Chemical and Pharmaceutical Bulletin
Online ISSN : 1347-5223
Print ISSN : 0009-2363
ISSN-L : 0009-2363
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Volume 61, Issue 7
Displaying 1-14 of 14 articles from this issue
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Regular Articles
  • Design and Synthesis of Some 3-Substituted-2-[(2,4-dichlorophenoxy)-methyl]quinazolin-4(3H)-one Derivatives as Potential Anticonvulsant Agents
    Safinaz El-Sayed Abbas, Fadi Mohsen Awadallah, Nashwa Ahmed Ibrahim, E ...
    2013 Volume 61 Issue 7 Pages 679-687
    Published: July 01, 2013
    Released on J-STAGE: July 01, 2013
    DOIhttps://doi.org/10.1248/cpb.c12-01064
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    Series of 2,3-disubstituted quinazolinone derivatives and a [1,2,4]triazino[2,3-c]quinazolinone featuring the pharmacophoric elements of anticonvulsant drugs were designed and synthesized. Target compounds were screened for their anticonvulsant activity using the subcutaneous pentylenetetrazole (s.c. PTZ) and maximal electroshock (MES) models. The s.c. PTZ test showed that the most active compound was the amide derivative 9c having a protective dose 50 (PD50) of 200.53 µmol/kg (PD50 of phenobarbitone=62.18 µmol/kg); nevertheless, this low potency is outweighed by the much higher safety profile of 9c (LD50 >3000 mg/kg). In the MES screening, seven compounds were equal to or more active than phenytoin; some of these compounds were less neurotoxic than phenytoin. Few compounds such as 9c and 10 were effective in both models. LD50 for the most active compounds was calculated.
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  • Fasudil Inhibits Epithelial-Myofibroblast Transdifferentiation of Human Renal Tubular Epithelial HK-2 Cells Induced by High Glucose
    Lingjia Gu, Qian Gao, Liansong Ni, Meirong Wang, Feixia Shen
    2013 Volume 61 Issue 7 Pages 688-694
    Published: July 01, 2013
    Released on J-STAGE: July 01, 2013
    DOIhttps://doi.org/10.1248/cpb.c13-00066
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    Renal fibrosis is a crucial pathologic process underlying diabetic nephropathy (DN). Central to this process is the epithelial-mesenchymal transformation (EMT) of tubular epithelial cells. Fasudil, a Rho-associated coiled-coil forming protein serine/threonine kimase (ROCK) inhibitor, protects against renal fibrosis in a variety of renal injury models. However, fasudil’s effects on renal fibrosis in DN remain unknown. The aim of the present study was to investigate the effects of fasudil on high glucose-induced EMT in human renal tubular epithelial (HK-2) cells. HK-2 cells were exposed to 5.5 or 60 mmol/L D-glucose for 72h, or to mannitol (osmotic control). RhoA activity was assessed using a RhoA pull-down assay, and ROCK activity was determined by myosin phosphatase target subunit-1 (MYPT1) phosphorylation. Myofibroblast (vimentin and α-smooth muscle actin [α-SMA]) and epithelial (E-cadherin) markers expressions were detected by immunocytochemistry and Western blotting. Transforming growth factor (TGF)-β1 and fibronectin secretion were detected with enzyme-linked immunosorbent assay (ELISA), and connective tissue growth factor (CTGF) was analyzed by Western blotting. Results showed that high glucose levels induced morphological changes, reduced E-cadherin expression (−73%), increased expression of vimentin (+148%) and α-SMA (+226%), increased TGF-β1 (from 116.0±5.2 µg/g to 351.0±3.2 µg/g) and CTGF (from 0.26±0.01 to 0.92±0.03) secretion, and increased RhoA and ROCK activation (p<0.05 for all). All these effects of high glucose stimulation were suppressed or abolished by fasudil. In conclusion, fasudil may attenuate EMT through reduced activation of RhoA/ROCK signaling, and decreased expression of TGF-β1 and CTGF. Thus, fasudil may be a renoprotective agent for the treatment of DN.
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  • Cyclic Sulfoxides Garlicnins B2, B3, B4, C2, and C3 from Allium sativum
    Toshihiro Nohara, Yukio Fujiwara, Tsuyoshi Ikeda, Kohtaro Murakami, Ma ...
    2013 Volume 61 Issue 7 Pages 695-699
    Published: July 01, 2013
    Released on J-STAGE: July 01, 2013
    DOIhttps://doi.org/10.1248/cpb.c13-00082
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    Several novel sulfides, called garlicnins B2 (1), B3 (2), B4 (3), C2 (4), and C3 (5), were isolated from acetone extracts of garlic, Allium sativum L. and characterized. These garlicnins are capable of suppressing M2 macrophage activation and they have a novel skeleton of cyclic sulfoxide. The structures of the former 3 and latter of 2 were deduced to be 2-(sulfenic acid)-5-(allyl)-3,4-dimethyltetrahydrothiophene-S-oxides and 2-(allyldithiine)-5-(propenylsulfoxide)-3,4-dimethyltetrahydrothiophene-S-oxides, respectively. The mechanism of the proposed production of these compounds is discussed. The identification of these novel sulfoxides from garlic accumulates a great deal of new chemistry in the Allium sulfide field, and future pharmacological investigations of these compounds will aid the development of natural, healthy foods and anti-cancer agents that may prevent or combat disease.
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  • Physicochemical Characterization of Tretinoin Tocoferil Emulsion and Povidone-Iodine Sugar Ointment Blend Developed for Improved Regulation of Wound Moisture
    Yasuhiro Noda, Mika Saito, Kazuya Watanabe, Akimasa Sanagawa, Yu Sobaj ...
    2013 Volume 61 Issue 7 Pages 700-705
    Published: July 01, 2013
    Released on J-STAGE: July 01, 2013
    Advance online publication: May 14, 2013
    DOIhttps://doi.org/10.1248/cpb.c13-00186
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    Maintenance of proper moisture and regulation of infection are simultaneously required to promote healing of pressure ulcers. Continuous use of water-rich ointment may often lead to excess moisture and induce edematous granulation tissue. Use of water soluble ointment may excessively absorb exudates and induce dry granulation tissue. Selection of appropriate topical ointment is desired to avoid worse clinical outcomes. For adjustment of wound moisture a novel blended ointment (tretinoin tocoferil-povidone-iodine (TR-PI)) was developed consisting of emulsion base, tretinoin tocoferil oil-in-water (o/w) emulsion (TR-cream), and sugar base, povidone-iodine and sugar (PI-sugar). For the characterization of TR-PI water absorption was tested using Franz diffusion cell with cellulose membrane. For rheological characteristics spreadability was tested using spread meter and yield value was calculated. Iodine permeation was tested using a permeation cell with silicon membrane. Water absorption rate constant of TR-PI with combination ratio of PI-sugar at 75% (TR-PI75, 18.5 mg cm−2 min−0.5) was equivalent to that of TR-cream alone (16.4 mg cm−2 min−0.5). The yield value of TR-PI75 (26.1 Pa) exhibited intermediate values as compared to those of TR-PI with combination ratio of PI-sugar at 50% (11.3 Pa) and TR-cream alone (46.8 Pa). The amount of released free-iodine from TR-PI75 was similar to that released from PI-sugar alone. TR-PI75 may have superior performance in keeping the moist environment in wounds and in preventing infection. TR-PI75 can be used to promote formation of favorable granulation tissue in pressure ulcers with moderate exudates.
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  • A Bioluminescent Assay System for Whole-Cell Determination of Hormones
    Sung Bae Kim, Toshiyuki Suzuki, Akira Kimura
    2013 Volume 61 Issue 7 Pages 706-713
    Published: July 01, 2013
    Released on J-STAGE: July 01, 2013
    Advance online publication: April 22, 2013
    DOIhttps://doi.org/10.1248/cpb.c13-00195
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    A bioluminescent-assay system was fabricated for an efficient determination of bioactive small molecules in physiological samples. The following three components were newly created for this assay system: (i) a single-chain probe exerting a 7.2-times stronger optical intensity than conventional ones, (ii) a high throughput assay device uniquely designed for the assay system with ca. one-fourth smaller standard deviation (S.D.) to samples than without the device, (iii) a buffer cocktail optimized for the assay system. The advantages of the assay system were evaluated by determining (i) the stress hormone levels in human saliva and (ii) multicolor imaging of genomic and nongenomic effects of woman sex hormones. This study guides on how to fabricate an efficient assay system for bioactive small molecules with convenience and high precision.
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  • Synthesis, Crystal Structures and DNA-Cleaving Activities of [Cemp]2[MCl4] (Cemp=N-Carbethoxymethyl-1,10-phenanthrolinium, M=CuII, ZnII, CoII, NiII and MnII)
    Ming-Zhen Chen, Ming Chen, Chun-Qiong Zhou, Wei-Er Lin, Jin-Xiang Chen ...
    2013 Volume 61 Issue 7 Pages 714-721
    Published: July 01, 2013
    Released on J-STAGE: July 01, 2013
    DOIhttps://doi.org/10.1248/cpb.c13-00198
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    N-Carbethoxymethyl-1,10-phenanthrolinium bromide (CempBr) and its five ionic metal complexes, [Cemp]2[MCl4] where M=CuII (1), ZnII (2), CoII (3), NiII (4) and MnII (5) were synthesized and fully characterized. Complexes 1–5 have similar structures, and consist of isolated [Cemp]+ cations and [MCl4]2− anions in which there are no obvious interactions between the oxygen or nitrogen donor atoms in [Cemp]+ and the metal center in [MCl4]2−. Agarose gel electrophoresis studies on the cleavage of plasmid pBR322 DNA by complexes 1–5 indicated that complex 1 was capable of efficiently cleaving DNA under physiological conditions, most probably via an oxidative mechanism. Kinetic assay of complex 1 afforded the maximal catalytic rate constant kmax of 0.55 h−1 and Michaelis constant KM of 47.6 µM, respectively, which gives about 1.5×107-fold rate acceleration over uncatalyzed cleavage of supercoiled DNA. Ethidium bromide displacement experiments indicated that complex 1 had a binding affinity of (1.58±1.12)×106 M−1 toward calf-thymus DNA, 20–100-fold higher than those shown by CempBr and complexes 2–5. The high cleaving efficacy of complex 1 is thought to be due to the efficient catalysis of the copper(II)-coordinated center and the efficient binding of the quaternized 1,10-phenanthroline cation to DNA.
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  • Synthesis, Antimicrobial and Cytotoxic Activities of Sulfonamidomethane Linked Heterocycles
    Mukkara Swapna, Chokkappagari Premakumari, Sanapalli Nagi Reddy, Adivi ...
    2013 Volume 61 Issue 7 Pages 722-730
    Published: July 01, 2013
    Released on J-STAGE: July 01, 2013
    DOIhttps://doi.org/10.1248/cpb.c13-00218
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    A new class of sulfonamidomethane pyrrolyl–oxadiazoles/thiadiazoles and pyrazolyl–oxadiazoles/thiadiazoles was prepared from arylsulfonylaminoacetic acid hydrazides and E-cinnamic acid. The lead compounds were tested for antimicrobial and cytotoxic activities. The thiadiazole compounds having chloro substituent on the aromatic ring 4c, 8c and 10c exhibited comparable antibacterial activity against Pseudomonas aeruginosa and also antifungal activity against Penicillium chrysogenum. The styryl oxadiazole compound 3c showed appreciable cytotoxic activity on A549 lung carcinoma cells which can be used as a lead compound in the future studies.
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  • Synthesis and in Vitro Antifungal Activities of New 2-Aryl-6,7-methylenedioxy-3,4-dihydroisoquinolin-2-ium Bromides
    Xinjuan Yang, Yao Yao, Yuyan Qin, Zhe Hou, Rui Yang, Fang Miao, Le Zho ...
    2013 Volume 61 Issue 7 Pages 731-739
    Published: July 01, 2013
    Released on J-STAGE: July 01, 2013
    Advance online publication: May 10, 2013
    DOIhttps://doi.org/10.1248/cpb.c13-00221
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    2-Aryl-3,4-dihydroisoquinolin-2-iums might be considered as a class of simple analogues of natural quaternary benzo[c]phenanthridine alkaloids. In this paper, 26 new 2-aryl-6,7-methylenedioxy-3,4-dihydroisoquinolin-2-ium bromides with various substituents in N-aromatic ring were synthesized from commercially available 1,3-benzodioxole in good to excellent yields. All the compounds were elucidated by MS, high resolution (HR)-MS, IR, 1H- and 13C-NMR analysis, and evaluated for antifungal activities in vitro against Alternaria alternate, Curvularia lunata and Fusarium oxysporum sp. niveum at 50 µg/mL. Most of the compounds showed higher activities against all the test fungi than their natural model compounds sanguinarine and chelerythrine. For A. alternate and Curvularia lunata, most of them were also more active than thiabendazole, a commercial fungicide standard. The structure–activity relationship indicated that the substituent in N-aromatic ring and its position had significant effect on the activity. The general trend was that halogen atoms and CF3 remarkably enhanced the activity while CH3 and OCH3 decreased the activity. Generally, o-substituted isomers were more active than m- and p-substituted isomer. The present results suggest that the title compounds are potential for the development of new isoquinoline antimicrobial agents.
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  • Hydroxynaphthoic Acids Identified in a High Throughput Screening Potently Ameliorate Endoplasmic Reticulum Stress as Novel Chemical Chaperones
    Kwi-wan Jeong, Jin-mo Ku, Myung-whan Park, Sun-mi Park, Jung-eun Yang, ...
    2013 Volume 61 Issue 7 Pages 740-746
    Published: July 01, 2013
    Released on J-STAGE: July 01, 2013
    DOIhttps://doi.org/10.1248/cpb.c13-00251
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    Folding of newly synthesized protein occurs in endoplasmic reticulum (ER) and is assisted by chaperone molecules. In ER stress conditions, misfolded proteins are enriched in a lumen of ER perturbing its normal function, which triggers cellular self-defense mechanism, the unfolded protein response (UPR). It was reported that tunicamycin-induced ER stress can be modulated with high concentration of chemicals such as 4-phenylbutyric acid and salicylate. In search of assay systems to identify such compounds, we have developed a cell-based reporter assay where renilla luciferase activity is driven by glucose-regulated protein 78 (GRP78) promoter. Using our reporter assay, we have screened chemical libraries and found that hydroxynaphthoic acids, especially 1-, 3-, and 6-hydroxy-2-naphthoic acids, potently decrease the ER stress signal, showing an order of magnitude better activity than salicylate. UPR markers such as GRP78, C/EBP homology protein (CHOP) and phosphorylated protein kinase RNA-activated (PKR)-like ER kinase (PERK) were significantly down-regulated with hydroxynaphthoic acids in western blot. Among the analogues, 1-hydroxy-2-naphthoic acid was the most potent in down-regulating those UPR markers. Further, both phosphorylated inositol-requiring enzyme 1α (IRE1α) and spliced form of X-box binding protein 1 (XBP1) were decreased in the protein and the mRNA level, implying both PERK and IRE1α branches in UPR mechanism are controlled with hydroxynaphthoic acids. Taken together, it was suggested that hydroxynaphthoic acids exert their ER stress-reducing activity prior to the UPR activation as chemical chaperones do. In summary, we report a cell-based assay system for the screening of ER stress-reducing compounds and hydroxynaphthoic acids as novel series of chemical chaperones.
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  • Novel Quinolinylaminoisoquinoline Bioisosteres of Sorafenib as Selective RAF1 Kinase Inhibitors: Design, Synthesis, and Antiproliferative Activity against Melanoma Cell Line
    Hye Jung Cho, Mohammed Ibrahim El-Gamal, Chang-Hyun Oh, So Ha Lee, Tae ...
    2013 Volume 61 Issue 7 Pages 747-756
    Published: July 01, 2013
    Released on J-STAGE: July 01, 2013
    DOIhttps://doi.org/10.1248/cpb.c13-00283
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    Design and synthesis of a new series of quinolinylaminoisoquinoline derivatives as conformationally restricted bioisosteres of Sorafenib are described. Their in vitro antiproliferative activity against A375P melanoma cell line was tested. Compounds 1b, 1d, 1g, and 1j showed the highest potency against A375P cell line with IC50 values in sub-micromolar scale. In addition, compound 1d exerted high selectivity towards RAF1 serine/threonine kinase with 96.47% inhibition at 10 µM, and IC50 of 0.96 µM. This compound can possess antiproliferative activity against melanoma cells through inhibition of RAF1 kinase.
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  • Synthesis and Antiproliferative Effect of Novel Curcumin Analogues
    Bingmi Liu, Mingyu Xia, Xiaoling Ji, Liying Xu, Jinhua Dong
    2013 Volume 61 Issue 7 Pages 757-763
    Published: July 01, 2013
    Released on J-STAGE: July 01, 2013
    Advance online publication: May 11, 2013
    DOIhttps://doi.org/10.1248/cpb.c13-00295
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    Novel curcumin analogues with α,β-unsaturated ketone moiety and/or α,β-saturated ketone structure were synthesized from curcumin via alkylation at the central carbon and the phenolic hydroxy groups, and hydrogenation of α,β-unsaturated ketone moiety. The antiproliferative activities were tested in five human solid tumor cell lines in vitro. Most of the compounds exhibited increased antiproliferative activities comparing with that of curcumin. Structure–activity relationship (SAR) analysis revealed that the α,β-unsaturated ketone structure was not required for antiproliferative activity of these curcumin analogues. Among these compounds, 1,7-bis(3-methoxy-4-(3-(4-methylpiperazinyl-1-yl)propoxy)phenyl)-4,4-dibenzylheptane-3,5-dione (16f) was the most effective one with IC50 value below 1 µM, which was 9- to 81-fold more potent than curcumin.
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