Journal of Chinese Pharmaceutical Sciences

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2012, 21(2): 109-112.

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CuI-catalyst N-arylation of 4-iodotryptophan derivatives: effort toward the total synthesis of indolactam V

Jing-Qian Jiang, Zheng-Ren Xu, Yan-Xing Jia^*

2012, 21(2): 113-123. DOI: 10.5246/jcps.2012.02.014

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Efforts toward the total synthesis of indolactam V via CuI-mediated inter- and intra-molecular N-arylation of 4-iodotryptophan derivatives for the introduction of 4-valine moiety from natural L-valine are described. Meanwhile, the efficient synthesis of several pyrroloquinoline derivatives by taking advantage of the CuI-catalyzed intramolecular N-arylation reaction of 4-iodotryptophan is disclosed.

Design and synthesis of benzimidamides as potential BACE1 inhibitors

Hai-Fei Gao, Yan Niu^*, Feng-Rong Xu, Lei Liang, Bo Zhou, Yong-Jian Li, Chao Wang, Peng Liu, Ping Xu^*

2012, 21(2): 124-131. DOI: 10.5246/jcps.2012.02.015

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Computer aided fragment-based lead discovery has been successfully applied to the design of inhibitors of aspartyl protease enzyme β-secretase (BACE1). A benzimidamide fragment, which binds to the two catalytic aspartic acid residues in the active site of the enzyme, was selected as the starting compound. A novel series of 3-phenethylbenzimidamide inhibitors were designed and synthesized. Although biological evaluation results showed that the compounds displayed poor inhibitory activity towards BACE1, 3-phenethylbenzimidamide analogs might be modified as potential BACE1 inhibitors.

Synthesis of an active peptide from Carapax Trionycis and its inhibitory effect on the proliferation of hepatic stellate cells

Chun-Ling Hu, Yin-Ping Tang, Yan-Wen Liu^*

2012, 21(2): 132-135. DOI: 10.5246/jcps.2012.02.016

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This study was aimed to synthesize an active peptide from Carapax Trionycis and to investigate its effect on the proliferation of hepatic stellate cells (HSCs). An active peptide from Carapax Trionycis, which was shown to have significant anti-hepatic fibrosis activity, was synthesized by solid phase method and characterized by MALDI-TOF MS analysis. The HSCs in log growth phase was treated with the synthetic peptide at different concentrations. Viability and apoptosis of hepatic stellate cells were determined by MTS assay and Annexin V-FITC/PI staining, respectively. The active peptide showed strong inhibition of proliferation and induction of apoptosis of HSC-T₆ in a concentration-dependent manner. The results suggest that the active peptide from Carapax Trionycis could be synthesized efficiently and has significant inhibitory effect on the proliferation of HSC-T₆.

Efficient synthesis of thiohydantoin derivatives from amino acid esters and isothiocyanates in alkaline Al₂O₃

Gang Li, Yu-Peng Liu, Meng Lei, Xin Wang^*, Tie-Ming Cheng, Run-Tao Li^*

2012, 21(2): 136-141. DOI: 10.5246/jcps.2012.02.017

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Various amino acid esters were reacted with different isothiocyanates in alkaline Al₂O₃ at room temperature for 1 h affording thiohydantoins in moderate to excellent yields.

Synthesis and evaluation of 8-deaza-5,6,7,8-tetrahydromethotrexate
derivatives as dihydrofolate reductase inhibitors

Chao Tian, Zhi-Li Zhang, Jun-Yi Liu^*

2012, 21(2): 142-148. DOI: 10.5246/jcps.2012.02.018

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A series of N⁵-substituted 8-deaza-5,6,7,8-tetrahydromethotrexate derivatives were synthesized and evaluated as inhibitors of dihydrofolate reductase (DHFR). The results indicated that modification of the pteridine ring of methotrexate (MTX) rendered poor activity against human DHFR.

Studies on tissue distribution and excretion of scopoletin after oral
administration in rats

Yu-Feng Xia^*, Yue Dai, Hui-Zhen Liang

2012, 21(2): 149-155. DOI: 10.5246/jcps.2012.02.019

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The present study aimed at studying the characteristics of tissue distribution and excretion of scopoletin, a coumarin compound, in Sprague-Dawley rats. Scopoletin was orally administered at a dose of 50 mg/kg, and the concentrations in heart, liver, spleen, lung, kidney, muscle, fat, brain, testis, uterus, stomach and small intestine were determined at 5, 15, 30, 60, 120, 240 min post-dose, respectively. It was shown that scopoletin was widely distributed into various tissues and reached the maximal concentrations in most tissues at 15 min post-dose, and the levels in liver, kidney, stomach and small intestine were relatively higher. Furthermore, the excretions of scopoletin in bile, urine and feces were only 0.032%, 3.752% and 0.784%, respectively, suggesting that scopoletin was mainly eliminated by metabolism rather than excretion as parent drug.

Quantitative determination of cyclophosphamide in rat plasma using
an on-line SPE HPLC-DAD

Xiao-Na Li, Ning Yu, Jian-Mei Zhang, Wen-Si Lin, Xiao-Mei Ling^*, Ge Fu, Run-Tao Li, Jing-Rong Cui

2012, 21(2): 156-161. DOI: 10.5246/jcps.2012.02.020

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A rapid and simple liquid chromatography method with on-line solid phase extraction was developed and validated for the quantitative determination of cyclophosphamide in rat plasma. The plasma sample was first extracted on an Acclaim^® Polar Advantage II C₁₈ guard column (PA II C₁₈, 10 mm×4.6 mm, 5 μm), which was also the on-line Extraction Cartridge SPE column, by washing with 100% H₂O for 1 min. The extracted sample was then eluted onto a PA II C₁₈ column (150 mm×4.6 mm, 5 μm) and separated by isocratic elution with acetonitrile–water (40:60, v/v). The mobile phase was run at a flow rate of 1.0 mL/min, and the UV detector was set at 195 nm. Retention time of cyclophosphamide was 4.3 min and the total run-time was 6 min. The linear range of the standard curve was from 1.0 to 200 μg/mL (r² = 0.9999), and the limits of quantification and detection were 1.0 μg/mL (RSD<10%, n = 5) and 0.3 μg/mL(RSD<13%, n = 5), respectively. Both intra- and inter-day variations were less than 5.6%. The developed method can be used for the therapeutic drug monitoring of cyclophosphamide in the clinic.

Pharmacokinetic study of repaglinide floating drug delivery system in rabbits by RP-HPLC method

T. Ramanjireddy^*, D. Dhachinamoorthi, K.B. Chandrasekhar

2012, 21(2): 162-168. DOI: 10.5246/jcps.2012.02.021

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The present work is aimed to study the pharmacokinetic parameters of optimized repaglinide floating drug delivery system (FDDS) by 2⁴ factorial designs, followed by comparison with a commercially available formulation. The main effects and interactions of formulation variables were studied by using normal and pareto charts. The optimized formulation shows a fickian diffusion drug release mechanism. Pharmacokinetic parameters of the designed drug delivery system were evaluated in rabbit models. Mean while a simple, specific high performance liquid chromatographic method was developed and validated as per biopharmaceutical specifications, the linearity was observed at the range of 110-550 ng/mL (r² = 0.999). By using methanol-phosphate buffer (pH 2.5) (70:30, v/v) as mobile phase at the flow rate of 1.0 mL/min the validation shows a better retention time of 5.2 min for repaglinide. And the same validation method was used for pharmacokinetic profile analysis of repaglinide marketed products and FDDS. The comparative pharmacokinetic results such as t_max, half-life, area under the curve, mean residence times were increased significantly for the repaglinide in FDDS than the marketed product of repaglinide except C_max and elimination rate constant.

Effect of Aspirin on DMBA-induced mammary gland carcinogenesis and its anti-tumor mechanism in MCF-7 breast cancer cell

Wei Guan, Wei Guo, Bo Xu, Fu-Xiang Ran, Jing-Rong Cui^*

2012, 21(2): 169-177. DOI: 10.5246/jcps.2012.02.022

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The effects of Aspirin on tumor chemoprevention and inhibition have been debated and researched in recent years and its effects on colorectal cancer are quite clear. For breast cancer, however, conclusions are inconsistent and the anti-tumor mechanism of Aspirin is not clear yet. In our study, we used DMBA-induced mammary gland carcinogenesis model to assess the chemoprevention effect of Aspirin on mammary precancerous lesions. After SD rats were treated with Aspirin, the total numbers of precancerous lesion in experimental groups were 16 (40 mg/kg Aspirin) and 13 (20 mg/kg Aspirin), while the number in control group was 35. In vitro, we found that Aspirin inhibited cell proliferation in human breast cancer cell line MCF-7 by SRB assay with no apparent cytotoxity under the doses of 10, 8, 6, 4 and 2 mM, the inhibitory rates were 86.96%, 54.56%, 24.83%, 14.24% and 4.49%, respectively. In mechanism research, the results of gene microarray assay demonstrated that 4 mM and 2 mM Aspirin were effective in changing gene expression profile in MCF-7 cells. The expression of cell cycle regulator, cyclin A, was significantly down-regulated under the same doses, while the down-regulation of Cdk2 was only remarkable at 4 mM. Our findings reveal that Aspirin is effective in tumor inhibition during initial phase in rats. In MCF-7 cells, Aspirin reduces cell proliferation without significant cytotoxity and its possible mechanism involves altering tumor-related gene expression and regulating cell cycle process.

Inhibition of protein tyrosine phosphatase 1B activity by triterpenes isolated from Aceriphyllum rossii

Long Cui^*, Zhi Li, Ya-Nan Sun, Nan Zhang, Young-Ho Kim

2012, 21(2): 178-182. DOI: 10.5246/jcps.2012.02.023

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An organic layer prepared from the seed of Aceriphyllum rossii was studied to identify the active compounds for protein tyrosine phosphatase 1B (PTP1B) inhibition. Bioassay guided fractionation resulted in the isolation of PTP1B inhibitory activity of triterpenes (1-4). These four compounds were identified as aceriphyllic acid C (1), aceriphyllic acid D (2), aceriphyllic acid E (3) and aceriphyllic acid F (4). The isolated 1-4 compounds inhibited PTP1B with IC₅₀ values ranged from (2.1±1.5) μmol/L to (11.2±2.5) μmol/L. Kinetic analysis of PTP1B inhibition by aceriphyllic acid C (1) and aceriphyllic acid D (2) suggested that oleanane-type triterpenes inhibited PTP1B activity in a mixed-type manner.

Isolation of metabolic products from the fungus Nectria sp. HLS206 that is associated with the marine sponge Gelliodes carnosa collected from the South China Sea

Rui-Shan Wang, Ting Gong, Ping Zhu^*, Ke-Di Cheng

2012, 21(2): 183-186. DOI: 10.5246/jcps.2012.02.024

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The sponge-associated fungus Nectria sp. HLS206, which belongs to the order of Hypocreales, was isolated from the marine sponge Gelliodes carnosa collected from the South China Sea. The secondary metabolites of the fungus were isolated. From the solid cultures, five compounds were purified, which are chalmicrin (1), hypocrealesate (2), fucosterol (3), stigmasterol (4) and β-sitosterol (5). The structures of the 5 compounds were elucidated by ESI-MS, 1D and 2D NMR spectra (COSY, HMQC and HMBC). To the best of our knowledge, it is the first time compound 1 was isolated from the order of Hypocreales, and the spectral data of compound 2 are also firstly reported.

Chemical constituents from processed seeds of Strychnos nux-vomica

Jia-Yu Zhang, Ning Li, Kua Hu, Peng-Fei Tu^*

2012, 21(2): 187-191. DOI: 10.5246/jcps.2012.02.025

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Fifteen compounds were isolated from the processed seeds of Strychnos nux-vomica and were identified as follows: strychnine (1), brucine (2), pseudostrychnine (3), pseudobrucine (4), secoxyloganin (5), caffeic acid (6), p-hydroxybenzoic acid (7), p-hydroxyphenylacetic acid (8), uvaol (9), stigmasta-7,22,25-triene-3-ol (10), lupeol (11), 11-oxo-α-amyrin palmitate (12), catechol (13), maltol (14), adenosine (15). Compounds 5-15 were isolated from genus Strychnos for the first time.

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Journal of Chinese Pharmaceutical Sciences

2012, 21(2): 192-199.

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Peking University Institute for Drug Discovery and Development Celebrated its 3rd Anniversary on FEB 13, 2012

Xue Qiao

2012, 21(2): 200-200.

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