Chemical and Pharmaceutical Bulletin
Online ISSN : 1347-5223
Print ISSN : 0009-2363
最新号
選択された号の論文の13件中1~13を表示しています
Review
  • Shadi Sedghi Masoud, Kazuo Nagasawa
    2018 年 66 巻 12 号 p. 1091-1103
    発行日: 2018/12/01
    公開日: 2018/12/01
    ジャーナル フリー HTML

    The i-motif is a high-order DNA structure formed by hemiprotonated cytosine–cytosine base pairs under acidic conditions. It is less well studied than other high-order DNA structures, such as G-quadruplexes. However, increasing numbers of i-motif-binding ligands are being reported, and they are being used as tools to investigate the i-motif’s structure and biological functions. It has become clear that the i-motif has a functional role in the regulation of gene expression. In this review, we provide an overview of i-motif ligands so far reported, and we summarize their effects on the structure and their use as tools to investigate its biological functions.

    Graphical Abstract Fullsize Image
    Editor’s picks

    The i-motif is a high-order DNA structure, forming in cytosine-rich sequences of gene promoters and telomeric regions. Due to the limited stability of this structure under the physiological conditions, the i-motif DNA was unknown for several years. Recently, the biological functions of this DNA and its application have been discovered by applying i-motif interacting agents which is showing the importance of these ligands in uncovering the distinctive features of i-motif.




Regular Articles
  • Erika Rocha-Del Castillo, Omar Gómez-García, Dulce Andrade-Pavón, Lour ...
    2018 年 66 巻 12 号 p. 1104-1113
    発行日: 2018/12/01
    公開日: 2018/12/01
    ジャーナル フリー HTML

    A series of organotin(IV) complexes was herein prepared and characterized. A one-pot synthetic strategy afforded reasonable to high yields, depending on the nature of the ligand. All new complexes were fully characterized by spectroscopic techniques, consisting of IR, MS and NMR (1H, 13C and 119Sn). The in vitro cytotoxicity tests demonstrated that the organotin complexes produced a greater inhibition, versus cisplatin (the positive control), of the growth of six human cancer cell lines: U-251 (glioblastoma), K-562 (chronic myelogenous leukemia), HCT-15 (colorectal), MCF-7 (breast), MDA-MB-231 (breast) and SKLU-1 (non-small cell lung). The potency of this cytotoxic activity depended on the nature of the substituent bonded to the aromatic ring. All complexes exhibited excellent IC50 values. The test compounds were also screened in vitro for their antifungal effect against Candida glabrata and Candida albicans, showing minimum inhibitory concentration (MIC) values lower than those obtained for fluconazole. A brine shrimp bioassay was performed to examine the toxic properties. Molecular docking studies demonstrated that the organotin(IV) complexes bind at the active site of topoisomerase I in a similar manner to topotecan, sharing affinity for certain amino acid side chains (Ile535, Arg364 and Asp533), as well as for similar DNA regions (DA113, DC112 and DT10).

    Graphical Abstract Fullsize Image
    Editor’s picks

    A novel series of pentacoordinated organotin(IV) complexes derived from L-DOPA were designed; the synthesis was performed by a one-pot strategy. The biological evaluation revealed that organotin complexes were substantially more cytotoxic than cisplatin and significantly more effective than Topotecan in inhibiting the growth of leukemia, breast and lung cancer cell lines. The cytotoxicity depended on the nature of the substituent bonded to the aromatic ring. The brine shrimp lethality assay was also used to determine the toxicity. Molecular docking revealed that organotin (IV) complexes bind to the active site of topoisomerase I. Antifungal activity was tested against species of Candida.




  • Yuanfeng Wei, Yunni Ling, Meiling Su, Lei Qin, Jianjun Zhang, Yuan Gao ...
    2018 年 66 巻 12 号 p. 1114-1121
    発行日: 2018/12/01
    公開日: 2018/12/01
    ジャーナル フリー HTML

    Tadalafil (TD), a phosphodiesterase-5 (PDE-5) inhibitor with poor oral bioavailability. The aim of the study was to prepare and characterize three crystalline polymorphs of TD (II, III, and IV) and the tadalafil amorphous form (TD-AM). TD polymorphs and TD-AM were prepared and characterized by polarized light microscope (PLM), scanning electron microscopy (SEM), differential scanning calorimetry (DSC), thermal gravimetric analysis (TGA), X-ray powder diffractometry (XRPD), and Fourier-transform (FT)IR, followed by the dissolution testing, physical stabilities and polymorphic transformation studies. TD-I and TD-II were found to be enantiotropically related, while TD-III was monotiotropically related to TD-I with heat release. Among all studied polymorphs, TD-AM demonstrated an extremely high intrinsic dissolution rate with most prolonged higher saturated concentration during dissolution, while TD-II, TD-III, and TD-IV converted to TD-I easily by supersaturation-mediated phase transformation. Upon heating under 60°C for 3 h and storing at long-term stability condition for 3 months, no phase transformation was detected for TD-I, TD-III, and TD-AM, while TD-II and TD-IV easily transformed to TD-I and TD-III, respectively. The higher intrinsic dissolution rate, prolonged supersaturated state during dissolution and favorable physical stability of TD-AM made it to be a very promising candidate for further product development.

    Graphical Abstract Fullsize Image
  • Hidenori Kawasaki, Toshinori Shimanouchi, Kanako Takahashi, Yukitaka K ...
    2018 年 66 巻 12 号 p. 1122-1130
    発行日: 2018/12/01
    公開日: 2018/12/01
    ジャーナル フリー HTML

    The freezing stage cannot be directly controlled, which leads to variation in product quality and low productivity during the lyophilization process. Our objective was to establish a robust design space for the primary drying stage using ice nucleation control based on the pressurization and depressurization technique. We evaluated the specific surface area (SSA), water content, scanning electron microscopy (SEM) images, and water vapor transfer resistance of the dried layer (Rp) of the products. The ice nucleation control resulted in a reduction of the SSA value and in an increase in water content. SEM observation suggested that the ice nucleation control enabled formation of large ice crystals, which was consistent with the reduction in the Rp value. As a result, the generation of collapsed cakes was inhibited, whereas 18% of the collapsed cakes were observed without ice nucleation control. Finally, this technique succeeded in determining a robust design space for the primary drying stage to produce uniform products of higher productivity. It was considered, from the present findings, that controlling the formation of large ice crystals impacted the product quality and productivity.

    Graphical Abstract Fullsize Image
  • Ko Morishita, Yoshimichi Shoji, Masaki Fukui, Yuma Ito, Tatsuya Kitao, ...
    2018 年 66 巻 12 号 p. 1131-1152
    発行日: 2018/12/01
    公開日: 2018/12/01
    ジャーナル フリー HTML

    A novel series of 2-acyl-3-carboxyl-tetrahydroisoquinoline derivatives were synthesized and biologically evaluated. Among them, (S)-2-{(E)-3-furan-2-ylacryloyl}-7-[(2E,4E)-5-(2,4,6-trifluorophenyl)penta-2,4-dienyloxy]-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (compound 17u) was identified as a potent protein tyrosine phosphatase 1B (PTP1B) inhibitor without peroxisome proliferator-activated receptor (PPAR) γ activation: PTP1B inhibition IC50=0.19 µM and PPARγ ΕC50>10 µM. Compound 17u exhibited mixed-type inhibition for PTP1B, and this mode of inhibition was rationalized by computational ligand docking into the catalytic and allosteric sites of PTP1B. Compound 17u also showed high oral absorption at 10 mg/kg (per os (p.o.), Cmax=4.67 µM) in rats, significantly reduced non-fasting plasma glucose and triglyceride levels with no side effects at 30 mg/kg/d (p.o.) for 4 weeks, and attenuated elevations in plasma glucose levels in the oral glucose tolerance test performed 24 h after its final administration in db/db mice. In conclusion, the substituted 2-acyl-3-carboxyl-tetrahydroisoquinoline is a novel scaffold of mixed-type PTP1B inhibitors without PPARγ activation, and compound 17u has potential as an efficacious and safe anti-diabetic drug as well as a useful tool for investigations on the physiological and pathophysiological effects of mixed-type PTP1B inhibition.

    Graphical Abstract Fullsize Image
  • Takashi Ikawa, Shigeaki Masuda, Shuji Akai
    2018 年 66 巻 12 号 p. 1153-1164
    発行日: 2018/12/01
    公開日: 2018/12/01
    ジャーナル フリー HTML

    Fluorinated aromatic compounds are found in a variety of biologically active compounds, including clinical drugs and agrochemicals. Therefore, the synthesis of aryl fluorides is particularly important in the medicinal and process chemistry fields. In this paper, we report a method for the synthesis of aryl fluorides by benzyne fluorination under microflow conditions using the efficient Comet X-01 micromixer. In comparison to our previously reported method under ordinary batch conditions, this approach facilitates a significant reduction in reaction times, to ca. 10 s, as well as increases in the yields of fluoroarenes (by up to 51%).

    Graphical Abstract Fullsize Image
    Editor’s picks

    Continuous flow synthesis has drawn increasing attention in current organic synthesis. In this paper, the authors demonstrate a new entry for the beneficial application of a microflow reactor to the synthesis of aromatic fluorinated compounds via domino benzyne generation/nucleophilic fluorination. In particular, the high mixing ability of the flow reactor significantly reduced the reaction times to ~10 s and improved the product yields in comparison to their previously reported method under ordinary batch conditions. In some cases, aryl fluorides were obtained only under microflow conditions. Thus, the flow chemistry is the method not only for continuous chemical production but also for achieving transformations that are otherwise inaccessible by the conventional batch method.




  • Hanan M. El-Laithy, Alia Badawi, Nevine Shawky Abdelmalak, Nihal El-Sa ...
    2018 年 66 巻 12 号 p. 1165-1173
    発行日: 2018/12/01
    公開日: 2018/12/01
    [早期公開] 公開日: 2018/09/19
    ジャーナル フリー HTML

    Clopidogrel bisulphate (CB) is a first line antiplatelet drug for treatment of myocardial infarction and stroke. Yet, its efficacy is limited by its poor solubility in intestinal pH, its main site of absorption. The main aim of this study is to enhance the intestinal release of CB by loading in cubosome nanoparticles. Glyceryl monooleate (GMO) based CB loaded cubosomes were prepared using a 33 factorial design to study the effect of polyvinyl alcohol (PVA), poloxamer 407 (PL407) concentrations and ratio of CB to the disperse phase on the average particle size, entrapment efficiency (%EE), in vitro release at 15 min (%Q15), and their morphology using transmission electron microscopy (TEM). The release of the optimized formula was compared in buffer transition media (pH 1.2 for 2 h then pH 6.8 for 6 h) to free drug to study the effect of the changing pH in the gastrointestinal tract (GIT) on CB release. The antihaemostatic properties of the optimized formula were compared to the commercial product Plavix® using bleeding time (BT) model in rabbits. The prepared cubosomes were in the nano range (115±6.47 to 248±4.63 nm) with high %EE (91.22±4.09% to 98.98±3.21%). The optimized formula showed significantly higher (p<0.05) CB release in intestinal pH and preserved the high% released (95.66±1.87%) in buffer transition release study compared to free drug (66.82±4.12%) as well as significantly (p<0.05) higher antihaemostatic properties with longer BT (628.47±6.12 s) compared to Plavix® (412.43±7.97 s). Thus, cubosomes proved to be a successful platform to enhance the intestinal release of CB and improve its absorption.

    Graphical Abstract Fullsize Image
  • Takashi Uchikura, Hidemi Sugiwaki, Morio Yoshimura, Hiromi Mitsuhashi, ...
    2018 年 66 巻 12 号 p. 1174-1180
    発行日: 2018/12/01
    公開日: 2018/12/01
    ジャーナル フリー HTML

    Polygala Root (the root of Polygala tenuifolia WILLDENOW; Japanese name “Onji”), a well-known crude drug, traditionally used as an expectorant and sedative, has been attracting increased interest in recent years owing to its newly found pharmacological effect related to neuroprotection. However, there is no specific method for identifying and estimating the quality of this crude drug in the Japanese Pharmacopoeia, 17th edition. Therefore, in order to develop a TLC-based simple and convenient identification method using characteristic chemical marker(s) for the drug and its extract products, UV-sensitive constituents of Polygala Root were first investigated. A total of 23 aromatic compounds were isolated and characterized. Two new compounds, namely, polygalaonjisides A (1) and B (2), were characterized as syringic acid 4-O-(2′-O-β-D-apiosyl)-β-D-glucoside and 2-O-(β-D-glucosyl)-3′-O-benzoylsucrose, respectively. Based on these phytochemical results, a TLC method focusing on three marker spots with Rf value of approximately 0.4–0.5 due to tenuifolisides A and B and 3,6′-di-O-sinapoylsucrose was proposed as a simple and convenient test to identify Polygala Root or its single-extract products on the market. The data presented in this paper could be useful in stipulating a confirmation test to identify Polygala Root.

    Graphical Abstract Fullsize Image
    Editor’s picks

    A TLC-based simple and convenient method using UV-sensitive constituents as markers to identify the crude drug Polygala Root (the root of Polygala tenuifolia Willdenow; Japanese name “Onji”) was investigated. Twenty-three aromatic compounds including two new compounds, polygalaonjisides A and B, were characterized. Based on the phytochemical results obtained, a TLC method focusing on three marker spots with Rf values of approximately 0.4-0.5 due to tenuifolisides A and B and 3,6-di-O-sinapoylsucrose was proposed as a simple and convenient test to identify Polygala Root and its single-extract products on the market. The data presented in this paper could be useful in stipulating a confirmation test to identify Polygala Root.




  • Mohammed K. Abd el hameid
    2018 年 66 巻 12 号 p. 1181-1195
    発行日: 2018/12/01
    公開日: 2018/12/01
    [早期公開] 公開日: 2018/10/05
    ジャーナル フリー HTML

    The work reported the design and cytotoxic screening of synthetic small molecules: carbonitriles 3ac, carboximidamides 4ac, and oxadiazoles 519 as antitumor molecules. Molecules 4c, 9, 12, and 14 show promising cytotoxicity profiles against two cell lines higher than prodigiosin (PG). The results of topoisomerase enzyme inhibition assay show that carboximidamide 4c and oxadiazole 14 display potent inhibitory activity in nano-molar concentration higher than PG. In addition, carboximidamide 4c and oxadiazoles 9, 12, and 14 exhibit antiproliferative activities over MCF-7 cells by cell cycle arrest at G1 phase and apoptosis inducing activity by increasing cell population percentages at pre G1 and G2/M phases as shown by DNA-flow cytometry assay and annexin V analysis. Moreover, measurement of p53 and cell death mediators, show that carboximidamide 4c and oxadiazoles 9, 12, and 14 significantly up-regulate p53, Puma and Bax/Bcl-2 ratio levels. Subsequently, pro-apoptotic activities are confirmed by active caspase 3/7 percentages green fluorescence assay.

    Graphical Abstract Fullsize Image
  • Mayuko Iwata, Motoi Kuwabara, Akinobu Matsuzawa, Kazuyuki Sugita
    2018 年 66 巻 12 号 p. 1196-1198
    発行日: 2018/12/01
    公開日: 2018/12/01
    ジャーナル フリー HTML

    Herein we describe a short total synthesis of (+)-spinoxazine B, which inhibits nitric oxide (NO) production in BV-2 microgrial cells. Spinoxazine B is the first example of a natural alkaloid containing an oxazinone-pyrrolidone nucleus, and it is expected to serve as a novel drug lead compound as well as a drug discovery scaffold.

    Graphical Abstract Fullsize Image
    Editor’s picks

    This paper describes a short total synthesis of (+)-spinoxazine B, which inhibits NO production in BV-2 microgrial cells. The synthesis features a double cyclization to rapidly construct the bicyclic skeleton of spinoxazine B. Spinoxazine B is the first example of a natural alkaloid containing an oxazinone-pyrrolidone nucleus. Because new ring system is considered to be a new resource for drug discovery, spinoxazine B is expected to serve as a novel drug lead compound as well as a drug discovery scaffold.




Notes
Errata
feedback
Top