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Chem Pharm Bull [journal]
- Synthesis and in vitro evaluation of the antitubercular and antibacterial activity of novel oxazolidinones bearing octahydrocyclopenta[c]pyrrol-2-yl moieties. [JOURNAL ARTICLE]
- Chem Pharm Bull (Tokyo) 2014 Oct 9.
A 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 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.
- Enantioselective desymmetrization of FTY720. [Journal Article]
- Chem Pharm Bull (Tokyo) 2014; 62(10):1041-4.
A method for enantioselective desymmetrization of N-Ac and N-Boc-FTY720 by nonenzymatic asymmetric acylation was developed. Effective enantioselective monobenzoylation using benzoyl chloride in the presence of the tetraphenylbisoxazoline (L2)-CuCl2 complex gave the desired products 3a and 3b in 52-62% yield with 64% ee.
- Synthesis and antiviral activities of some 2,4,6-trisubstituted 1,3,5-triazines. [Journal Article]
- Chem Pharm Bull (Tokyo) 2014; 62(10):1032-40.
We describe the synthesis and results of biological evaluation of newly designed 2,4,6-trisubstituted symmetrical 1,3,5-triazine (TAZ) derivatives. Among the tested trisubstituted TAZ derivatives, some CS-symmetrical alkoxy-amino-substituted TAZ derivatives, including 7ggp and 6dpp, showed significant antiviral activity against herpes simplex virus type 1 (HSV-1). The compound with the highest level of antiviral activity was C3-symmetrical trialkoxy-TAZ derivative 4bbb, which showed a considerably high selectivity index (IC50/EC50=256.6). The structure-activity relationships for anti-HSV-1 activity of the tested 2,4,6-trisubstituted TAZ derivatives are also described.
- Chemical Structures and Hepatoprotective Effects of Constituents from Cassia auriculata Leaves. [Journal Article]
- Chem Pharm Bull (Tokyo) 2014; 62(10):1026-31.
An 80% aqueous acetone extract of Cassia auriculata leaves was found to show a protective effect on D-galactosamine-induced cytotoxicity in primary cultured mouse hepatocytes. From the 80% aqueous acetone extract, we isolated a new benzocoumarin glycoside, avaraoside I (1), and a new flavanol dimer, avaraol I (2), together with 29 known constituents. The structures of the new compounds were elucidated on the basis of chemical and physicochemical evidence. In addition, three isolated compounds, pseudosemiglabrin (15, 0.0011%), (2S)-7,4'-dihydroxyflavan(4β→8)-catechin (22, 0.00075%), and (2S)-7,4'-dihydroxyflavan(4β→8)-gallocatechin (23, 0.092%), displayed hepatoprotective effects equivalent to that of the hepatoprotective agent, silybin.
- Taxiphyllin 6'-O-Gallate, Actinidioionoside 6'-O-Gallate and Myricetrin 2″-O-Sulfate from the Leaves of Syzygium samarangense and Their Biological Activities. [Journal Article]
- Chem Pharm Bull (Tokyo) 2014; 62(10):1013-8.
Three new compounds were isolated from a MeOH extract of the leaves of Syzygium samarangense, one new cyanogenic glucoside, taxiphyllin 6'-O-gallate (1), one new megastigmane glucoside, actinidioionoside 6'-O-gallate (2), and one new sulfated flavonoid rhamnoside, myricetrin 2″-O-sulfate (3), together with 14 known compounds, lupeol (4), demethoxymatteucinol (5), cryptostrobin (6), betulinic acid (7), β-sitosterol glucoside (8), 2R-prunasin (9), myrciaphenone A (10), 1-feruloyl-β-D-glucopyranoside (11), (3S,5R,6R,7E,9S)-3,5,6,9-tetrahydroxymegastigman-7-ene (12), guaijaverin (13), myricetin 4'-methyl ether 3-O-α-L-rhamnopyranoside (14), myricetrin (15), gallic acid (16) and actinidioionoside (17). The structures of the new compounds were determined through a combination of spectroscopic, HPLC and chemical analyses.
- Sesquiterpenoids and Lignans from the Roots of Syringa pinnatifolia. [Journal Article]
- Chem Pharm Bull (Tokyo) 2014; 62(10):1009-12.
Two new sesquiterpenoids, pinnatifone A (1) and pinnatifone B (2), and two new lignans, pinnatifolin (3) and isopinnatifolin (4), along with six known lignans (5-10), were isolated from the roots of Syringa pinnatifolia. The structures of the new compounds were elucidated by extensive spectroscopic methods, including NMR, MS, UV, and IR spectra. The lignans were screened for their anti-oxidant activity (2,2-diphenyl-1-picrylhydrazyl (DPPH) assay). Most of them showed potent anti-oxidant activity, especially compound 5, whose potent anti-oxidant activity had an SC50 value higher than that of the positive control vitamin C.
- A Novel Selenadiazole Derivative Induces Apoptosis in Human Glioma Cells by Dephosphorylation of AKT. [Journal Article]
- Chem Pharm Bull (Tokyo) 2014; 62(10):994-9.
Selenadiazole derivatives are synthetic organoselenium compounds with improved anticancer activity and greater selectivity than inorganic selenium. In this study, 4-(benzo[c][1,2,5]selenadiazol-6-yl)-benzene-1,2-diamine (BSBD) was shown to induce time- and dose-dependent apoptosis in SWO-38 human glioma cells by accumulation of a sub-G1 cell population, DNA fragmentation, nuclear condensation, caspase activation and poly(ADP-ribose) polymerase (PARP) cleavage. Further mechanistic investigation showed that BSBD treatment induced dephosphorylation of AKT and DNA damage-mediated activation of p53, leading to extensive apoptosis through the mitochondrial pathway. Our findings suggest that BSBD represents a potential human glioma therapeutic.
- Contribution of glucose to crystallization of phenytoin in injectable dosage form by dilution with infusion fluids. [Journal Article]
- Chem Pharm Bull (Tokyo) 2014; 62(10):989-93.
The crystallization of phenytoin occurring after its dilution with infusion fluid is a major concern in the clinical use of injectable phenytoin. To gain further understanding of the crystallization, this study assessed details of the involvement of glucose in this action. For sample preparation, phenytoin crystals were created by diluting the injectable phenytoin with infusion fluids with different glucose concentrations at different temperature, and then the characteristics of the crystallization (e.g., crystal size in the long direction, accumulated amount over 24 h, and crystallization rate constant) were measured. Results of the analysis of variance indicated that the glucose concentration and temperature had significant impacts on the crystallization. The mode of action of the glucose concentration was suggested to be different from that of the incubation temperature. This study also examined the molecular mobility of components (i.e., glucose, propylene glycol, phenytoin) in the admixtures using diffusion NMR techniques. The findings will provide valuable information for the clinical use of injectable phenytoin.
- Development of 2-Thioxoquinazoline-4-one Derivatives as Dual and Selective Inhibitors of Dynamin-Related Protein 1 (Drp1) and Puromycin-Sensitive Aminopeptidase (PSA). [Journal Article]
- Chem Pharm Bull (Tokyo) 2014; 62(10):979-88.
An established inhibitor of dynamin-related protein 1 (Drp1), 3-(2,4-dichloro-5-methoxyphenyl)-2-thioxoquinazoline-4-one (mdivi-1), was recently reported also to show potent puromycin-sensitive aminopeptidase (PSA)-inhibitory activity. Herein, we report structural development of mdivi-1 derivatives and structure-activity relationship (SAR) analysis of the synthesized compounds, as well as the structurally related PSA-specific inhibitor 3-(2,6-diethylphenyl)quinazoline-2,4-dione (PAQ-22), with the aim of identifying key structural features for inhibitory activity in order to develop selective inhibitors of Drp1, which is a potential target for treatment of Huntington's disease. Among the synthesized compounds, 3-(4-chloro-3-methoxyphenyl)-2-thioxoquinazoline-4-one (10g) exhibited more potent Drp1-inhibitory activity than mdivi-1 with high selectivity for Drp1 over PSA.
- Preparation of polypseudorotaxanes composed of cyclodextrin and polymers in microspheres. [Journal Article]
- Chem Pharm Bull (Tokyo) 2014; 62(10):962-6.
We prepared polypseudorotaxanes (PPRXs) composed of cyclodextrin (CyD) and polyethylene glycol (PEG) inside microspheres (MSs) by an emulsifying process using polypropylene glycol (PPG) that shows temperature-dependent hydrophilicity changes; PPG is hydrophobic at high temperatures but hydrophilic at low temperatures. An aqueous solution of CyD and PEG was dispersed as droplets in PPG at 60°C then cooled to 0°C to allow water of droplets to transfer into PPG. On removal of water in the droplets, CyD and PEG were left behind as a CyD/PEG PPRX inside the solid-state MSs. Examination of α-, β-, and γ-CyD revealed that α-CyD was suitable for the formation of PPRX containing PEG in this MS preparation procedure. Interestingly, a new PPRX composed of α-CyD and PPG was formed in the α-CyD MSs when they were prepared in the absence of PEG from the aqueous solution of α-CyD. This MS fabrication procedure can control the size and shape of PPRX particles, and will contribute to the production of new types of CyD inclusion complexes.