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Volume 64, Issue 5
Displaying 1-17 of 17 articles from this issue
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Regular Articles
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Ki Hyun Kim, So-Hyun Park, Pratik Adhikary, Jin Hun Cho, Nae-Gyu Kang, ...2016 Volume 64 Issue 5 Pages 381-389
Published: May 01, 2016
Released on J-STAGE: May 01, 2016
JOURNAL FREE ACCESS FULL-TEXT HTMLEven though β-lapachone is a promising compound with antitumor, antiinflammatory, antineoplastic, and wound-healing effects, there are still issues concerning its chemical stability and degradation mechanisms. The objective of this study was to obtain degradation profiles of β-lapachone and evaluate its chemical stability under various stress conditions. Moreover, the correlation between stability and efficacy was evaluated. The degradation study of β-lapachone was performed using heat, acid, base, oxidation, and light conditions. Kinetics and degradation profiles were investigated with HPLC and LC-MS. The stability indicated in the LC method was validated according to the International Conference on Harmonization guidelines. Human dermal fibroblast (HDF) cells were cultured with the standard and its degraded samples in the cellular activity and cytotoxicity test. β-Lapachone was relatively unstable upon exposure to light, and its photodegradation was accelerated with high relative humidity. Three degradants were identified, and their degradation followed zero-order kinetics. It was shown to degrade to phthalic acid under oxidative conditions, and the degradation kinetics were dependent on the concentration of hydrogen peroxide. Two degradation products were identified upon exposure to basic conditions, which followed first-order kinetics. β-Lapachone was relatively stable under acidic and thermal conditions. It increased the synthesis of collagen compared with the control. However, as the contents decreased, the synthesis of collagen also decreased in the photodegraded samples. β-Lapachone did not exert cytotoxic effects at the effective concentration in the cytotoxicity test. Therefore, in order to ensure efficacy and safety, the chemical stability of β-lapachone needs to be controlled carefully while considering instability mechanisms.Graphical Abstract Fullsize ImageView full abstractDownload PDF (1737K) Full view HTML -
Dan Ge, Kyohei Higashi, Daichi Ito, Kenichi Nagano, Ryota Ishikawa, Yu ...2016 Volume 64 Issue 5 Pages 390-398
Published: May 01, 2016
Released on J-STAGE: May 01, 2016
JOURNAL FREE ACCESS FULL-TEXT HTMLChondroitin sulfate (CS) has been accepted as an ingredient in health foods for the treatment of symptoms related to arthritis and cartilage repair. However, CS is poorly absorbed through the gastrointestinal tract because of its high negative electric charges and molecular weight (MW). In this study, poly-ion complex (PIC) formation was found in aqueous solutions through electrostatic interaction between CS and polyamines—organic molecules having two or more primary amino groups ubiquitously distributed in natural products at high concentrations. Characteristic properties of various PICs generated by mixing CS and natural polyamines, including unusual polyamines, were studied based on the turbidity for PIC formation, the dynamic light scattering for the size of PIC particles, and ζ-potential measurements for the surface charges of PIC particles. The efficiency of PIC formation between CS and spermine increased in a CS MW-dependent manner, with 15 kDa CS being critical for the formation of PIC (particle size: 3.41 µm) having nearly neutral surface charge (ζ-potential: −0.80 mV). Comparatively, mixing tetrakis(3-aminopropyl)ammonium and 15 kDa of CS afforded significant levels of PIC (particle size: 0.42±0.16 µm) despite a strongly negative surface charge (−34.67±1.15 mV). Interestingly, the oral absorption efficiency of CS was greatly improved only when PIC possessing neutral surface charges was administered to mice. High formation efficiency and electrically neutral surface charge of PIC particles are important factors for oral CS bioavailability.Graphical Abstract Fullsize ImageView full abstractDownload PDF (2011K) Full view HTML -
Design, Synthesis and Biological EvaluationDinesh Kumar, Fayaz Malik, Preet Mohinder Singh Bedi, Subheet Jain2016 Volume 64 Issue 5 Pages 399-409
Published: May 01, 2016
Released on J-STAGE: May 01, 2016
JOURNAL FREE ACCESS FULL-TEXT HTMLIn the present study, a series of 2,4-diarylpyrano[3,2-c]chromen-5(4H)-ones were synthesised and evaluated as antiproliferative agents. The compounds were evaluated against a panel of human cancer cell lines. CH-1 exhibited significant cytoxicity against HCT 116 cell lines with an IC50 value of 1.4 and 4.3 µM against “MiaPaCa-2” cell lines. The compound CH-1 was found to induce apoptosis as evidenced by phase contrast microscopy, Hoechst 33258 staining and mitochondrial membrane potential (MMP) loss. The cell phase distribution studies indicated that the apoptotic population increased from 10.22% in the control sample to 57.19% in a sample treated with 20 µM compound CH-1.Graphical Abstract Fullsize ImageView full abstractDownload PDF (3576K) Full view HTML -
Hiroyoshi Teramoto, Takayasu Yamauchi, Yasushi Terado, Sanae Odagiri, ...2016 Volume 64 Issue 5 Pages 410-419
Published: May 01, 2016
Released on J-STAGE: May 01, 2016
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Supplementary materialThe matrine-type alkaloid 4-dimethylamino-1-pentanoylpiperidine (3a) has an antinociceptive effect through its impact on the κ-opioid receptor (KOR). Derivatives of 3a were synthesized by altering its amide and tertiary amine groups, and were evaluated for their antinociceptive effects. The results indicated that the distance between these groups on 3a was optimal for the antinociceptive effect. The effects obtained with compounds 8 and 9 indicated that the relative configuration of the 3- and 4-substituents influenced the effect mediated through the KOR.Graphical Abstract Fullsize ImageView full abstractDownload PDF (805K) Full view HTML -
Hiroyoshi Teramoto, Takayasu Yamauchi, Shigeru Sasaki, Kimio Higashiya ...2016 Volume 64 Issue 5 Pages 420-431
Published: May 01, 2016
Released on J-STAGE: May 01, 2016
JOURNAL FREE ACCESS FULL-TEXT HTMLA series of new κ opioid receptor (KOR) agonists were developed from the lead compound 4-dimethylamino-1-pentanoylpiperidine (3), a matrine-type alkaloid. Derivatives of 3 were synthesized with a variety of phenyl substituents and evaluated for their antinociceptive effects. Additionally, their selectivity for an opioid receptor was investigated for cis-4c and d, and trans-4g, all of which had high activity exerted through the KOR.Graphical Abstract Fullsize ImageView full abstractDownload PDF (731K) Full view HTML -
Keita Takagi, Takashi Ohgita, Takenori Yamamoto, Yasuo Shinohara, Kent ...2016 Volume 64 Issue 5 Pages 432-438
Published: May 01, 2016
Released on J-STAGE: May 01, 2016
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Supplementary materialLiposomes are closed-membrane vesicles comprised of lipid bilayers, in which the inside of the vesicles is isolated from the external environment. Liposomes are therefore often used as models for biomembranes and as drug delivery carriers. However, materials encapsulated within liposomes often cannot respond to changes in the external environment. The ability of enclosed materials to maintain their responsiveness to changes in the external environment following encapsulation into liposomes would greatly expand the applicability of such systems. We hypothesize that embedding pore-like “access points” into the liposomal membrane could allow for the transmission of information between the internal and external liposomal environments and thus overcome this inherent limitation of conventional liposomes. To investigate this, we evaluated whether a change in the pH of an external solution could be transmitted to the inside of liposomes through the pore-forming protein, yeast voltage-dependent anion channel (VDAC). Transmission of a pH change via VDAC was evaluated using a polyglutamic acid/doxorubicin complex (PGA/Dox) as an internal pH sensor. Upon encapsulation into conventional liposomes, PGA/Dox exhibits no pH sensitivity due to isolation from the external environment. On the other hand, PGA/Dox was found to retain its pH sensitivity upon encapsulation into VDAC-reconstituted liposomes, suggesting that VDAC facilitated the transmission of information on the pH of the external environment to the inside of the liposomes. In conclusion, we successfully demonstrated the transmission of information between the external and internal liposomal environments by a stable pore-like structure embedded into the liposomal membranes, which serve as access points.Graphical Abstract Fullsize ImageView full abstractDownload PDF (603K) Full view HTML -
Mohamed Emad Azab, Sameh Ahmed Rizk, Naglaa Fawzy Mahmoud2016 Volume 64 Issue 5 Pages 439-450
Published: May 01, 2016
Released on J-STAGE: May 01, 2016
JOURNAL FREE ACCESS FULL-TEXT HTMLThe present work describes convenient synthesis of the novel Schiff bases 5a and b by reacting phthalazinones 4a and b with 4-methoxybenzaldehyde Reaction of the Schiff bases with phenylisothiocyanate afforded diazetidine derivatives 7a and b. Also, compounds 4a and b reacted with 2-bromoglucoside tetraacetate giving peracetylated N-glycosides 6a and b, which were deacetylated to afford N-glycosylated phthalazinones 8a and b. On the other hand, when compound 3 was treated with POCl3/PCl5 and/or ethyl chloroacetate, chlorophthalazine and ethyl acetate derivatives 9 and 10 were obtained, respectively. Hydrazinolysis of compounds 9 and 10 produced the hydrazino and hydrazide derivatives 11 and 12, respectively. When compound 11 reacted with 2-furanaldehyde, acetic anhydride, and/or carbon disulphide, it gave compounds 13–15, respectively. Treatment of the hydrazide 12 with aromatic aldehydes, acetic anhydride, ethyl acetoacetate, acetyl acetone, ammonium thiocyanate, and/or phthalic anhydride furnished compounds 17–21. Meanwhile, reacting Schiff base 22 with the chlorophthalazine derivative 9 produced compound 23, which on treatment with furoyl chloride produced compound 24. The structures of the novel compounds were confirmed by IR, 1H-NMR, 13C-NMR, MS, and elemental analysis. The newly synthesized compounds were tested against Bacillus subtilis and Staphylococcus aureus as Gram-positive bacteria, Escherichia coli and Pseudomonas aurignosa as Gram-negative bacteria, and Candida albicans and Aspergillus niger as fungi strains. Compounds 5a and b, 23, and 24 showed greater antimicrobial activity than the stranded compounds, suggesting that they could be considered as promising antimicrobial agents.Graphical Abstract Fullsize ImageView full abstractDownload PDF (1046K) Full view HTML -
Yosuke Hisamatsu, Yuya Miyazawa, Kakeru Yoneda, Miki Miyauchi, Mohd Zu ...2016 Volume 64 Issue 5 Pages 451-464
Published: May 01, 2016
Released on J-STAGE: May 01, 2016
JOURNAL FREE ACCESS FULL-TEXT HTMLWe previously reported on supramolecular complexes 4 and 5, formed by the 4 : 4 : 4 or 2 : 2 : 2 assembly of a dimeric zinc(II) complex (Zn2L1) having 2,2′-bipyridyl linker, dianion of cyanuric acid (CA) or 5,5-diethylbarbituric acid (Bar), and copper(II) ion (Cu2+) in an aqueous solution. The supermolecule 4 possesses Cu2(μ-OH)2 centers and catalyzes hydrolysis of phosphate monoester dianion, mono(4-nitrophenyl)phosphate (MNP), at neutral pH. In this manuscript, we report on design and synthesis of hydrophobic supermolecules 9 and 10 by 4 : 4 : 4 and 2 : 2 : 2 self-assembly of hydrophobic Zn2L2 and Zn2L3 containing long alkyl chains, CA or Bar, and Cu2+ and their phosphatase activity for the hydrolysis of MNP and bis(4-nitrophenyl)phosphate (BNP) in two-phase solvent systems. We assumed that the Cu2(μ-OH)2 active sites of 9 and 10 would be more stable in organic solvent than in aqueous solution and that product inhibition of the supermolecules might be avoided by the release of HPO42− into the aqueous layer. The findings indicate that 9 and 10 exhibit phosphatase activity in the two-phase solvent system, although catalytic turnover was not observed. Furthermore, the hydrolysis of BNP catalyzed by the hydrophobic 2 : 2 : 2 supermolecules in the two-phase solvent system is described.Graphical Abstract Fullsize ImageView full abstractDownload PDF (1966K) Full view HTML -
Mai Ohba, Tomoichiro Oka, Takayuki Ando, Saori Arahata, Asaka Ikegaya, ...2016 Volume 64 Issue 5 Pages 465-475
Published: May 01, 2016
Released on J-STAGE: May 01, 2016
JOURNAL FREE ACCESS FULL-TEXT HTMLThere is an urgent need for structurally novel anti-norovirus agents. In this study, we describe the synthesis, anti-norovirus activity, and structure–activity relationship (SAR) of a series of heterocyclic carboxamide derivatives. Heterocyclic carboxamide 1 (50% effective concentration (EC50)=37 µM) was identified by our screening campaign using the cytopathic effect reduction assay. Initial SAR studies suggested the importance of halogen substituents on the heterocyclic scaffold and identified 3,5-di-boromo-thiophene derivative 2j (EC50=24 µM) and 4,6-di-fluoro-benzothiazole derivative 3j (EC50=5.6 µM) as more potent inhibitors than 1. Moreover, their hybrid compound, 3,5-di-bromo-thiophen-4,6-di-fluoro-benzothiazole 4b, showed the most potent anti-norovirus activity with a EC50 value of 0.53 µM (70-fold more potent than 1). Further investigation suggested that 4b might inhibit intracellular viral replication or the late stage of viral infection.Graphical Abstract Fullsize ImageView full abstractDownload PDF (647K) Full view HTML -
Shawkat Ahmed Abdel-Mohsen, Talaat Ibrahim El-Emary, Hussein Salama El ...2016 Volume 64 Issue 5 Pages 476-482
Published: May 01, 2016
Released on J-STAGE: May 01, 2016
JOURNAL FREE ACCESS FULL-TEXT HTMLA novel series of 6-substituted pyrazolo[3,4-g]pteridines 2–9 and pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pteridin-2(3H)-one (thione) 10 and 11 was synthesized using the starting compound 3,7-dimethyl-1-phenylpyrazolo[4′,3′:5,6]pyrazino[2,3-d][1,3]oxazin-5(1H)-one 2. The structure of the newly synthesized compounds was elucidated by IR, 1H-NMR, 13C-NMR, mass spectroscopy and elemental analyses. The anti-inflammatory activity of all the newly synthesized compounds was evaluated using the carrageenan-induced paw oedema test in rats using indomethacin as the reference drug. Compound 11 and the two derivatives 7f and 8b were the most active compounds, showing an activity comparable to indomethacin. Also, the synthesized compounds were evaluated for their antibacterial activity against Gram-positive bacteria (Staphylococcus aureus and Bacillus cereus) and Gram-negative bacteria (Escherichia coli and Pseudomonas aeruginosa) using chloramphenicol as control. The pyrazolotriazolopteridin-2-thione 11, 6-hydroxyethyl- 6a, 6-(4-nitrophenyl)-7g, and 6-(phenylamino) 8b derivatives were found to be the most active compounds against the Gram-positive species. None of them showed any activity against Gram-negative species.Graphical Abstract Fullsize ImageView full abstractDownload PDF (534K) Full view HTML -
Magdy Mohamed Hemdan, Amira Abd-Elhaleem El-Sayed2016 Volume 64 Issue 5 Pages 483-489
Published: May 01, 2016
Released on J-STAGE: May 01, 2016
JOURNAL FREE ACCESS FULL-TEXT HTMLPhthalimidoacetyl isothiocyanate underwent addition-cyclization reactions with some nitrogen and carbon nucleophilic reagents. Simultaneous or subsequent cyclization of the obtained adducts gave target heterocyclic systems such as 1,2,4-triazoles, 1,3-diazines, 1,3-oxazines and thiourea attached to a phthalimido moiety. The antimicrobial activity of the synthesized compounds was tested.Graphical Abstract Fullsize ImageView full abstractDownload PDF (552K) Full view HTML
Notes
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Asmaa Elsayed Kassab, Ehab Mohamed Gedawy, Afaf Ali El-Malah, Tamer Mo ...2016 Volume 64 Issue 5 Pages 490-496
Published: May 01, 2016
Released on J-STAGE: May 01, 2016
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Supplementary materialA novel series of hexahydrocyclooctathieno[2,3-d]pyrimidines was synthesized. Investigation of the anticancer activity of these derivatives revealed that compounds 2a and b showed broad-spectrum anticancer activity in nanomolar to micromolar concentrations. In particular, compound 2b showed a concentration required for 50% inhibition of cell growth (GI50) value of less than 1 µM against 20 cancer cell lines. Compounds 2a and b induced G2/M- and S-phase cell cycle arrest in human colon adenocarcinoma (HCT116) and human breast adenocarcinoma (MCF7) cell lines with a concomitant increase in the pre-G cell population in a time-dependent manner. Furthermore, compound 2b increased the nuclear expression of the proapoptotic protein cleaved caspase-3, indicating that apoptosis has an important role, at least in part, in the cancer cell death induced by the new compounds.Graphical Abstract Fullsize ImageView full abstractDownload PDF (2293K) Full view HTML -
Li-Hua Su, Yan-Ping Li, Hong-Mei Li, Wei-Feng Dai, Dan Liu, Lang Cao, ...2016 Volume 64 Issue 5 Pages 497-501
Published: May 01, 2016
Released on J-STAGE: May 01, 2016
JOURNAL FREE ACCESS FULL-TEXT HTMLTwo new [neougonins A (1) and B (2)] and nine known prenylated flavonoids were isolated from the whole plants of Helminthostachys zeylanica. The structures of the new isolates were elucidated by extensive NMR techniques, including one and two dimensional (1D)- and (2D)-NMR experiments, as well as comparison with spectroscopic data of known analogous compounds. Moreover, compound 1 inhibited lipopolysaccharide (LPS)-induced nitric oxide (NO) production in RAW264.7 cells with an IC50 value of 3.32 µM.Graphical Abstract Fullsize ImageView full abstractDownload PDF (428K) Full view HTML -
Harlen Gerardo Torres Castañeda, Ana Julia Colmenares Dulcey, José Hip ...2016 Volume 64 Issue 5 Pages 502-506
Published: May 01, 2016
Released on J-STAGE: May 01, 2016
JOURNAL FREE ACCESS FULL-TEXT HTMLTwo new flavonol glycosides were isolated from the leaves of Siparuna gigantotepala. Their structures were determined to be kaempferol 3-O-β-xylopyranosyl-(1→2)-α-arabinofuranoside (1) and kaempferol 3,7-di-O-methyl-4′-O-α-rhamnopyranosyl-(1→2)-β-glucopyranoside (2). In addition, three known flavonol glycosides, rutin (3), kaempferol 3-O-rutinoside (4), and kaempferol 3,7-di-O-methyl-4′-O-rutinoside (5), and three flavonol aglycones, quercetin (6), kaempferol 3,7-dimethyl ether (7), and kaempferol 3,7,4′-trimethyl ether (8), were also isolated and are reported here for the first time in this species. The structures of compounds 1 and 2 were established on the basis of their LC-MS and one- and two-dimensional (1D)- and (2D)-NMR spectroscopic analyses, combined with acid methanolysis and silylation of sugar moieties for GC-MS. Evaluation of the antioxidant activity, conducted in the 96-well plate format, showed that the flavonoids isolated possess strong 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical-scavenging activity and moderate oxygen radical absorption capacity.Graphical Abstract Fullsize ImageView full abstractDownload PDF (488K) Full view HTML -
Le Son Hoang, Manh Hung Tran, Joo-Sang Lee, Quynh Mai Thi Ngo, Mi Hee ...2016 Volume 64 Issue 5 Pages 507-511
Published: May 01, 2016
Released on J-STAGE: May 01, 2016
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Supplementary materialThree new sesquiterpenoids, 13-hydroxyl-atractylenolide II (1), 4-ketone-atractylenolide III (2), and eudesm-4(15)-ene-7β,11-diol (3), along with eleven known compounds (4–14), were isolated from the rhizomes of Atractylodes macrocephala. The structures and relative configurations of 1–3 were determined by analysis of the spectroscopic data, and the absolute configurations of 1 and 2 were assigned by circular dichroism technique. The anti-inflammatory activities of these isolates were evaluated against lipopolysaccharide-induced nitric oxide production in macrophage RAW264.7 cells; compounds 4, 7, and 8 exhibited moderate efficacy with IC50 values of 48.6±0.5, 46.4±3.2, and 32.3±2.9 µM, respectively.Graphical Abstract Fullsize ImageView full abstractDownload PDF (509K) Full view HTML -
Shohei Nakamura, Natsuki Otsuka, Yukari Yoshino, Takatoshi Sakamoto, H ...2016 Volume 64 Issue 5 Pages 512-516
Published: May 01, 2016
Released on J-STAGE: May 01, 2016
JOURNAL FREE ACCESS FULL-TEXT HTMLSticking is a failure of pharmaceutical production that occurs when a powder containing a large amount of adhesive is being tableted. This is most frequently observed when long-term tableting is carried out, making it extremely difficult to predict its occurrence during the tablet formula design stage. The efficiency of the pharmaceutical production process could be improved if it were possible to predict whether a particular formulation was likely to stick during tableting. To address this issue, in the present study we prepared tablets composed of blended ibuprofen (Ibu), a highly adhesive drug, and measured the degree of adherence of powder particles to the surface of the tablet punch. We also measured the shear stress of the powder to determine the practical angle of internal friction (Φp) of the powder bed as well as the angle of wall friction (Φw) relative to the punch surface. These values were used to define a sticking index (SI), which showed a high correlation with the amount of Ibu that adhered to the punch during tableting; sticking occurred at SI >0.3. When the amount of lubricant added to the formulation was changed to yield tablets exhibiting different SI values without changing the compounding ratio, sticking did not occur at SI ≤0.3. These results suggest that determining the SI of a pharmaceutical powder before tableting allows prediction of the likelihood of sticking during tableting.Graphical Abstract Fullsize ImageView full abstractDownload PDF (878K) Full view HTML -
Retno Widyowati, Sachiko Sugimoto, Yoshi Yamano, Sukardiman, Hideaki ...2016 Volume 64 Issue 5 Pages 517-521
Published: May 01, 2016
Released on J-STAGE: May 01, 2016
JOURNAL FREE ACCESS FULL-TEXT HTMLThree new flavonoid glycosides named isolinariins C, D and E (1–3), two known flavonoid glycosides (4, 5) and three known flavonoids (6–8) were isolated from the whole plant of Linaria japonica. The structures of these compounds were determined mainly by spectroscopic analyses. The bioactivities of these isolated compounds were evaluated for their inhibitory activities against human cell line A549, collagenase, and advanced glycation end product (AGE) formation. Among the isolated compounds, isolinariins C, D and E (1, 2 and 3) showed inhibition toward AGE formation (IC50 values of 34.8, 35.0 and 19.5 µM, respectively). And linariin (4), pectolinarin (5) and luteolin (8) were found to be active against collagenase with IC50 values of 79.4, 78.6 and 40.5 µM, respectively, without significant cytotoxicity at these concentrations.Graphical Abstract Fullsize ImageView full abstractDownload PDF (440K) Full view HTML
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