Chemical and Pharmaceutical Bulletin
Online ISSN : 1347-5223
Print ISSN : 0009-2363
ISSN-L : 0009-2363
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63 巻, 12 号
選択された号の論文の15件中1～15を表示しています
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Regular Articles
  • Importance of Proton-Coupled Electron Transfer from Natural Phenolic Compounds in Superoxide Scavenging
    Tatsushi Nakayama, Bunji Uno
    2015 年 63 巻 12 号 p. 967-973
    発行日: 2015/12/01
    公開日: 2015/12/01
    DOIhttps://doi.org/10.1248/cpb.c15-00447
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    The superoxide O2·− scavenging reaction of (+)-catechin (Cat), quercetin (Que), rutin, and α-tocopherol (α-TOH) as natural phenolic compounds is investigated on the basis of electrochemical and ESR spectral measurements with the aid of density functional theory (DFT) calculations. Reversibility of the O2/O2·− redox couple is significantly affected by the presence of the phenolic compounds. The catechol moiety of Cat, Que, and rutin plays an essential role in concerted proton-coupled electron transfer (PCET) to HO2· derived from O2·− to give H2O2 and the corresponding o-benzoquinone radical anions. On the other hand, the presence of α-TOH causes sequential electron and proton transfers to HO2· to give H2O2 and the α-tocopheroxyl radical. These electron transfers in the presence of the phenolic compounds are inferred from the ESR spectral measurements. The DFT calculation results suggest that the O2·− scavenging reaction of the natural phenolic compounds proceeds efficiently with the one-step concerted PCET or sequential PCET mechanism.
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  • Synthesis and Anti-cancer Activity of Novel Thiazolidinone Analogs of 6-Aminoflavone
    Sudheer Moorkoth
    2015 年 63 巻 12 号 p. 974-985
    発行日: 2015/12/01
    公開日: 2015/12/01
    [早期公開] 公開日: 2015/09/15
    DOIhttps://doi.org/10.1248/cpb.c15-00454
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    Novel heterocyclic analogs were synthesized by combining a flavone nucleus and thiazolidinone ring in an effort to potentiate the existing anti-cancer activity of flavone. The syntheses of 6-aminoflavone, 6-amino-3-methoxyflavone, 6-amino-3-methoxy-3′,4′-dimethxyflavone and their corresponding thiazolidinone analogs were performed. Fifteen novel analogs were synthesized and evaluated for their anti-cancer activity using cell-based assay techniques and in vivo testing. As expected, the analogs improved cytotoxicity and were shown to increase the life span of cancer-bearing mice. Cytotoxicity was evaluated using 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assays in HeLa, MDA-MB-435, and Vero cell lines. In vivo evaluation of anti-cancer activity performed in albino mice bearing Dalton’s ascites carcinoma showed that the new analogs enhanced life span and prevented increases in body weight owing to tumor volumes. Moreover, cell-cycle analysis and Hoechst staining analysis proved the apoptotic potential of these analogs. Preliminary pharmacokinetic evaluation was carried out on the synthesized compounds to determine the lipophilicity and pKa. Lipophilicity was determined using high-performance liquid chromatography and the results showed a direct correlation between the observed anti-cancer activity and log P value, while pKa values indicated the ionizing range which is a prediction tool for solubility and permeability.
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  • Development and Assessment of a Nomogram to Propose the Initial Dosage Regimen of a Meropenem Infusion Based on Serum Creatinine and Age Using a Monte Carlo Simulation
    Noriyuki Shino, Takahiro Uchida, Miyako Yoshida, Yasuo Nomura
    2015 年 63 巻 12 号 p. 986-991
    発行日: 2015/12/01
    公開日: 2015/12/01
    DOIhttps://doi.org/10.1248/cpb.c15-00494
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    A conventional nomogram, based on serum creatinine (sCr) and age, was developed in order to determine the correct initial dosage regimen for meropenem (MEPM) infusions in elderly patients with severe community-acquired pneumonia (CAP), using a target minimum inhibitory concentration (MIC) of 2 mg/L. A correlation between age and actual bodyweight (BW) in a development cohort of 44 males and 45 females was performed by linear regression using the least-squares method (male: y=−0.4676x+80.281, R2=0.4888; female: y=−0.4373x+77.502, R2=0.3194). There were no significant differences between actual BW and the BW (e-BW) estimated using this equation in this cohort (male: e-BW 41.6±3.1 kg, BW 41.7±3.5 kg, p=0.93; female: e-BW 39.5±2.1 kg, BW 39.5±3.7 kg, p=0.20). By integrating these equations using the Monte Carlo simulation method, a dosage regime was calculated which would have an 80% probability of maintaining plasma drug levels above the MIC for more than 40% of the time (>40%TAM), using only the age and sCr of individual patients. This relationship was summarized as a nomogram. The nomogram was validated using an independent validation cohort (n=28) of patients. An optimized dosage regimen could be predicted in 84 patients (94.4%) in the development cohort and 25 patients (89.3%) in the validation cohort. This nomogram may be a useful tool for clinicians and pharmacists in determining an initial MEPM regimen in elderly patients with severe CAP, based only on age and sCr.
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  • Development of Novel Polymeric Prodrugs Synthesized by Mechanochemical Solid-State Copolymerization of Hydroxyethylcellulose and Vinyl Monomers
    Naoki Doi, Yasushi Sasai, Yukinori Yamauchi, Tetsuo Adachi, Masayuki K ...
    2015 年 63 巻 12 号 p. 992-997
    発行日: 2015/12/01
    公開日: 2015/12/01
    [早期公開] 公開日: 2015/10/01
    DOIhttps://doi.org/10.1248/cpb.c15-00497
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    Novel polymeric prodrugs were synthesized by mechanochemical solid-state copolymerization of hydroxyethylcellulose and the methacryloyloxy derivative of 5-fluorouracil (5-FU). Copolymerization was about 94% complete after 4 h, and the polymeric prodrug was quantitatively obtained after 14 h of reaction. The number average molecular weight (Mn) and polydispersity (H) of the polymeric prodrug were 39000 g/mol and 6.20, respectively. Mechanical fracturing of the polymer in a stainless steel twin-shell blender improved these properties (Mn=16000 g/mol and H=1.94). 5-FU was sustainably released from the polymeric prodrugs, and the rate was not affected by the molecular weight or molecular weight distribution of the prodrug under the experimental conditions used. These results suggest that novel polymeric prodrugs composed of a polysaccharide and a synthetic polymer can be fabricated by mechanochemical solid-state copolymerization under anaerobic conditions.
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  • Novel 2,7-Substituted (S)-1,2,3,4-Tetrahydroisoquinoline-3-carboxylic Acids: Peroxisome Proliferator-Activated Receptor γ Partial Agonists with Protein–Tyrosine Phosphatase 1B Inhibition
    Kazuya Otake, Satoru Azukizawa, Shigemitsu Takeda, Masaki Fukui, Arisa ...
    2015 年 63 巻 12 号 p. 998-1014
    発行日: 2015/12/01
    公開日: 2015/12/01
    DOIhttps://doi.org/10.1248/cpb.c15-00508
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    A novel series of 2,7-substituted 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid derivatives were synthesized and biologically evaluated. (S)-2-(2-Furylacryloyl)-7-[2-(2-methylindane-2-yl)-5-methyloxazol-4-yl]methoxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid tert-butylamine salt (13jE) was identified as a potent human peroxisome proliferator-activated receptor γ (PPARγ)-selective agonist (EC50=85 nM) and human protein–tyrosine phosphatase 1B (PTP-1B) inhibitor (IC50=1.0 µM). Compound 13jE partially activated PPARγ, but not PPARα or PPARδ, and antagonized farglitazar, a full PPARγ agonist. Cmax after the oral administration of 13jE at 10 mg/kg was 28.6 µg/mL (53 µM) in male Sprague-Dawley (SD) rats. Repeated administration of 13jE and rosiglitazone for 14 d at 10 mg/kg/d decreased plasma glucose and triglyceride levels significantly in male KK-Ay mice. Rosiglitazone, but not 13jE, significantly increased the plasma volume and liver weight. In conclusion, 13jE showed stronger hypoglycemic and hypolipidemic effects and weaker hemodilution and hepatotoxic effects than rosiglitazone, suggesting that its safer efficacy may be due to its partial PPARγ agonism and PTP-1B inhibition.
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  • Discovery of Potent Antiproliferative Agents Targeting EGFR Tyrosine Kinase Based on the Pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidin-4-amine Scaffold
    Yasmine Mohamed Abdel Aziz, Mohamed Mokhtar Said, Hosam Ahmed El Shiha ...
    2015 年 63 巻 12 号 p. 1015-1028
    発行日: 2015/12/01
    公開日: 2015/12/01
    DOIhttps://doi.org/10.1248/cpb.c15-00592
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    A series of pyridothieno[3,2-d]pyrimidin-4-amines was designed and synthesized as congeners to the classical 4-anilinoquinazolines as ATP-competitive epidermal growth factor receptor (EGFR) inhibitors. Compound 5a exhibited the most potent and selective inhibitory activity against EGFR with an IC50 value of 36.7 nM. Moreover, compounds 4b and 5a showed remarkable cell growth inhibition against leukemia, central nervous system cancer, and non-small cell lung cancer cell lines that overexpress EGFR, with growth inhibition of 50% (GI50) values of around 10 nM in the full U.S. National Cancer Institute 60 cell panel assay. Cell cycle studies indicated that compounds 4b and 5a induced significant cell cycle arrest in the S-phase and G0/G1, respectively, in addition to boosting P27kip expression. Compound 5a did not alter the viability of placental trophoblasts, which reflects its safety for normal cells. The standard COMPARE analyses demonstrated considerable correlation levels between compounds 4b and 5a and erlotinib, with pyridinium chlorochromate (PCC) values of 0.707 and 0.727, respectively.
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  • Design, Synthesis, Biological Evaluation, and Antioxidant and Cytotoxic Activity of Heteroatom-Substituted 1,4-Naphtho- and Benzoquinones
    Nahide Gülşah Deniz, Cemil Ibis, Zeliha Gokmen, Maryna Stasevych, Volo ...
    2015 年 63 巻 12 号 p. 1029-1039
    発行日: 2015/12/01
    公開日: 2015/12/01
    DOIhttps://doi.org/10.1248/cpb.c15-00607
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    In the present paper, we report the synthesis, characterization, and biological evaluation as antifungal, antibacterial, antioxidant, and cytotoxic/anticancer agents of N-, S-, O-substituted-1,4-naphtho- and 2,5-bis(amino-substituted)-1,4-benzoquinone derivatives. In the synthesized compounds, antimicrobial activity at low concentrations against Escherichia coli B-906, Staphylococcus aureus 209-P, and Mycobacterium luteum B-917 bacteria and Candida tenuis VKM Y-70 and Aspergillus niger F-1119 fungi in comparison with controls was identified. 2-(N-Diphenylmethylpiperazin-1-yl)-3-chloro-1,4-naphthoquinone 9a was the most potent, with a minimum inhibitory concentration value of 3.9 µg/mL against test culture M. luteum. The synthesized compounds were screened for their antioxidant capacity using the cupric-reducing antioxidant capacity (CUPRAC) method. 2,2′-[1-(2-Aminoethyl)piperazin-1-yl]-3,3′-dichloro-bis(1,4-naphthoquinone) 10 showed the highest antioxidant capacity, with a 0.455 CUPRAC-trolox equivalent antioxidant capacity (TEAC) coefficient. Other parameters of antioxidant activity (scavenging effects on OH·, O2·－, and H2O2) of these compounds were also determined. The cytotoxic activity of the compounds was investigated by employing the sulforhodamine B cell viability assay against A549 (lung), MCF-7 (breast), DU145 (prostate), and HT-29 (colon) cancer cell lines. Compound 10 exhibited the most powerful cytotoxic activity at a concentration of 20 µM against all cell lines. In addition to the strongest antioxidant activity of compound 10, it also had lowest IC50 values (<3 µM), warranting further in vivo studies due to its anticancer activity.
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  • Adsorption of As(III) from Aqueous Solutions by Novel Fe–Mg Type Hydrotalcite
    Fumihiko Ogata, Naohito Kawasaki
    2015 年 63 巻 12 号 p. 1040-1046
    発行日: 2015/12/01
    公開日: 2015/12/01
    DOIhttps://doi.org/10.1248/cpb.c15-00613
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    Morphological and chemical evaluation of Fe–Mg hydrotalcite (Fe-HT) was performed using scanning electron microscopy, X-ray diffraction analysis, and electron microanalysis for application as an adsorbent for water treatment. The adsorption of arsenic III (As(III)) on Fe-HT was evaluated via examination of the effect of the contact time and analysis of the adsorption isotherm. The amount of As(III) adsorbed increased slightly with increasing temperature. The results of the adsorption isotherm studies suggested that As(III) adsorption can be well described by both the Freundlich and Langmuir equations. The adsorption of As(III) on Fe-HT reached equilibrium within 24 h, and the adsorption kinetic data fit the pseudo-second-order kinetic model better than the pseudo-first-order model. The amount of As(III) present on the surface of Fe-HT increased after As(III) adsorption, and the crystalline structure of Fe-HT was maintained after adsorption of As(III). The (003) and (006) peaks in the X-ray diffraction patterns were attributed to basal reflections, and these peaks shifted from respective 2θ values of 10.86 and 21.94° to 11.12 and 22.52°, indicating exchange of As(III) with chloride ions in Fe-HT with consequent narrowing of the inter-layer spacing. Collectively, these results suggest that Fe-HT is prospectively useful for the adsorption of As(III) from aqueous solutions.
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  • Crotocascarins I–K: Crotofolane-Type Diterpenoids, Crotocascarin γ, Isocrotofolane Glucoside and Phenolic Glycoside from the Leaves of Croton cascarilloides
    Susumu Kawakami, Katsuyoshi Matsunami, Hideaki Otsuka, Masanori Inagak ...
    2015 年 63 巻 12 号 p. 1047-1054
    発行日: 2015/12/01
    公開日: 2015/12/01
    DOIhttps://doi.org/10.1248/cpb.c15-00635
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    From the 1-BuOH-soluble fraction of a methanol (MeOH) extract of the leaves of Croton cascarilloides, crotofolanes: crotocascarins I–K, nor-crotofolane: crotocascarin γ, isocrotofolane glucoside and phenolic glycoside were isolated by a combination of various separation techniques. Their structures were elucidated mainly from the NMR spectroscopic evidence. The structure of crotocascarin K was first elucidated by spectroscopic analysis and then was confirmed by X-ray crystallographic analysis. Its absolute structure was finally determined by the modified Mosher’s method. Isocrotofolane glucoside was found to possess a new skeleton, however, its absolute structure remains to be determined.
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  • Multicomponent Reactions of Acetoacetanilide Derivatives with Aromatic Aldehydes and Cyanomethylene Reagents to Produce 4H-Pyran and 1,4-Dihydropyridine Derivatives with Antitumor Activities
    Rasha Abdallah Azzam, Rafat Milad Mohareb
    2015 年 63 巻 12 号 p. 1055-1064
    発行日: 2015/12/01
    公開日: 2015/12/01
    DOIhttps://doi.org/10.1248/cpb.c15-00685
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    The multi-component reaction of either acetoacetanilide derivative 1a or b with any of the aldehyde derivatives 2a–d and malononitrile 3 in the presence of triethylamine as a catalyst gave the 4H-pyran derivatives 4a–g, respectively. Carrying the same reaction but using a catalytic amount of ammonium acetate gave the 1,4-dihydropyridine derivatives 5a–f, respectively. The use of ethyl cyanoacetate instead of malononitrile in the presence of a catalytic amount of triethylamine gave the 4H-pyran derivatives 7a–d, respectively. Compound 4e was used to synthesize 1,4-dihydropyridine 9a–c and arylhydraone 11a–e derivatives were synthesized from 4a and e. The anti-tumor evaluations of the newly synthesized products were tested against six human cancer and normal cell lines. The results showed that compounds 4a, b, f, 5d, f, 9 and 11a–d had optimal cytotoxic effect against cancer cell lines with IC50<550 nM. The toxicity of the most active compounds was further measured against shrimp larvae.
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