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Volume 62, Issue 12
Displaying 1-13 of 13 articles from this issue
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Review
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Kenji Watanabe2014 Volume 62 Issue 12 Pages 1153-1165
Published: December 01, 2014
Released on J-STAGE: December 01, 2014
JOURNAL FREE ACCESS FULL-TEXT HTMLIn the past few years, there has been impressive progress in elucidating the mechanism of biosynthesis of various natural products accomplished through the use of genetic, molecular biological and biochemical techniques. Here, we present a comprehensive overview of the current results from our studies on fungal natural product biosynthetic enzymes, including nonribosomal peptide synthetase and polyketide synthase–nonribosomal peptide synthetase hybrid synthetase, as well as auxiliary enzymes, such as methyltransferases and oxygenases. Specifically, biosynthesis of the following compounds is described in detail: (i) Sch210972, potentially involving a Diels–Alder reaction that may be catalyzed by CghA, a functionally unknown protein identified by targeted gene disruption in the wild type fungus; (ii) chaetoglobosin A, formed via multi-step oxidations catalyzed by three redox enzymes, one flavin-containing monooxygenase and two cytochrome P450 oxygenases as characterized by in vivo biotransformation of relevant intermediates in our engineered Saccharomyces cerevisiae; (iii) (−)-ditryptophenaline, formed by a cytochrome P450, revealing the dimerization mechanism for the biosynthesis of diketopiperazine alkaloids; (iv) pseurotins, whose variations in the C- and O-methylations and the degree of oxidation are introduced combinatorially by multiple redox enzymes; and (v) spirotryprostatins, whose spiro-carbon moiety is formed by a flavin-containing monooxygenase or a cytochrome P450 as determined by heterologous de novo production of the biosynthetic intermediates and final products in Aspergillus niger. We close our discussion by summarizing some of the key techniques that have facilitated the discovery of new natural products, production of their analogs and identification of biosynthetic mechanisms in our study.View full abstractDownload PDF (1729K) Full view HTML
Communication to the Editor
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Omar Maged El-Said, Mostafa Mohamed Hamed, Stefan Laufer, Ashraf Hassa ...2014 Volume 62 Issue 12 Pages 1166-1172
Published: December 01, 2014
Released on J-STAGE: December 01, 2014
JOURNAL FREE ACCESS FULL-TEXT HTMLThe aim of this work was to synthesize 4-acetamido-, 4-amino- and 4-oxo-6-substituted aminoquinazolines and to evaluate them as phosphoinositide 3-kinases (PI3Ks) inhibitors. The respective chemotype was designed based on combining the structural features of two previously reported scaffolds acting as potent PI3Kγ inhibitors, which are quinazoline derivatives and amino-heterocyclic derivatives. In vitro enzymatic assay at 10 µM against all the eight human PI3K isoforms showed that an unsubstituted benzamide group at position 6 and an acetyl group at N4 gave the best inhibitory activity on PI3Kγ. Interestingly, compounds 5a and 5e showed a significant, inhibitory effect on Class II PI3K-C2γ. This is of high value since there are very few inhibitors for this isoform reported in the literature.View full abstractDownload PDF (557K) Full view HTML
Regular Articles
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Hongxing Ma, Mingjuan Chu, Kiyoshi Itagaki, Ping Xin, Xuegang Zhou, Da ...2014 Volume 62 Issue 12 Pages 1173-1179
Published: December 01, 2014
Released on J-STAGE: December 01, 2014
JOURNAL FREE ACCESS FULL-TEXT HTMLThe liquid self-emulsifying drug delivery system (L-SEDDS), commonly used to deliver effective but poorly water-soluble oleanolic acid (OA), has many limitations such as high manufacturing costs, few choices of dosage forms, risk of leakage from hard gelatin capsules, low stability, limited portability, incompatibility with capsule materials, and relatively restricted storage conditions. Thus the main purpose of our study was to develop a promising solid lipid-based drug delivery system (S-SEDDS) for OA. The S-SEDDS, prepared from wet granulation with an optimized L-SEDDS formulation and mannitol, was characterized by particle size analysis, scanning electron microscopy, differential scanning calorimetry, and X-ray powder diffraction. Finally, the solubility of the OA-loaded S-SEDDS was compared with that of OA powder in the dissolution assay. Our new S-SEDDS for OA was developed from the optimum L-SEDDS with ethyl oleate (oil phase), Labrasol (surfactant), and Transcutol P (cosurfactant) at a volume ratio of 15 : 71 : 14 with 1.5% w/v OA and mannitol. The dissolution of OA was improved by 60% compared with that of the pure OA powder. All the problems associated with the L-SEDDS were resolved. The methodologies we developed for OA delivery could also be utilized for the delivery of other drugs with the S-SEDDS.View full abstractDownload PDF (1500K) Full view HTML -
Shigesaburo Ogawa, Kouichi Asakura, Shuichi Osanai2014 Volume 62 Issue 12 Pages 1180-1184
Published: December 01, 2014
Released on J-STAGE: December 01, 2014
JOURNAL FREE ACCESS FULL-TEXT HTML
Supplementary materialThe properties of low molecular weight glycolipids at subzero temperatures have been paid much attention due to their great potential for applications in cryopreservation. In this study, the ability of glycolipids to maintain their lyotropic properties was investigated by analyzing the aggregation behavior of octyl-β-D-glucoside (β-OGlu) during solidification and melting of electrolyte/ice eutectic mixtures using a simultaneous X-ray diffraction–differential scanning calorimetry measurement and cryomicroscopic observation. During the freezing process, eutectic formation increased the concentration of the β-OGlu micelle solution in the unfrozen phase, leading to ordering of the molecular assembly. The molecular assembly exhibited a reversible phase transformation between liquid crystalline phases (e.g., lamellar (Lα) and hexagonal (H) phases) and an isotropic micelle solution (I), depending on the degree of eutectic formation, which was regulated by temperature. Because the coexistence of electrolyte/ice eutectic often induces the dehydration of lipids, the persistence of lyotropic properties under such arid conditions demonstrates an attractive performance of glycolipids for use in low temperature applications, such as the cryopreservation of poorly water-soluble drugs or proteins.View full abstractDownload PDF (1175K) Full view HTML -
Shiliang Tu, Hang Yuan, Jie Hu, Chengguang Zhao, Rui Chai, Hongfeng Ca ...2014 Volume 62 Issue 12 Pages 1185-1191
Published: December 01, 2014
Released on J-STAGE: December 01, 2014
JOURNAL FREE ACCESS FULL-TEXT HTMLNovel nitro oxide (NO)-donating N-hydroxycinnamamide derivatives 12a–j were designed and synthesized by coupling the carboxyl group of N-hydroxycinnamamides with phenylsulfonylfuroxan through various diols or alkylol amines, and their in vitro biological activities were evaluated. It was discovered that most of target compounds showed good histone deacetylases (HDACs) inhibition and anti-tumor activities, particularly for 12j, which had great HDACs inhibitory activities (IC50s=0.15–0.26 µM) and antiproliferative effects (IC50s=3.21–7.12 µM) comparable to suberoylanilide hydroxamic acid (SAHA) (IC50s=0.16–1.41 µM for HDACs, IC50s=3.15–7.45 µM for cancer cell inhibition). Furthermore, compound 12j with strong antitumor activities produced high levels of NO (up to 8.0 µM of nitrites/nitrates) in colon cancer cells, and its antiproliferative activity was nearly half-diminished by hemoglobin (10 µM), an NO scavenger. These results suggest that the strong antiproliferative activity of 12j could be attributed to the additive effects of high levels of NO production and inhibition of HDAC in the cancer cells.View full abstractDownload PDF (546K) Full view HTML -
Yukiko Matsuo, Hiroshi Sakagami, Yoshihiro Mimaki2014 Volume 62 Issue 12 Pages 1192-1199
Published: December 01, 2014
Released on J-STAGE: December 01, 2014
JOURNAL FREE ACCESS FULL-TEXT HTMLA rare type of sesquiterpene with a spiro bicyclic system (1) and seven new (2–8) and four known (9–12) β-santalol derivatives were isolated from the heartwood of Santalum album (Santalaceae). The structures of these new compounds were determined by analysis of extensive spectroscopic data. The isolated compounds and derivatives were evaluated for their cytotoxic activity against HL-60 human promyelocytic leukemia cells, A549 human lung adenocarcinoma cells, HSC-2 and HSC-4 human oral squamous cell carcinoma cell lines, and TIG-3 normal human diploid fibroblasts. cis-β-Santalol (9) and β-santaldiol (10) induced apoptotic cell death in HL-60 cells.View full abstractDownload PDF (755K) Full view HTML -
Wataru Hamaguchi, Naoyuki Masuda, Kiyohiro Samizu, Takuma Mihara, Kaor ...2014 Volume 62 Issue 12 Pages 1200-1213
Published: December 01, 2014
Released on J-STAGE: December 01, 2014
JOURNAL FREE ACCESS FULL-TEXT HTMLA novel class of phosphodiesterase 10A (PDE10A) inhibitors with improved metabolic stability in mouse liver microsomes were designed and synthesized starting from 2-({4-[1-methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl]phenoxy}methyl)quinoline (MP-10). Replacement of the phenoxymethyl part of MP-10 with an oxymethyl phenyl unit led to the identification of 2-[4-({[1-methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl]oxy}methyl)phenyl]quinoline (14), which showed moderate PDE10A inhibitory activity with improved metabolic stability in mouse and human liver microsomes over MP-10. Compound 14 showed high concentrations in plasma and brain after intraperitoneal administration and dose-dependently attenuated the hyperlocomotion induced by phencyclidine in mice, and oral administration of 14 (0.1, 0.3 mg/kg) also improved visual-recognition memory impairment in mice.View full abstractDownload PDF (1782K) Full view HTML -
Deepak Bhattarai, Ju-hyeon Lee, Seon Hee Seo, Ghilsoo Nam, Hyunah Choo ...2014 Volume 62 Issue 12 Pages 1214-1224
Published: December 01, 2014
Released on J-STAGE: December 01, 2014
Advance online publication: October 09, 2014JOURNAL FREE ACCESS FULL-TEXT HTMLA novel series of oxazolidinone-class antimicrobial agents with 5-substituted octahydrocyclopenta[c]pyrrole moieties at the C-ring of linezolid and an acetamide or 1,2,3-triazole ring as the C-5 side chain of the oxazolidinone ring were prepared. The resulting series of compounds were evaluated for in vitro antimicrobial activity against Mycobacterium tuberculosis and a panel of clinically important resistant Gram-positive and -negative bacteria. Among them, endo-alcohol 2a and exo-alcohol 2b showed potent inhibitory activity against M. tuberculosis H37Rv, which was superior to that of linezolid. Several analogues in this series showed potent in vitro antibacterial activity against the clinically important vancomycin-resistant bacteria and showed similar or better potency against linezolid-resistant methicillin-resistant Staphylococcus aureus (MRSA) strains. The hydroxyl group in the azabicyclic C-ring interacted with the same hydrophobic pocket as linezolid based on a docking study. Selected compounds with high antimicrobial activity showed good human microsomal stability and low CYP isozyme and monoamine oxidase (MAO) inhibition.View full abstractDownload PDF (1705K) Full view HTML -
Koji Mochizuki, Kozo Takayama2014 Volume 62 Issue 12 Pages 1225-1230
Published: December 01, 2014
Released on J-STAGE: December 01, 2014
JOURNAL FREE ACCESS FULL-TEXT HTMLThis study reports the results of applying the time–temperature superposition principle (TTSP) to the prediction of color changes in liquid formulations. A sample solution consisting of L-tryptophan and glucose was used as the model liquid formulation for the Maillard reaction. After accelerated aging treatment at elevated temperatures, the Commission Internationale de l’Eclairage (CIE) LAB color parameters (a*, b*, L*, and E*ab) of the sample solution were measured using a spectrophotometer. The TTSP was then applied to a kinetic analysis of the color changes. The calculated values of the apparent activation energy of a*, b*, L*, and ΔE*ab were 105.2, 109.8, 91.6, and 103.7 kJ/mol, respectively. The predicted values of the color parameters at 40°C were calculated using Arrhenius plots for each of the color parameters. A comparison of the relationships between the experimental and predicted values of each color parameter revealed the coefficients of determination for a*, b*, L*, and ΔE*ab to be 0.961, 0.979, 0.960, and 0.979, respectively. All the R2 values were sufficiently high, and these results suggested that the prediction was highly reliable. Kinetic analysis using the TTSP was successfully applied to calculating the apparent activation energy and to predicting the color changes at any temperature or duration.View full abstractDownload PDF (1851K) Full view HTML -
Mariane Cristovão Bagatin, Camila Santos Suniga Tozatti, Layara Akemi ...2014 Volume 62 Issue 12 Pages 1231-1237
Published: December 01, 2014
Released on J-STAGE: December 01, 2014
JOURNAL FREE ACCESS FULL-TEXT HTMLThe purpose of this study was to investigate the effects of the chronic administration of a racemic mixture of 8-prenylnaringenin (8-PN) on rats submitted to the elevated T-maze (ETM) model of generalized anxiety and panic disorders. The selective serotonin (SERT) reuptake inhibitor fluoxetine was used as a positive control. Rat locomotion was assessed in a circular arena following each drug treatment. The administration of racemic 8-PN for 21 d in rats increased one-way escape latencies from the ETM open arm, indicating a panicolytic effect. To evaluate the interactions of 8-PN with monoamine transporters, a docking study was performed for both the R and S configurations of 8-PN towards SERT, norepinephrine (NET) and dopamine transporters (DAT). The application of the docking protocol showed that (R)-8-PN provides greater affinity to all transporters than does the S enantiomer. This result suggests that enantiomer (R)-8-PN is the active form in the in vivo test of the racemic mixture.View full abstractDownload PDF (2338K) Full view HTML -
Ghaneya Sayed Hassan, Doaa Ezzat Abdel Rahman, Dalia Osama Saleh, Geha ...2014 Volume 62 Issue 12 Pages 1238-1251
Published: December 01, 2014
Released on J-STAGE: December 01, 2014
JOURNAL FREE ACCESS FULL-TEXT HTMLThe benzofuran–morpholinomethyl–pyrazoline hybrids 4a–e, 5a–e and 6a–j were synthesized via reaction of α,β-unsaturated carbonyl compounds 3a–e with hydrazine hydrate, semicarbazide or thiosemicarbazide. Applying the Mannich reaction to 5-(5-aryl-4,5-dihydro-1H-pyrazol-3-yl)-4-methoxybenzofuran-6-ols 7a–e with morpholine hydrochloride and paraformaldehyde afforded positional isomeric 7-morpholinomethyl derivatives 4a–e and N-morpholinomethyl derivatives 8a–e. All the synthesized compounds showed significant vasodilatation properties in isolated thoracic aortic rings of rats precontracted using the standard norepinephrine hydrochloride technique. Compounds 3d, 3e, 5a–c, 6b, 6c, 6f, 6h and 6i exhibited activity (IC50 0.3185–0.4577 mM) superior to that of prazocin (IC50 0.487 mM), while 5d, 6j and 8c showed comparable activity (IC50 0.4789–0.4951 mM). The quantitative structure–activity relationship study revealed a correlation between the observed vasorelaxant activities of the newly synthesized compounds and their different physicochemical parameters, especially solubility, in addition to structure connectivity and energetic quantities calculated from stored three dimensional (3D) conformations. Absorption, distribution, metabolism and elimination (ADME) evaluation showed good agreement with the biological results obtained.View full abstractDownload PDF (981K) Full view HTML -
Miyako Yoshida, Tamami Haraguchi, Takahiro Uchida2014 Volume 62 Issue 12 Pages 1252-1258
Published: December 01, 2014
Released on J-STAGE: December 01, 2014
JOURNAL FREE ACCESS FULL-TEXT HTMLThe objective of this study was to evaluate an improved bitterness sensor which has been developed to allow the precise and sensitive prediction of the bitterness of acidic bitter pharmaceutical active ingredients, using as examples nine non-steroidal anti-inflammatory drugs (NSAIDs). The bitterness of the nine NSAIDs was measured using a multichannel taste-sensing system incorporating a bitterness sensor, C00, which has a membrane surface with high hydrophobicity, and was developed to allow an enhanced hydrophobic interaction with acidic bitter substances. The sourness intensities of the nine NSAIDs were also determined in gustatory sensation testing and by a taste sensor using a sourness-sensitive membrane, CA0. The ‘Change in membrane Potential caused by Adsorption’ (CPA) of sodium diclofenac and etodolac were also determined in the presence of increasing concentrations of tartaric acid using membrane C00. Multiple regression analysis performed on the data on bitterness intensity obtained using the taste sensor and in gustatory sensation testing showed that CPA values from C00 could be used to predict the bitterness of the NSAIDs. The derived equation was y=−0.0413×CPA+0.3164, where y represents the predicted bitterness intensity. There were concentration-dependent changes in the bitterness intensities of diclofenac sodium and etodolac without any change in their sourness intensities. For diclofenac sodium and etodolac, there was a good correlation between predicted and actual bitterness intensities in the presence of increasing concentrations of tartaric acid. The taste sensor may be useful for predicting the bitterness intensity of acidic bitter pharmaceutical active ingredients such as NSAIDs.View full abstractDownload PDF (728K) Full view HTML -
Mohammad Sayed Alam, Junaid Uddin Ahmed, Dong-Ung Lee2014 Volume 62 Issue 12 Pages 1259-1268
Published: December 01, 2014
Released on J-STAGE: December 01, 2014
JOURNAL FREE ACCESS FULL-TEXT HTML
Supplementary materialA novel series of 2-arylidenehydrazinyl-4-arylthiazole analogues (3a–p) was designed and synthesized in excellent yields using a rapid, simple, efficient methodology. Sixteen novel compounds were screened for in vitro antimicrobial activities against eleven bacteria, namely, Staphylococcus aureus, Listeria monocytogenes, Enterococcus faecalis, Bacillus subtilis, Klebsiella pneumonia, Citrobacter freundii, Cronobacter sakazakii, Salmonella enteritidis, Escherichia coli, Yersinia pestis, and Pseudomonas aeruginosa. All 16 compounds showed significant anti-bacterial activities against both Gram-positive and Gram-negative bacteria. In particular, compound 3g showed potent inhibition of E. coli and K. pneumonia, compound 3i inhibited E. faecalis, compound 3n S. tythi and E. faecalis, and compound 3c E. coli and C. sakazakii. In fact, our results indicate that most of the compounds synthesized exhibit strong antibacterial activity. The qualitative structure–antibacterial activity relationships (QSAR) were studied using the physicochemical and quantum-chemical parameters of the ab initio Hartree–Fock model at the RHF/6-31G level of theory. A good qualitative correlation between predicted physicochemical parameters (log P and polar surface area (PSA)) and antibacterial activity has been found. The synthesized compounds were also evaluated for antioxidant activity. Compounds 3j, 3a and 3i exhibited the greatest antioxidant activity, with IC50 values of 0.66, 0.81, and 1.08 µM, respectively, which were comparable to that of ascorbic acid (IC50 0.87 µM). The promising antibacterial and antioxidant activities of some of these synthesized 2-arylidenehydrazinyl-4-arylthiazole derivatives, together with the results of quantum-chemical studies, could be helpful for the development of drugs to combat diseases caused by microorganisms and oxidative stress.View full abstractDownload PDF (1825K) Full view HTML
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