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Chem Pharm Bull [journal]
- New Norclerodane Diterpenoids from the Tubers of Dioscorea bulbifera L. [JOURNAL ARTICLE]
- Chem Pharm Bull (Tokyo) 2014 Apr 15.
Phytochemical investigations of the tubers of Dioscorea bulbifera L. resulted in the isolation of nine norclerodane diterpenoids, including two new compounds, diosbulbins N (1) and P (3), a new naturally occurring compound, diosbulbin O (2), and six known ones, diosbulbins A-D, F and G (4-9). Their structures were established by spectroscopic and chemical methods. The absolute stereochemistry of 1 was determined by a modified Mosher's method, and the absolute configuration of 2 was determined by a single-crystal X-ray diffraction analysis with Cu Kα irradiation. Compounds 1-3 were evaluated for in vitro cytotoxicity against five human cancer cell lines.
- Potential Use of a Megamolecular Polysaccharide Sacran as a Hydrogel-based Sustained Release System. [JOURNAL ARTICLE]
- Chem Pharm Bull (Tokyo) 2014 Apr 16.
A megamolecular polysaccharide sacran was newly extracted from cyanobacterium Aphanothece sacrum. Sacran has many preferable properties for transdermal application, e.g. a safe biomaterial, a high moisturizing effect, a formation of film and hydrogel. Additionally, it was recently discovered that sacran has an anti-inflammatory effect for atopic dermatitis model mice. In this study, in order to evaluate the feasibility of sacran-hydrogel as a novel sustained release system, we prepared a sacran-hydrogel containing 4-biphenyl acetic acid (BPAA, an acidic drug), prednisolone (PD, a neutral drug) or chlorpheniramine maleate (CPM, a basic drug), and performed the in vitro release studies. The sacran-hydrogel containing BPAA, PD or CPM provided a sustained release profile in accordance with a quasi-Fickian diffusion model. Furthermore, the release rate of drugs from sacran-hydrogels can be controlled by adjusting the concentration of aluminum chloride as a cross linker. These results suggest the potential use of sacran-hydrogel as a sustained release system for drugs.
- Development and Validation of a Sensitive GC-MS Method for the Determination of Alkylating Agent, 4-Chloro-1-butanol, in Active Pharmaceutical Ingredients. [Journal Article]
- Chem Pharm Bull (Tokyo) 2014; 62(4):395-8.
The analysis of genotoxic impurities (GTIs) in active pharmaceutical ingredients (APIs) is a challenging task. The target detection limit (DL) in an API is typically around 1 ppm (1 µg/g API). Therefore, a sensitive and selective analytical method is required for their analysis. 4-Chloro-1-butanol, an alkylating agent, is one of the GTIs. It is generated when tetrahydrofuran and hydrochloric acid are used during the synthesis of the APIs. In this study, a sensitive and robust gas chromatography-mass spectrometry (GC-MS) method was developed and validated for the identification of 4-chloro-1-butanol in APIs. In the GC-MS method, 3-chloro-1-butanol was employed as an internal standard to ensure accuracy and precision. Linearity was observed over the range 0.08 to 40 ppm (µg/g API), with a R(2) value of 0.9999. The DL and quantitation limit (QL) obtained were 0.05 ppm and 0.08 ppm (0.13 ng/mL and 0.20 ng/mL as the 4-chloro-1-butanol concentration), respectively. These DL and QL values are well over the threshold specified in the guidelines. The accuracy (recovery) of detection ranged from 90.5 to 108.7% between 0.4 ppm and 20 ppm of 4-chloro-1-butanol. The relative standard deviation in the repeatability of the spiked recovery test was 6.0%. These results indicate the validity of the GC-MS method developed in this study. The GC-MS method was applied for the determination of 4-chloro-1-butanol in the API (Compound A), which is under clinical trials. No 4-chloro-1-butanol was found in Compound A (below QL, 0.08 ppm).
- Aliphatic Substitution of o-Carboranyl Phenols Enhances Estrogen Receptor Beta Selectivity. [Journal Article]
- Chem Pharm Bull (Tokyo) 2014; 62(4):386-91.
The two subtypes of estrogen receptor (ER), ERα and ERβ, differ greatly in expression pattern and biological functions, and ERβ-selective ligands candidates to treat immune-related disorders. ERβ-selective ligands have mostly been designed based the idea of introducing a substituent that interferes sterically with the ligand's interaction with Met421 to selectively decrease the affinity for ERα (the equivalent residue in ERβ is Ile373). Therefore, we designed and synthesized a series of carboranyl phenol derivatives bearing an aliphatic substituent as candidate ERβ-selective ligands. Introduction of a longer aliphatic substituent into the carboranyl moiety enhanced the ERβ selectivity of o-carboranyl phenol derivatives 4, but not m-carboranyl bisphenol derivatives 5. Compound 4c showed 7.4-fold ERβ selectivity in ER-binding assay and exhibited moderate estrogenic activity in cell proliferation assay using MCF-7 cell line.
- Quality Evaluation of Medicinal Products and Health Foods Containing Chaste Berry (Vitex agnus-castus) in Japanese, European and American Markets. [Journal Article]
- Chem Pharm Bull (Tokyo) 2014; 62(4):379-85.
The aim of present study was to evaluate the qualities of chaste berry (fruit of Vitex agnus-castus L.) preparations using HPLC fingerprint analysis. Seven medicinal products 1 from Japan and 6 from Europe, and 17 health foods, 6 from Japan and 11 from the United States were analyzed. HPLC profile and 26 authentic peaks were compared medicinal products and health foods. Whereas medicinal products had similar HPLC profiles, health foods had various profiles and each peak was also greatly different. The measured amounts of two markers in 5 traditional medicinal products, agnuside and casticin specified in the European Pharmacopoeia (EP), the U.S. Pharmacopoeia (USP) or the WHO monographs of chaste berry, were much lower than those in 2 medicinal products defined as "well-established use" by the European Medicines Agency. The amounts of two markers for 17 health foods differed in a great deal from 14-5054% and 3-1272%, respectively. Furthermore the amount ratios of two markers, agnuside/casticin, in about half of the health foods were remarkably larger than the standard crude drug and the ratios were closer to one of the related Chinese herbs, Vitex negundo L. It is concluded that a combination of HPLC fingerprints and the amount ratios of the marker compounds of chaste berry preparations serves as a useful tool to evaluate the qualities of these preparations.
- Synthesis, Characterization and Anti-proliferation Activities of Novel Cyano Oximino Sulfonate Esters. [Journal Article]
- Chem Pharm Bull (Tokyo) 2014; 62(4):373-8.
A series of novel cyano oximino sulfonate derivatives were prepared from the reaction of arylsulfonyl chloride with different cyanoacetamide-based oximes ranging from the simplest unsubstituted amide to analogues containing N-ethyl (mimicking the Oxyma template), N-piperidinyl and N-morpholinyl chains. In addition, the cyano oximes, N-hydroxybenzimidoyl cyanide and N-hydroxypicolinimidoyl cyanide were also used in the synthesis of the novel cyano oximino sulfonate derivatives. The structures of the prepared compounds were confirmed by (1)H-NMR, (13)C-NMR, and elemental analysis. The preliminary bioassays showed that some of the title compounds, such as 2-oxo-2-(piperidin-1-yl)-N-(tosyloxy)acetimidoyl cyanide (TsPipOx), N-(tosyloxy)benzimidoyl cyanide (TsPhOX), N-(naphthalen-2-ylsulfonyloxy)-2-oxo-2-(piperidin-1-yl)acetimidoyl cyanide (NpsPipOx), 2-amino-N-(naphthalen-2-ylsulfonyloxy)-2-oxoacetimidoyl cyanide (NpsAmOx), N-(naphthalen-2-ylsulfonyloxy)benzimidoyl cyanide (NpsPhCN), and N-(naphthalen-2-ylsulfonyloxy)picolinimidoyl cyanide (NpsPyCN), showed anti-proliferation effect on the mouse fibroblast L929. The calculated IC50-values were ranging between 36.5 µg/mL and 0.235 mg/mL. However the anti-proliferation effects seem to be cytostatic rather than cytotoxic. The compounds only minimize the growth activity without completely killing the cells.
- Grevillosides J-Q, Arbutin Derivatives from the Leaves of Grevillea robusta and Their Melanogenesis Inhibitory Activity. [Journal Article]
- Chem Pharm Bull (Tokyo) 2014; 62(4):364-72.
From the 1-BuOH-soluble fraction of a MeOH extract of the leaves of Grevillea robusta, new arbutin derivatives and related compounds, named grevillosides J-Q (1-8), together with eight known compounds (9-18) were isolated. Various kind of acyl groups were attached to β-D-glucose at the 6-position through an ester linkage. Their structures were mainly elucidated from one- and two-dimensional NMR spectroscopic data. For exploitation as skin-lightening and anti-chloasma agents, the inhibitory activities of the isolated compounds as well as ones isolated in previous experiments (19-31) toward tyrosinase and melanin-producing B16 cells were assayed. Several compounds showed promising activity.
- Synthesis of a Human Urate Transporter-1 Inhibitor, an Arginine Vasopressin Antagonist, and a 17β-Hydroxysteroid Dehydrogenase Type-3 Inhibitor, Using Ring-Expansion of Cyclic Ketoximes with DIBALH. [Journal Article]
- Chem Pharm Bull (Tokyo) 2014; 62(4):354-63.
Synthesis of three clinical candidates for medicines, a human urate transporter-1 inhibitor, an arginine vasopressin antagonist, and a 17β-hydroxysteroid dehydrogenase type-3 inhibitor, is described. These compounds were synthesized via construction of their 3,4-dihydro-2H-benzo[b][1,4]oxazine, dibenzodiazepine, and dibenzazocine skeletons, respectively, using the reductive ring-expansion reaction of the corresponding bicyclic or tricyclic oximes with diisobutylaluminum hydride.
- Synthesis and in Vitro Biological Evaluation of Hybrids from Tetrahydro-β-carboline and Hydroxylcinnamic Acid as Antitumor Carcinoma Agents. [Journal Article]
- Chem Pharm Bull (Tokyo) 2014; 62(4):343-9.
Novel hybrids 8a-j and 9a-j were designed and synthesized by coupling the carboxyl group of hydroxylcinnamic acids with tetrahydro-β-carboline alkaloids which were linked with different substituted nitrogen-containing heterocycles at the positions-N9, and their in vitro biological activities were evaluated. It was found that most hybrids showed good to moderate anti-tumor activities. Especially, compound 9j had a great potency superior to 5-fluorouracil (5-FU) and comparable to adriamycin in human cancer cells, and could selectively inhibit tumor cells, but not inhibit non-tumor cell proliferation in vitro. More importantly, apoptosis assay indicated that 9j could significantly induce tumor cell apoptosis in a dose-dependent manner. Therefore, our novel findings may provide a new framework for the design of new hybrids for the intervention of human cancers.
- Molecular Modeling, Design, Synthesis, and Biological Activity of 1H-Pyrrolo[2,3-c]pyridine-7-amine Derivatives as Potassium-Competitive Acid Blockers. [Journal Article]
- Chem Pharm Bull (Tokyo) 2014; 62(4):336-42.
A series of 1H-pyrrolo[2,3-c]pyridine-7-amine derivatives were designed and synthesized based on our docking model as potassium-competitive acid blockers (P-CABs). Molecular modeling of these derivatives led us to introduce a substituent at the 1-position to access two lipophilic sites and polar residues. We identified potent P-CABs that exhibit excellent inhibitory activity in vitro and in vivo. These results indicate that the 1H-pyrrolo[2,3-c]pyridine-7-amine derivatives are promising lead compounds as P-CABs.