Chemical and Pharmaceutical Bulletin
Online ISSN : 1347-5223
Print ISSN : 0009-2363
ISSN-L : 0009-2363
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61 巻, 10 号
選択された号の論文の17件中1～17を表示しています
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Review
  • Synthesis of Heterocyclic Compounds through Palladium-Catalyzed C–H Cyclization Processes
    Kiyofumi Inamoto
    2013 年 61 巻 10 号 p. 987-996
    発行日: 2013/10/01
    公開日: 2013/10/01
    DOIhttps://doi.org/10.1248/cpb.c13-00420
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    Herein, we describe our development of synthetic methods for heterocyclic compounds based on the palladium-catalyzed carbon–hydrogen bond (C–H) functionalization/intramolecular carbon–heteroatom (nitrogen or sulfur) bond formation process. By this C–H cyclization method, we efficiently prepared various N-heterocycles, including indazoles, indoles, and 2-quinolinones, as well as S-heterocycles such as benzothiazoles and benzo[b]thiophenes. Yields are typically good to high and good functional-group tolerance is observed for each process, thereby indicating that the method provides a novel, highly applicable synthetic route to the abovementioned biologically important heterocyclic frameworks. As an application of this approach, an auto-tandem-type, one-pot process involving the oxidative Heck reaction and subsequent C–H cyclization using cinnamamides and arylboronic acids as starting materials in the presence of a palladium catalyst was also developed for the rapid construction of the 2-quinolinone nucleus.
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Regular Articles
  • Synthetic Models Related to Methoxalen and Menthofuran–Cytochrome P450 (CYP) 2A6 Interactions. Benzofuran and Coumarin Derivatives as Potent and Selective Inhibitors of CYP2A6
    Yuki Yamaguchi, Ichie Akimoto, Kyoko Motegi, Teruki Yoshimura, Keiji W ...
    2013 年 61 巻 10 号 p. 997-1001
    発行日: 2013/10/01
    公開日: 2013/10/01
    [早期公開] 公開日: 2013/08/01
    DOIhttps://doi.org/10.1248/cpb.c12-00872
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    Human microsomal cytochrome P450 (CYP) 2A6 contributes extensively to nicotine detoxication but also activates tobacco-specific procarcinogens to mutagenic products. We prepared a series of benzofuran and coumarin derivatives that have inhibitory effects on the activity of human CYP2A6. The reported compounds methoxalen and menthofuran had potent inhibitory effects on the activity of CYP2A6 with IC50 values of 0.47 µM and 1.27 µM, respectively. Synthetic benzofuran (4-methoxybenzofuran: IC50=2.20 µM) and coumarin (5-methoxycoumarin: IC50=0.13 µM and 6-methoxycoumarin: IC50=0.64 µM) derivatives, which have more selective effects than those of methoxalen and menthofuran, exhibited comparable activities against CYP2A6. These compounds can be used as a lead compounds in the design of CYP2A6 inhibitor drugs to reduce smoking and tobacco-related cancers.
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  • Methyl 5-Chloro-4,5-didehydrojasmonate (J7) Inhibits Macrophage-Derived Chemokine Production via Down-Regulation of the Signal Transducers and Activators of Transcription 1 Pathway in HaCaT Human Keratinocytes
    Gyeoung-Jin Kang, Hung-The Dang, Sang-Chul Han, Na-Jin Kang, Dong-Hwan ...
    2013 年 61 巻 10 号 p. 1002-1008
    発行日: 2013/10/01
    公開日: 2013/10/01
    DOIhttps://doi.org/10.1248/cpb.c13-00145
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    Jasmonates are lipid-based stress hormones that are critical for the defense of plants against insects. Two naturally occurring jasmonates, jasmonic acid and methyl jasmonate, have recently been explored for their efficacy as anti-cancer agents. Furthermore, certain synthetic jasmonates (e.g., the cyclopentenone isoprostane J2) exert anti-inflammatory actions in lipopolysaccharide (LPS)-challenged murine macrophages via down-regulation of chemokines and other inflammatory mediators. Chemokines participate in the development and progression of many inflammatory disorders, such as atopic dermatitis (AD) and Crohn’s disease, as exemplified by the role of macrophage-derived chemokine (MDC/CCL22) in the pathology of AD. The current study therefore investigated the impact of jasmonate derivatives (jasmonic acid and methyl jasmonate) and their synthetic analogues (J2 and J7) on the expression of MDC in interferon (IFN)-γ- and tumor necrosis factor (TNF)-α-stimulated HaCaT human keratinocytes, as well as the attendant mechanism of action. Jasmonic acid, methyl jasmonate, and J2 failed to inhibit the cytokine-stimulated production of MDC. By contrast, J7 suppressed the mRNA and protein expression levels of MDC in a dose-dependent manner. Moreover, J7 diminished the activation of signal transducers and activators of transcription 1 (STAT1), but had no inhibitory effect on the nuclear factor kappa B (NF-κB) or mitogen-activated protein kinase (MAPK) pathways. These results demonstrate that J7 impairs IFN-γ- and TNF-α-induced inflammatory chemokine production by targeting the STAT1 pathway.
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  • A Simple High-Throughput Method for Determination of Antiepileptic Analogues of γ-Aminobutyric Acid in Pharmaceutical Dosage Forms Using Microplate Fluorescence Reader
    Boštjan Martinc, Tomaž Vovk
    2013 年 61 巻 10 号 p. 1009-1014
    発行日: 2013/10/01
    公開日: 2013/10/01
    [早期公開] 公開日: 2013/07/12
    DOIhttps://doi.org/10.1248/cpb.c13-00322
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    Pregabalin (PGB), gabapentin (GBP), and vigabatrin (VGB) are structural analogues of γ-aminobutyric acid used for the treatment of different forms of epilepsy. Their analytical determination is challenging since these molecules have no significant UV or visible absorption. Several derivatization methods have been developed and used for their determination in bulk or pharmaceutical dosage forms. We aimed to develop a high- throughput method using a microplate reader with fluorescence detection and simple derivatization with fluorescamine. Obtained method involves derivatization step of only 5 min at room temperature and simultaneous measurements of 96 samples (λex 395, λem 476 nm) thus rendering excellent high-throughput analysis. The method was found to be linear with r2>0.998 across investigated analytical ranges of 0.75 to 30.0 µg/mL for PGB, 2.00 to 80.0 µg/mL for GBP, and 1.50 to 60.0 µg/mL for VGB. Intraday and interday precision values did not exceed 4.93%. The accuracy was ranging between 96.6 to 103.5%. The method was also found to be specific since used excipients did not interfere with the method. The robustness study showed that derivatization procedure is more robust than spectrofluorimetric conditions. The developed high-throughput method was successfully applied for determination of drug content and dissolution profiles in pharmaceutical dosage forms of studied antiepileptic drugs.
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  • Antiproliferative, Cell-Cycle Dysregulation Effects of Novel Asiatic Acid Derivatives on Human Non-small Cell Lung Cancer Cells
    Liang Wang, Jie Xu, Chunhui Zhao, Longxuan Zhao, Bin Feng
    2013 年 61 巻 10 号 p. 1015-1023
    発行日: 2013/10/01
    公開日: 2013/10/01
    [早期公開] 公開日: 2013/08/06
    DOIhttps://doi.org/10.1248/cpb.c13-00328
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    Asiatic acid (AA) is a pentacyclic triterpene in Centella asiatica known to inhibit proliferation and induce apoptosis in several tumor cell lines. In the current study, we synthesized five AA derivatives and examined their inhibitory activities on growth in non-small cell lung cancer cell lines, A549 and PC9/G. Four derivatives were found to have stronger cell growth inhibitory activity than AA. Among them, compound A-3 showed the most significant antiproliferative effects on tumor. Growth of A549 and PC9/G cells was inhibited by A-3 in a dose- and time-dependent manner. To determine the cellular gene expression changes in A549 and PC9/G cells treated with A-3, Affymetrix GeneChip® Human Genome U133 Plus 2.0 Array were used to screen transcriptome differences. Expression levels of 1121 genes in A549 and 1873 genes in PC9/G were significantly altered upon treatment with 10 µM A-3 after 48 h, with 357 overlapping genes. The signaling pathways molecules involved in the antiproliferative and cell cycle dysregulation effects of A-3 identified using microarray were further validated via Western blot analyses. The results collectively indicate that A-3 induces inhibition of cell proliferation via downregulation of the Ras/Raf/MEK/ERK pathway and cell cycle arrest at G1/S and G2/M.
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  • Synthetic Studies of Cortistatin A Analogue from the CD-Ring Fragment of Vitamin D2
    Naoyuki Kotoku, Kohei Mizushima, Satoru Tamura, Motomasa Kobayashi
    2013 年 61 巻 10 号 p. 1024-1029
    発行日: 2013/10/01
    公開日: 2013/10/01
    DOIhttps://doi.org/10.1248/cpb.c13-00375
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    Syntheses of analogue compounds of cortistatin A (1), an anti-angiogenic steroidal alkaloid from Indonesian marine sponge, were investigated by utilizing the CD-ring fragment of vitamin D2. The incidental preparation of a new analogue having CD-cis-fused skeleton and its biological evaluation revealed the importance of the CD-trans-fused structure for the potent and selective antiproliferative activity of 1 against human umbilical vein endothelial cells (HUVECs).
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  • Phosphate-Ion-Adsorption Capability of Granulated Boehmite Fabricated Using Organic Binder (Polyethylene Terephthalate)
    Fumihiko Ogata, Ayaka Ueda, Naohito Kawasaki
    2013 年 61 巻 10 号 p. 1030-1036
    発行日: 2013/10/01
    公開日: 2013/10/01
    DOIhttps://doi.org/10.1248/cpb.c13-00392
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    We investigated a method for producing granulated boehmite (BE) by using an organic binder and measured its phosphate-ion-adsorption capacity. BE was granulated using polyethylene terephthalate (PET), and its structure was characterized by scanning electron microscopy and X-ray diffraction analyses. The properties of granulated BE such as specific surface area, mean pore diameter, pore volume, amount of hydroxyl groups, and solution pH were also investigated. Furthermore, adsorption isotherm; effects of contact time, temperature, and solution pH on phosphate-ion adsorption; and recovery of phosphate ions (using sodium hydroxide solution) were evaluated. BE granulated by PET (BE-PET30S) could be successfully used for phosphate-ion removal by adsorption. The specific surface area and amount of hydroxyl groups of BE-PET30S were found to be 119.8 m2/g and 1.4 mmol/g, respectively. Granulated BEs reached equilibrium adsorption capacities within 24 h. The phosphate-ion-adsorption rate data were fitted to the pseudo-second-order kinetic model (r=0.981–0.998). The adsorption isotherm data were fitted to both the Freundlich (0.987–0.989) and Langmuir (0.905–0.944) equations. Based on the thermodynamic study, it was found that the phosphate-ion adsorption by granulated BEs is a spontaneous and exothermic process. The phosphate ions adsorbed onto BE-PET30S could be easily recovered by using a sodium hydroxide solution (1–1000 mmol/L) and their recovery percentage was found to be between 63.3% and 94.0%. The results obtained from this study could be useful for recovering phosphate ions and preventing problems related to water pollution.
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  • Synthesis and Biological Evaluation of Thiophene-C-glucosides as Sodium-Dependent Glucose Cotransporter 2 Inhibitors
    Shigeki Sakamaki, Eiji Kawanishi, Yuichi Koga, Yasuo Yamamoto, Chiaki ...
    2013 年 61 巻 10 号 p. 1037-1043
    発行日: 2013/10/01
    公開日: 2013/10/01
    DOIhttps://doi.org/10.1248/cpb.c13-00407
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    The synthesis and structure–activity relationship (SAR) of thiophene-C-glucosides have been explored, and the human sodium-dependent glucose cotransporter 2 (hSGLT2) inhibitory activities and rat urinary glucose excretion (UGE) effects of 3a–f were evaluated. As a result, they showed good hSGLT2 inhibitory activities and rat UGE effects. In particular, the chlorothiophene derivative 3f showed remarkable inhibitory activity against hSGLT2.
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  • Steroidal Constituents from the Starfish Astropecten polyacanthus and Their Anticancer Effects
    Nguyen Phuong Thao, Nguyen Xuan Cuong, Bui Thi Thuy Luyen, Nguyen Hoai ...
    2013 年 61 巻 10 号 p. 1044-1051
    発行日: 2013/10/01
    公開日: 2013/10/01
    DOIhttps://doi.org/10.1248/cpb.c13-00490
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    Using various chromatographic methods, four new steroids, astropectenols A–D (1–4), along with three known compounds (5–7) were isolated from a methanol extract of the starfish Astropecten polyacanthus. The structure elucidation was confirmed by spectroscopic methods, including one dimensional (1D)-, 2D-NMR and Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR-MS). The CH2Cl2 fraction and compound 7 exhibit potent cytotoxic effects against HL-60 human leukemia cells with the IC50 of 8.29 µg/mL and 2.70 µM, respectively, comparing to the positive control, mitoxantrone (IC50=6.80 µM). When HL-60 cells were treated with the CH2Cl2 fraction or compound 7, several apoptosis events like chromatin condensation and the increase of the population of sub-G1 hypodiploid cells were observed. Investigations for the possible mechanism underlying the induction of apoptosis showed that CH2Cl2 fraction or compound 7 induced apoptosis through down-regulation of Bcl-2, up-regulation of Bax, cleavage of caspase-9, cleavage of caspase-3 and cleavage of poly(ADP-ribose) polymerase (PARP) in HL-60 cells. Furthermore, the apoptosis induction of HL-60 cell by CH2Cl2 fraction or compound 7 was attended by the decreasing of phospho-extracellular signal-regulated kinase (ERK) 1/2 and C-myc. These results indicated that the CH2Cl2 fraction and compound 7 could induce the apoptosis of HL-60 cells via the inactivation of ERK 1/2 and the decrease of C-myc. Our finding suggested the potential using of the CH2Cl2 fraction and compound 7 for leukemia treatment.
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  • Chemistry of Ecteinascidins. Part 4: Preparation of 2′-N-Acyl Ecteinascidin 770 Derivatives with Improved Cytotoxicity Profiles
    Mitsuhiro Tsujimoto, Witaya Lowtangkitcharoen, Nanae Mori, Waree Pangk ...
    2013 年 61 巻 10 号 p. 1052-1064
    発行日: 2013/10/01
    公開日: 2013/10/01
    DOIhttps://doi.org/10.1248/cpb.c13-00525
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    We report herein eleven 2′-N-acyl derivatives that were prepared from ecteinascidin 770 (Et 770: 1b) via 18,6′-O-bisallyl protected compound (4) in excellent yields. 2′-N-Acyl derivatives (6a–k) generally showed higher cytotoxicity than 1b. Among them, 3-quinolineacyl derivative (6g) and 4-fluorocinnamoyl derivative (6h) exhibited approximately 50- and 70-fold higher cytotoxicity to the HCT116 human colon carcinoma cell line, respectively, than 1b. Both compounds are potent inhibitors of the in vitro growth of several tumor cells and are therefore promising leads for further optimization. We also report the transformation of 1b into Et 788 (3), which is the first example of an ecteinascidin derivative having a primary amide at C-21 position.
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