sea along the Japanese Archipelago for analysis of polycyclic aromatic hydrocarbons (PAHs). Water samples were fractionated by filtration through a glass fiber membrane (pore size 0.5 µm) and analyzed by high-performance liquid chromatography with fluorescence detection. Thirteen PAHs having 3 to 6 rings were found in the dissolved phase (DP) and 12 were found in the particulate phase (PP). The total (DP+PP) PAH concentration ranged from 6.83 to 13.81 ng/L with the mean±standard deviation (S.D.) concentration of 9.36±1.92 ng/L. The mean±S.D. PAH concentration in the DP and PP was 5.99±1.80 and 3.38±0.65 ng/L, respectively. Three-ring PAHs predominated in the DP, while the proportion of 4-ring PAHs was higher in the PP. The mean total PAH concentration in the southeastern Japan Sea was higher than the concentration in the northwestern Japan Sea (8.5 ng/L). The Tsushima Current, which originates from the East China Sea with higher PAH concentration, is considered to be responsible for this higher concentration.
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  • Jong-Woon Jung, Jin-Kyung Kim, Jong-Gab Jun
    2016 Volume 64 Issue 6 Pages 632-637
    Published: June 01, 2016
    Released: June 01, 2016
    [Advance publication] Released: March 30, 2016
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    First syntheses of five natural 1,3-diarylpropenes (cinnamylphenols) 24, 7, and 8 along with synthesis of two other natural 1,3-diarylpropenes 1 and 5 and E-isomer of mucronulastyrene (6) were achieved by Friedel–Crafts alkylation as a key step. Subsequently, their anti-inflammatory effects were also investigated in lipopolysaccharide (LPS)-induced RAW264.7 macrophages. The compounds exhibited significant inhibition of inflammatory mediated nitric oxide (NO) production with no cytotoxicity except compound 8 (dalberatin B) at 10 µM concentration and IC50 values were found in the range from 4.05 to 16.76 µM.
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  • Yuka Uemura, Susumu Kawakami, Sachiko Sugimoto, Katsuyoshi Matsunami, ...
    2016 Volume 64 Issue 6 Pages 638-643
    Published: June 01, 2016
    Released: June 01, 2016
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    Chemical study of the leaves of Meliosma pinnata spp. arnottiana afforded five sulfated glucosides of oct-1-en-3-ol (1) and cyclic linalool derivatives (25), and two megastigmanes (6, 7). Their structures were elucidated by extensive investigation of one- and two-dimensional NMR spectroscopic data, and the absolute structures of the megastigmanes were determined by the modified Mosher’s method.
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Notes
  • Shouichi Hosaka, Yasufumi Okamura, Yuji Tokunaga
    2016 Volume 64 Issue 6 Pages 644-649
    Published: June 01, 2016
    Released: June 01, 2016
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    A new type of fluidized-bed granulator equipped with a particle-sizing mechanism was used for the preparation of fine particles that improved the solubility of a poorly water-soluble drug substance. Cefteram pivoxyl (CEF) was selected as a model drug substance, and its solution with a hydrophilic polymer, hydroxypropyl cellulose (HPC-L), was sprayed on granulation grade lactose monohydrate (Lac). Three types of treated particles were prepared under different conditions focused on the spraying air pressure and the amount of HPC-L. When the amount of HPC-L was changed, the size of the obtained particles was similar. However, particle size distribution was dependent on the amount of HPC-L. Its distribution became more homogenous with greater amounts of HPC-L, but the particle size distribution obtained by decreasing the spraying air pressure was not acceptable. By processing CEF with HPC-L using a complex fluidized-bed granulator equipped with a particle-sizing mechanism, the dissolution ratio was elevated by approximately 40% compared to that of unprocessed CEF. Moreover, in the dissolution profile of treated CEF, the initial burst was suppressed, and nearly zero order release was observed up to approximately 60% in the dissolution profile. This technique may represent a method with which to design fine particles of approximately 100 µm in size with a narrow distribution, which can improve the solubility of a drug substance with low solubility.
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  • Masanori Terasaki, Takeshi Wada, Satoshi Nagashima, Masakazu Makino, H ...
    2016 Volume 64 Issue 6 Pages 650-654
    Published: June 01, 2016
    Released: June 01, 2016
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    We investigated the kinetics of in vitro transformation of a dichlorinated propyl paraben (2-propyl 3,5-dichloro-4-hydroxybenzoate; Cl2PP) by the rat liver S9 fraction and assessed the aryl hydrocarbon receptor (AhR) agonist activity of the metabolite products identified in HPLC and GC/MS analysis and by metabolite syntheses. The results indicated that the chlorination of Cl2PP reduced its degradation rate by approximately 40-fold. Two hydroxylated metabolite products showed AhR agonist activity of up to 39% of that of the parent Cl2PP when assessed in a yeast (YCM3) reporter gene assay. The determination of the metabolic properties of paraben bioaccumulation presented here provides further information on the value of risk assessments of chlorinated parabens as a means to ensure human health and environmental safety.
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