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Volume 61, Issue 2
Displaying 1-18 of 18 articles from this issue
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Review
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Tomoya HiranoArticle type: Review
2013 Volume 61 Issue 2 Pages 111-120
Published: February 01, 2013
Released on J-STAGE: February 01, 2013
JOURNAL FREE ACCESSNuclear receptors and their endogenous ligands are involved in key biological functions, including development, homeostasis and metabolism, and functional molecules that can modulate receptor activities are of interest for basic research to elucidate the signaling pathways, as well as having potential therapeutic applications. Here, we summarize our recent work on the development of nuclear receptor ligands, focusing on thyroid hormone receptor (TR) antagonists, fluorescent ligands for progesterone receptors (PR), and inhibitors of histone methyltransferase (HMT). We have developed a series of potent TR antagonists bearing a thiazolidinedione group as a bioisoster of a polar amino acid group. Utilizing our library of fluorescent coumarin derivatives, we obtained a PR antagonist that exhibits fluorescence enhancement upon binding to PR. We also developed a series of HMT inhibitors based on the structure of adenosylmethionine (AdoMet), a cofactor in the methylation reaction, by introducing various alkylamino groups onto the nitrogen atom in place of the sulfur atom of AdoMet. Our compounds should be useful in functional analysis of these nuclear receptors and investigations of their signaling pathways.View full abstractDownload PDF (1516K)
Regular Articles
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Gang Wu, Qiang Xie, Lin Xu, Hong Jiang, Zhengrong Huang, Congxin HuangArticle type: Regular Article
2013 Volume 61 Issue 2 Pages 121-124
Published: February 01, 2013
Released on J-STAGE: February 01, 2013
Advance online publication: December 03, 2012JOURNAL FREE ACCESSPrevious studies have demonstrated that statin can reduce the risk of acute coronary syndrome. In order to explore the mechanism, we observed the effects of pravastatin on plaque stability in atherosclerotic rabbits. Sixteen male rabbits were fed with a high fat diet following their damaged abdominal aortic endothelium by using catheter. Eight of them were administered with pravastatin (10 mg·kg−1·d−1) for 4 weeks. Then the rabbit atherosclerotic plaque rupture and thrombosis were triggered by injection of viper venom and histamine. Compared with model group, the thrombus area on aorta in pravastatin-treated group was reduced. Fibre cap on plaque was more thick and integrant, and inflammatory cell infiltration was also decreased. Serum total cholesterol, triglyceride, low density lipoprotein-cholesterol and contents of cholesterol in abdominal aorta were decreased. 6-Keto-prostaglandin F1α (6-keto-PGF1α) level and ratio of 6-keto-PGF1α/thromboxane B2 (TXB2) in aorta were significantly increased. These results suggested that pravastatin could increase plaque stability and inhibit thrombosis through both lipid-dependent and lipid-independent way.View full abstractDownload PDF (1306K) -
Suvadra Das, Partha Roy, Md Ataul Islam, Achintya Saha, Arup MukherjeeArticle type: Regular Article
2013 Volume 61 Issue 2 Pages 125-133
Published: February 01, 2013
Released on J-STAGE: February 01, 2013
Advance online publication: November 29, 2012JOURNAL FREE ACCESSPolymer nanoparticles are veritable tools for pharmacokinetic and therapeutic modifications of bioactive compounds. Nanoparticle technology development and scaling up are however often constrained due to poor payload and improper particle dissolution. This work was aimed to develop descriptor based computational models as prior art tools for optimal payload in polymeric nanoparticles. Loading optimization experiments were carried out both in vitro and in-silico. Molecular descriptors generated in three different platforms DRAGON, molecular operating environment (MOE) and VolSurf+ were used. Multiple linear regression analysis (MLR) provided computation models which were further validated based on goodness of fit statistics and correlation coefficients (DRAGON, R2=0.889, Q2=0.657, R2pred=0.616; MOE, R2=0.826, Q2=0.572, R2pred=0.601; and VolSurf+, R2=0.818, Q2=0.573, R2pred=0.653). Pharmacophore space modeling studies were carried out in order to understand the fundamental molecular interactions necessary for drug loading in poly(DL-lactide-co-glycolic acid). The space modeling study (R2=0.882, Q2=0.662, R2pred=0.725, Δcost=108.931) indicated that hydrogen bond acceptors and ring aromatic features are of primary significance for nanoparticle drug loading. Results of in vitro experiments have also confirmed the fact as a viable prognosis in case of nanoparticle payload. Polymeric nanoparticles payload prediction can therefore be a useful tool for wider benefits at the preformulation stages itself.View full abstractDownload PDF (1509K) -
Toshihiro Murata, Atsushi Suzuki, Nagisa Mafune, Eriko Sato, Toshio Mi ...Article type: Regular Article
2013 Volume 61 Issue 2 Pages 134-143
Published: February 01, 2013
Released on J-STAGE: February 01, 2013
Advance online publication: December 03, 2012JOURNAL FREE ACCESSAn extract of Clethra barbinervis with an inhibitory effect on hyaluronidase activity was fractionated guided by the results of an assay. From the active fractions, seven new triterpene saponins (1–4, 6–8) and a new lignan glycoside (14) were isolated together with 14 known compounds (5, 9–13, 15–22). Some of the saponins (2, 3, 9) were revealed as hyaluronidase inhibitors similar to epicatechin (17).View full abstractDownload PDF (846K) -
Vida Mashayekhi, Kamaleddin Haj Mohammad Ebrahim Tehrani, Salimeh Amid ...Article type: Regular Article
2013 Volume 61 Issue 2 Pages 144-150
Published: February 01, 2013
Released on J-STAGE: February 01, 2013
Advance online publication: November 16, 2012JOURNAL FREE ACCESSBased on the existing reports regarding the antiplatelet aggregation activity of hydrazone derivatives, a series of indole hydrazone derivatives were considered as potential antiplatelet agents and synthesized. The structures of the synthesized compounds were confirmed by spectral data and elemental analysis. The new indole hydrazone derivatives were evaluated for their ability to inhibit platelet aggregation induced by adenosine diphosphate (ADP) and arachidonic acid (AA). Compounds 1h and 3h exhibited remarkable activity against arachidonic acid induced platelet aggregation with IC50 values comparable to that of indomethacin and compound 1i efficiently inhibited platelet aggregation induced by both ADP and AA.View full abstractDownload PDF (509K) -
Doaa Ezzat Abdel RahmanArticle type: Regular Article
2013 Volume 61 Issue 2 Pages 151-159
Published: February 01, 2013
Released on J-STAGE: February 01, 2013
JOURNAL FREE ACCESSSynthesis of 2,5-disubstituted-1,3,4-oxadiazole (2a–c), 3-substituted aminomethyl-5-substituted-1,3,4-oxadiazole-2(3H)-thione (4a–m) and 2-substituted thio-5-substituted-1,3,4-oxadiazole (5a, b) had been described. All the synthesized derivatives were screened for anticancer activity against HT29 and MCF7 cancer cell lines using Sulfo-Rodamine B (SRB) standard method. Most of the tested compounds exploited potent antiproliferative activity against HT29 cancer cell line rather than MCF7 cancer cell line. Compounds 2a–c, 4f and 5a exhibited potent cytotoxicity (IC50 1.3–2.0 µM) and selectivity against HT29 cancer cell line. Quantitative structure–activity relationship (QSAR) study was applied to find a correlation between the experimental antiproliferative activities of the newly synthesized oxadiazole derivatives with their physicochemical parameter and topological index.View full abstractDownload PDF (671K) -
Kamaleddin Haj Mohammad Ebrahim Tehrani, Soroush Sardari, Vida Mashay ...Article type: Regular Article
2013 Volume 61 Issue 2 Pages 160-166
Published: February 01, 2013
Released on J-STAGE: February 01, 2013
Advance online publication: November 27, 2012JOURNAL FREE ACCESSConsidering the structural features of a group of known potent inhibitors of human platelet aggregation containing hydrazone structural backbone, a series of novel hydrazone derivatives of 2-hydrazinyl-1,3,4-thiadiazole were synthesized using a one-pot process and tested for their inhibitory activity against platelet aggregation induced by arachidonic acid and ADP. Among the derivatives, compounds 3l, 3o and 3p exhibited the highest antiplatelet aggregation activity. The derivatives were also screened for their potential antimycobacterial activity and compounds 3g, 3k, 3p and 3q were among the most active compounds.View full abstractDownload PDF (560K) -
Yongbin Song, Yihui Yang, Jun You, Bo Liu, Lijun Wu, Yunlong Hou, Wenj ...Article type: Regular Article
2013 Volume 61 Issue 2 Pages 167-175
Published: February 01, 2013
Released on J-STAGE: February 01, 2013
Advance online publication: November 12, 2012JOURNAL FREE ACCESS
Supplementary materialA series of novel N3,N11-bis(2-hydroxyethyl)-14-aryl-14H-dibenzo[a,j]xanthenes-3,11-dicarboxamide, three N3,N11-bis(2-hydroxyethyl)-14-aryl-14H-dibenzo[a,j]xanthene-3,11-dimethanamine derivatives and their intermediates 14-aryl-14H-dibenzo[a,j]xanthenes-3,11-dicarboxylic acid, were synthesized, and the structures of which were characterized by 1H-NMR, 13C-NMR, high resolution (HR)-MS, and IR spectra. The antitumor activities of these molecules were evaluated on five cancer cell lines. The results of in vitro assay against human hepatocellular carcinoma cell lines (SK-HEP-1 and HepG2 and SMMC-7721 cells), acute promyelocytic leukemia NB4 cells and uterine cervix cancer HeLa cells, show several compounds to be endowed with cytotoxicity in micromolar to submicromolar range. The carboxamide derivatives 6c and 6e exhibitted good inhibition on NB4 cancer cells, and the IC50 values of which were 0.82 µM and 0.96 µM, respectively, much lower than 5.01 µM of the positive control As2O3. Flow cytometric analysis results revealed that compounds 6e and 6f may induce tumor cell apoptosis.View full abstractDownload PDF (1030K) -
Luiz Fabrício Gardini Brandão, Glaucia Braz Alcantara, M ...Article type: Regular Article
2013 Volume 61 Issue 2 Pages 176-183
Published: February 01, 2013
Released on J-STAGE: February 01, 2013
Advance online publication: December 03, 2012JOURNAL FREE ACCESSAtranorin, lichexanthone, and the (+)-usnic, diffractaic, divaricatic, perlatolic, psoromic, protocetraric, and norstictic acids isolated from the lichens Parmotrema dilatatum (VAIN.) HALE, Usnea subcavata MOTYKA, Usnea sp., Ramalina sp., Cladina confusa (SANT.) FOLMM. & AHTI, Dirinaria aspera HäSäNEN, and Parmotrema lichexanthonicum ELIASARO & ADLER were evaluated against UACC-62 and B16-F10 melanoma cells and 3T3 normal cells. Sulforhodamine B assay revealed significant cytotoxic activity in protocetraric, divaricatic, and perlatolic acids on UACC-62 cells (50% growth inhibitory concentration (GI50) 0.52, 2.7, and 3.3 µg/mL, respectively). Divaricatic and perlatolic acids proved the most active on B16-F10 cells (GI50 4.4, 18.0 µg/mL, respectively) and the most cytotoxic to 3T3 normal cells. Diffractaic, usnic, norstictic, and psoromic acids were cytotoxic to UACC-62 cells in the 24.7 to 36.6 µg/mL range, as were protocetraric and diffractaic acids to B16-F10 cells (GI50 24.0, 25.4 µg/mL, respectively). Protocetraric acid was highly selective (selectivity index (SI*) 93.3) against UACC-62 cells, followed by norstictic, perlatolic, psoromic, and divaricatic acids, while norstictic and divaricatic acids were more selective against B16-F10 cells. The high SI* value obtained for protocetraric acid on UACC-62 cells makes it a potential candidate for the study of melanomas in experimental models. Chemometric analysis was performed to evaluate the general behavior of the compounds against the cell lines tested.View full abstractDownload PDF (724K) -
Nirmal Marasini, Tuan Hiep Tran, Bijay Kumar Poudel, Han-Gon Choi, Chu ...Article type: Regular Article
2013 Volume 61 Issue 2 Pages 184-193
Published: February 01, 2013
Released on J-STAGE: February 01, 2013
JOURNAL FREE ACCESSThe present study systematically and simultaneously investigates the influence of process variables of spray-drying on the properties of solid self-microemulsifying drug delivery system (SMEDDS) using design of experiment (DOE) and optimizes them in order to produce solid-SMEDDS satisfying pre-defined powder quality attributes. Flurbiprofen-loaded liquid-SMEDDS was dispersed in dextran and spray-dried. After preliminary screening, the independent factors selected according to three-factor, three-level Box–Behnken design were inlet temperature (X1), feed rate (X2) and carrier concentration (X3). The responses used to compute the effects of independent factors were moisture content (Y1), yield (Y2), drug content (Y3) and droplet size (Y4) of the micro-emulsion. SMEDDS powder characteristics such as morphology, thermal behavior, crystallinity and flowability were also considered. Models were developed and model fitting analysis showed an adequate fit for all responses, indicating good predictability. Significant effects of processing parameters on powder characteristics were observed. The spray-drying process parameters were optimized as inlet temperature (134°C), feed rate (5%) and carrier concentration (0.6%) to produce solid-SMEDDS with acceptable moisture content (0.72±0.02%), yield (58.5±2.9%), drug content (70.1±2.7 mg/g) and droplet size (166.8±13.8 nm). Validation of the optimization process in five batches showed experimental value very close to the predicted one, ensuring the reproducibility of the developed models. Furthermore, optimized parameters resulted a highly crystalline flurbiprofen changed to an amorphous form. In conclusion, this study demonstrated the applicability of the DOE approach for optimizing the process parameters to manufacture solid-SMEDDS with desired quality attributes.View full abstractDownload PDF (3977K) -
Pichit Sudta, Payung Jiarawapi, Apichart Suksamrarn, Poonpilas Hongman ...Article type: Regular Article
2013 Volume 61 Issue 2 Pages 194-203
Published: February 01, 2013
Released on J-STAGE: February 01, 2013
Advance online publication: November 12, 2012JOURNAL FREE ACCESSA new series of mangostin analogs of natural α-mangostin from mangosteen was prepared and their antimycobacterial activity was evaluated in vitro against Mycobacterium tuberculosis H37Ra. The results showed that the monoalkyl tetrahydro α-mangostin analogs displayed increased antimycobacterial activity as compared with the lead natural xanthone, α-mangostin. Among the tested compounds, 6-methoxytetrahydro α-mangostin (16) exhibited the most potent antimycobacterial activity with minimum inhibitory concentration (MIC) of 0.78 µg/mL. The activity of the monoalkylated and monoacylated tetrahydro α-mangostins decreases as the length of carbon chain increases. The methyl ether analog was also active against the multidrug-resistant (MDR) strains with pronounced MICs of 0.78–1.56 µg/mL.View full abstractDownload PDF (793K) -
Yan-Ni Ma, Xin-Juan Yang, Le Pan, Zhe Hou, Hui-Ling Geng, Xiao-Ping So ...Article type: Regular Article
2013 Volume 61 Issue 2 Pages 204-211
Published: February 01, 2013
Released on J-STAGE: February 01, 2013
Advance online publication: December 05, 2012JOURNAL FREE ACCESSBy employing sanguinarine, a natural active quaternary isoquinoline alkaloid, as a model molecule, a series of structurally simple quaternary 2-aryl-3,4-dihydroisoquinolin-2-ium compounds were designed and synthesized and evaluated for in vitro acaricidal activity against P. cuniculi. A new approach towards the title compounds was developed with isochroman as starting material. The results showed that 22 of 24 tested compounds displayed the activity in varying degrees at 0.4 mg/mL. Fourteen compounds were significantly more effective than ivermectin, a standard acaricide, and 6-methoxy dihydrosanguinarine, a derivative of sanguinarine (p<0.05). And their comprehensive relative activity was 1.4 to 16.5 times than that of ivermectin and 1.5 to 18.8 times than that of 6-methoxy dihydrosanguinarine. The structure–activity relationship indicated that the introduction of a substituent to N-benzene ring, especially halogen atom and trifluoromethyl group, led to great improvement of the activity. The position of fluorine atom, methyl group and hydroxyl group made very significant effects on the activity. It was concluded that 2-aryl-3,4-dihydroisoquinolin-2-iums are very promising candidates for the development of new isoquinoline acaricidal agents.View full abstractDownload PDF (752K) -
Ghaneya Sayed Hassan, Doaa Ezzat Abdel RahmanArticle type: Regular Article
2013 Volume 61 Issue 2 Pages 212-221
Published: February 01, 2013
Released on J-STAGE: February 01, 2013
JOURNAL FREE ACCESSNew series of substituted glutamine 5a–l and glutamic acid diamides, diureide and dihydrazide 7a–e were synthesized from parent glutamic acid compound 3 and evaluated for their cytotoxic activity against tumor cell line PC3 (prostate cancer cell line). Most of the tested compounds exploited potent growth inhibitory activity with IC50 values ranging 0.034–3.97 µM. Particularly, compounds 5a, 3, 5j, 5b, 7c, 7e, 5l, and 5k exhibited superior potency (IC50=0.034, 0.04, 0.05, 0.074, 0.25, 0.4, 0.49, 0.522 µM, respectively) to the reference drug Doxorubicin (IC50=0.63 µM), while compound 7b showed IC50, 0.71 µM, comparable to that of Doxorubicin. In summary, the newly synthesized compounds provided promising new lead for the future design and development of glutamine and glutamic acid derivatives as novel antitumor agents. The quantitative structure–activity relationship (QSAR) study was applied to find a mathematical correlation between the structures of compounds and their activity against PC3 cell line expressed as IC50 values.View full abstractDownload PDF (767K) -
Khaled Abouzid Mohamed Abouzid, Nadia Abdalla Khalil, Eman Mohamed Ahm ...Article type: Regular Article
2013 Volume 61 Issue 2 Pages 222-228
Published: February 01, 2013
Released on J-STAGE: February 01, 2013
JOURNAL FREE ACCESSA series of nicotinic acid derivatives structurally related to niflumic acid and certain pyridazine-containing compounds have been synthesized and characterized by analytical and spectral data. All compounds were screened for their potential analgesic and anti-inflammatory activities. The compounds which displayed analgesic and anti-inflammatory activities were tested for ulcerogenicity and screened for in vivo inhibition of certain inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and cyclooxygenase-2 (COX-2). Compounds 1c, 2a, 2b, and 5a have shown potent analgesic and anti-inflammatory activities.View full abstractDownload PDF (1301K)
Notes
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Jason Taylor Schott, Charles Edward Mordaunt, Anthony Joseph Vargas, M ...Article type: Note
2013 Volume 61 Issue 2 Pages 229-236
Published: February 01, 2013
Released on J-STAGE: February 01, 2013
Advance online publication: November 27, 2012JOURNAL FREE ACCESSChalcones share some structural similarities with GW-1929, a highly-selective and potent agonist for peroxisome proliferator-activated receptor-gamma (PPARγ). In this study, we tested 53 structurally diverse chalcones to identify characteristics essential for PPARγ activation in a GAL4-based transactivation assay. This screen identified several novel chalcone agonists of PPARγ. Our results indicate that chalcones with an electron rich group or sterically large groups such as naphthyl on the carbonyl side tend to activate PPARγ. The absence of any strict structural or electronic requirements suggests that the flexibility of the PPARγ ligand binding pocket may allow binding of diverse chalcones with some preference for a slightly larger electron-rich group on the carbonyl side. We predict that further structure–activity relationship studies on chalcones with naphthalene or electron-rich groups near the carbonyl moiety will lead to the development of more potent PPARγ agonists.View full abstractDownload PDF (457K) -
Masaharu Nakamura, Yotaro Matsumoto, Masaaki Toyama, Masanori Baba, Yu ...Article type: Note
2013 Volume 61 Issue 2 Pages 237-241
Published: February 01, 2013
Released on J-STAGE: February 01, 2013
JOURNAL FREE ACCESS
Supplementary materialAggressive forms of adult T-cell leukemia (ATL) respond poorly to conventional anticancer chemotherapy, and new lead compounds are required for the development of drugs to treat this fatal disease. Recently, we developed ATL cell-selective proliferation inhibitors based on a tetrahydrotetramethylnaphthalene (TMN) skeleton 1, and here we report the design and synthesis of silicon analogs of TMN derivatives. Among them, compound 13 showed the most potent growth-inhibitory activity towards the ATL cell line S1T, though its selectivity for S1T over the non-ATL cell line MOLT-4 was only moderate. This result, as well as computational studies, suggests that sila-substitution (C/Si exchange) is useful for structure optimization of these inhibitors.View full abstractDownload PDF (2242K) -
Hari Prasad Devkota, Masato Watanabe, Takashi Watanabe, Shoji YaharaArticle type: Note
2013 Volume 61 Issue 2 Pages 242-244
Published: February 01, 2013
Released on J-STAGE: February 01, 2013
Advance online publication: November 14, 2012JOURNAL FREE ACCESSTwo new C-methyl flavonoids, diplomorphanins A (1) and B (2) were isolated from the aerial parts of Diplomorpha canescens (MEISN.) C. A. MEYER along with a known compound, farrerol 7-O-β-D-glucopyranoside (3). Structures of these compounds were determined on the basis of spectroscopic data.View full abstractDownload PDF (421K) -
Junpei Ohtaka, Akinari Hamajima, Tetsuhiro Nemoto, Yasumasa HamadaArticle type: Note
2013 Volume 61 Issue 2 Pages 245-250
Published: February 01, 2013
Released on J-STAGE: February 01, 2013
JOURNAL FREE ACCESSFor the total synthesis of novel cyclodepsipeptide homophymine A, (2R,3R,4R)-2-amino-3-hydroxy-4,5-dimethylhexanoic acid was successfully synthesized by Evans’ asymmetric alkylation and the anti-selective asymmetric hydrogenation of a chiral α-amino-β-keto ester as the key steps.View full abstractDownload PDF (648K)
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