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Volume 63, Issue 3
Displaying 1-11 of 11 articles from this issue
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Regular Articles
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Takefumi Yamashita, Akihiko Ueda, Takashi Mitsui, Atsushi Tomonaga, Sh ...2015 Volume 63 Issue 3 Pages 147-155
Published: March 01, 2015
Released on J-STAGE: March 01, 2015
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Supplementary materialIn this study, we propose a supercomputer-assisted drug design approach involving all-atom molecular dynamics (MD)-based binding free energy prediction after the traditional design/selection step. Because this prediction is more accurate than the empirical binding affinity scoring of the traditional approach, the compounds selected by the MD-based prediction should be better drug candidates. In this study, we discuss the applicability of the new approach using two examples. Although the MD-based binding free energy prediction has a huge computational cost, it is feasible with the latest 10 petaflop-scale computer. The supercomputer-assisted drug design approach also involves two important feedback procedures: The first feedback is generated from the MD-based binding free energy prediction step to the drug design step. While the experimental feedback usually provides binding affinities of tens of compounds at one time, the supercomputer allows us to simultaneously obtain the binding free energies of hundreds of compounds. Because the number of calculated binding free energies is sufficiently large, the compounds can be classified into different categories whose properties will aid in the design of the next generation of drug candidates. The second feedback, which occurs from the experiments to the MD simulations, is important to validate the simulation parameters. To demonstrate this, we compare the binding free energies calculated with various force fields to the experimental ones. The results indicate that the prediction will not be very successful, if we use an inaccurate force field. By improving/validating such simulation parameters, the next prediction can be made more accurate.Graphical Abstract Fullsize ImageView full abstractDownload PDF (1555K) Full view HTML -
Yasuyuki Ikematsu, Shinya Uchida, Noriyuki Namiki2015 Volume 63 Issue 3 Pages 156-163
Published: March 01, 2015
Released on J-STAGE: March 01, 2015
JOURNAL FREE ACCESS FULL-TEXT HTMLThe purpose of the present study was to develop orally disintegrating tablets (ODTs) containing fat-soluble drugs that disintegrate rapidly while having appropriate tablet strength. We chose vitamin E (VE) as a model drug; d-α-tocopheryl acetate, as the oily VE (VE-OI), and d-α-tocopheryl acid succinate, as the powder VE (VE-PO), were used. The oily VE was added directly to ODTs (VE-OI ODTs) and also used for the preparation of two types of VE granule, i.e., granules prepared using adsorption to calcium silicate (VE-FL granules) and granules prepared using spray-drying with gelatin (VE-SD granules); each type of granule was added to ODTs (VE-FL ODTs and VE-SD ODTs). Powder VE was added directly to ODTs (VE-PO ODTs). Various VE ODTs were prepared using these four additional methods with varying amounts of VE per tablet and were evaluated with respect to their manufacturability, physicochemical characteristics, and stability. It was demonstrated that a tablet porosity of 30% to 35% and tensile strength of 7 kg/cm2 or greater are required to provide VE ODTs with rapid disintegration and appropriate tablet strength, and that VE-SD granules and powder VE are suitable forms of VE to be added. When stability tests of VE-SD ODTs and VE-PO ODTs were performed, VE-PO ODTs exhibited prolongation of disintegration time and increased tensile strength, whereas VE-SD ODTs showed none of these changes. These changes were thought to be attributable to a decrease in the pore size of VE-PO ODTs resulting from the softening and migration of powder VE under hot storage conditions.Graphical Abstract Fullsize ImageView full abstractDownload PDF (1134K) Full view HTML -
Jumpei Uchiyama, Shigeru Aoki, Yoshifumi Uemoto2015 Volume 63 Issue 3 Pages 164-179
Published: March 01, 2015
Released on J-STAGE: March 01, 2015
JOURNAL FREE ACCESS FULL-TEXT HTMLThe principles of thermal effusivity are applied to an understanding of the detailed mechanisms of the lubrication process in a rotating mixer. The relationships and impact of the lubrication process by the pattern of powder flow, the filling level, and the rotating mixer size were investigated. Thermal effusivity profiles of the lubrication process, as obtained, indicate that lubrication is a two-phase process. The intersection point of the first and second phases (IPFS) is influenced by changing the filling level, thus changing the resulting number of avalanche flows created. The slope of the second phase (SSP) is influenced by the relationship between the number and the length of avalanche flows. Understanding this difference between the first and second phases is important to successfully evaluate the impact of proposed changes in the lubrication process. From this knowledge, a predictive model of the lubrication profile can be generated to allow an evaluation of proposed changes to the lubrication process. This model allows estimation of the lubrication profile at different filling levels and in different rotating mixer sizes. In this study, the actual lubrication profile almost coincides with the model predicted lubrication profile. Based on these findings, it is assumed that lubrication profiles at a commercial scale can be predicted from data generated at the laboratory scale. Further, it is assumed that changes in the filling level can also be estimated from the laboratory or current data.Graphical Abstract Fullsize ImageView full abstractDownload PDF (2113K) Full view HTML -
Zi-Ming Zhao, Yu Wang, Jin Han, Hui-Dong Zhu, Lin An2015 Volume 63 Issue 3 Pages 180-186
Published: March 01, 2015
Released on J-STAGE: March 01, 2015
JOURNAL FREE ACCESS FULL-TEXT HTMLTwo types of amphoteric calix[n]arene carboxylic acid (CnCA) derivative, i.e., calix[6]arene hexa-carboxylic acid (C6HCA) and calix[8]arene octo-carboxylic acid (C8OCA), were synthesized by introducing acetoxyls into the hydroxyls of calix[n]arene (n=6, 8). C6HCA and C8OCA nanoparticles (NPs) were prepared successfully using the dialysis method. CnCA NPs had regular spherical shapes with an average diameter of 180–220 nm and possessed negative charges of greater than −30 mV. C6HCA and C8OCA NPs were stable in 4.5% bovine serum albumin solutions and buffers (pH 5–9), with a low critical aggregation concentration value of 5.7 mg·L−1 and 4.0 mg·L−1, respectively. C6HCA and C8OCA NPs exhibited good paclitaxel (PTX) loading capacity, with drug loading contents of 7.5% and 8.3%, respectively. The overall in vitro release behavior of PTX from the CnCA NPs was sustained, and C8OCA NPs had a slower release rate compared with C6HCA NPs. These favorable properties of CnCA NPs make them promising nanocarriers for tumor-targeted drug delivery.Graphical Abstract Fullsize ImageView full abstractDownload PDF (1432K) Full view HTML -
Jin Qi, Zheng-fang Hu, Yi-feng Zhou, Yuan-jia Hu, Bo-yang Yu2015 Volume 63 Issue 3 Pages 187-194
Published: March 01, 2015
Released on J-STAGE: March 01, 2015
JOURNAL FREE ACCESS FULL-TEXT HTMLTwo new steroidal glycosides (1 and 2), together with 15 known compounds (3–17) were isolated from the fibrous roots of Ophiopogon japonicus, and three new steroidal glycosides (18–20), together with 14 known compounds (21–34) were isolated from the fibrous roots of Liriope spicata var. prolifera. The structures of the new compounds were elucidated on the basis of extensive one-dimensional (1D)- and 2D-NMR spectroscopic analyses and mass spectrometry. The isolated compounds were evaluated for their anti-inflammatory activity in vitro. Most of these steroidal glycosides showed significant inhibitory activity against neutrophil respiratory burst stimulated by phorbol myristate acetate.Graphical Abstract Fullsize ImageView full abstractDownload PDF (848K) Full view HTML -
Ken-ichiro Matsumoto, Megumi Ueno, Ikuo Nakanishi, Kazunori Anzai2015 Volume 63 Issue 3 Pages 195-199
Published: March 01, 2015
Released on J-STAGE: March 01, 2015
Advance online publication: January 14, 2015
JOURNAL FREE ACCESS FULL-TEXT HTMLThe density of hydroxyl radicals (·OH) produced in aqueous samples by exposure to X-ray or carbon-ion beams was investigated. The generation of ·OH was detected by the electron paramagnetic resonance (EPR) spin-trapping technique using 5,5-dimethyl-1-pyrroline-N-oxide (DMPO) as the spin-trapping agent. When the concentration of DMPO is in excess of the generated ·OH, the production of DMPO-OH (spin-trapped ·OH) should be saturated. Reaction mixtures containing several concentrations (0.5–1685 mM) of DMPO were then irradiated by a 32 Gy 290 MeV carbon-ion beam (C290-beam) or X-ray. C290-beam irradiation was performed at the Heavy-Ion Medical Accelerator in Chiba (HIMAC, National Institute of Radiological Sciences, Chiba, Japan), applying different linear energy transfers (LET) (20–169 keV/µm). The amount of DMPO-OH in the irradiated samples was detected by EPR spectroscopy. The generation of DMPO-OH increased with the concentration of initial DMPO, displayed a shoulder around 3.3 mM DMPO, and reached a plateau. This plateau suggests that the generated ·OH were completely trapped. Another linear increase in DMPO-OH measured in solutions with higher DMPO concentrations suggested very dense ·OH generation (>1.7 M). Generation of ·OH is expected to be localized on the track of the radiation beam, because the maximum concentration of measured DMPO-OH was 40 µM. These results suggested that both sparse (≈3.3 mM) and dense (>1.7 M) ·OH generation occurred in the irradiated samples. The percentage of dense ·OH generation increased with increasing LET. Different types of dense ·OH generation may be expected for X-ray and C290-beams.Graphical Abstract Fullsize ImageView full abstractDownload PDF (567K) Full view HTML -
Hitomi Uchimoto, Tomoko Tsuji, Ikuo Kawasaki, Kenji Arimitsu, Hiroyuki ...2015 Volume 63 Issue 3 Pages 200-209
Published: March 01, 2015
Released on J-STAGE: March 01, 2015
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Supplementary materialReuse of chiral ruthenium catalyst in catalytic asymmetric transfer hydrogenation (CATH) has attracted attention from economic and environmental viewpoints, and reactions using ionic liquids (ILs) as solvent are recognized as one of the most useful methods for reuse of the catalyst. We synthesized (1S,2S)-N-(p-toluenesulfonyl)-1,2-diphenylethylenediamine (TsDPEN) derivatives with various ionic moieties, and investigated the effect of their structure with respect to catalytic ability and recyclability in CATH with ILs. Ligand 3a having an imidazolium group showed the best results, and significant differences were observed depending on the structure of the ionic moiety or the length of the alkyl chain connecting the ligand site and the ionic moiety. Among various prochiral ketones used as substrates at various cycles, 3a showed a relatively good result.Graphical Abstract Fullsize ImageView full abstractDownload PDF (680K) Full view HTML -
Mehmet Koca, Kadir Ozden Yerdelen, Baris Anil, Zeynep Kasap2015 Volume 63 Issue 3 Pages 210-217
Published: March 01, 2015
Released on J-STAGE: March 01, 2015
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Supplementary materialA novel series of meta-substituted ethanediamide and 2-butenediamide derivatives were synthesized and tested for their ability to inhibit electric eel acetylcholinesterase (AChE) and equine serum butyrylcholinesterase (BuChE). The synthesized compounds were evaluated against ChE enzymes using the colorimetric method described by Ellman et al. (Biochem. Pharmacol., 7, 1961). It was revealed that some synthesized compounds exhibited high anticholinesterase activity, among which compounds 1f and 2f were the most active inhibitors against BuChE (IC50 value=1.47 µM) and AChE (IC50 value=2.09 µM), respectively. Docking simulations revealed that the inhibitors 1f and 2f are capable of simultaneously binding the peripheral anionic site as well as the catalytic anionic site of both ChE enzymes. These derivatives are considered interesting candidates for Alzheimer’s disease treatment.Graphical Abstract Fullsize ImageView full abstractDownload PDF (1116K) Full view HTML -
Yosuke Demizu, Hiroko Yamashita, Takashi Misawa, Mitsunobu Doi, Masaka ...2015 Volume 63 Issue 3 Pages 218-224
Published: March 01, 2015
Released on J-STAGE: March 01, 2015
JOURNAL FREE ACCESS FULL-TEXT HTMLThe influence of D-Leu residues on the helical structures of L-Leu-based-nonapeptides was investigated. Specifically, the preferred conformations of four diastereomeric nonapeptides, Boc-(L-Leu-L-Leu-Aib)3-OMe (1); Boc-(L-Leu-L-Leu-Aib)2-L-Leu-D-Leu-Aib-OMe (2), which contained one D-Leu residue; Boc-L-Leu-D-Leu-Aib-L-Leu-L-Leu-Aib-L-Leu-D-Leu-Aib-OMe (3), which contained two D-Leu residues; and Boc-(L-Leu-D-Leu-Aib)3-OMe (4), were analyzed in solution and in the crystalline state. Peptide 1 formed a right-handed (P) 310-helix in solution. Peptides 2 and 3 both formed (P) 310-helices in solution and (P) α-helices in the crystalline state. Peptide 4 formed a (P) α-helix both in solution and in the crystalline state.Graphical Abstract Fullsize ImageView full abstractDownload PDF (1421K) Full view HTML -
Joanna Stefanska, Grażyna Nowicka, Marta Struga, Daniel Szulczyk, Anna ...2015 Volume 63 Issue 3 Pages 225-236
Published: March 01, 2015
Released on J-STAGE: March 01, 2015
JOURNAL FREE ACCESS FULL-TEXT HTMLA series of new thiourea derivatives of 1,3-thiazole have been synthesized. All obtained compounds were tested in vitro against a number of microorganisms, including Gram-positive cocci, Gram-negative rods and Candida albicans. Compounds were also tested for their in vitro tuberculostatic activity against the Mycobacterium tuberculosis H37Rv strain, as well as two ‘wild’ strains isolated from tuberculosis patients. Compounds 3 and 9 showed significant inhibition against Gram-positive cocci (standard strains and hospital strain). The range of MIC values is 2–32 µg/mL. Products 3 and 9 effectively inhibited the biofilm formation of both methicillin-resistant and standard strains of S. epidermidis. The halogen atom, especially at the 3rd position of the phenyl group, is significantly important for this antimicrobial activity. Moreover, all obtained compounds resulted in cytotoxicity and antiviral activity on a large set of DNA and RNA viruses, including Human Immunodeficiency Virus type 1 (HIV-1) and other several important human pathogens. Compound 4 showed activity against HIV-1 and Coxsackievirus type B5. Seven compounds resulted in cytotoxicity against MT-4 cells (CC50<10 µM).Graphical Abstract Fullsize ImageView full abstractDownload PDF (1368K) Full view HTML
Note
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Lin Jing, Yang-Mei Zhang, Jian-Guang Luo, Ling-Yi Kong2015 Volume 63 Issue 3 Pages 237-243
Published: March 01, 2015
Released on J-STAGE: March 01, 2015
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Supplementary materialNine new tirucallane-type triterpenoids, ficutirucins A–I (1–9), were isolated from the fruit of Ficus carica. Their structures were established on the basis of spectroscopic data and chemical methods. All isolates were evaluated for their cytotoxic activities against three human cancer cell lines, MCF-7, HepG-2, and U2OS. Compounds 1–3, 6, 7, and 9 exhibited moderate cytotoxic activities with IC50 values of 11.67–45.61 µM against one or more of the three cancer cell lines.Graphical Abstract Fullsize ImageView full abstractDownload PDF (564K) Full view HTML
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