Table of Content

15 March 2011, Volume 20 Issue 2

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Journal of Chinese Pharmaceutical Sciences

2011, 20(2):  101-104. 

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Review

Novel nanovectors as liver targeting MRI contrast agents

Yong-Jun Liu, Zhi-Jin Chen, Na Zhang^*

2011, 20(2):  105-117.  DOI: 10.5246/jcps.2011.02.013

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Accurate diagnosis of hepatocellular carcinoma (HCC) in the early stage is vital for its treatment. Contrast-enhanced dynamic magnetic resonance imaging (MRI) performed in the presence of extracellular contrast agents such as gadolinium chelates is considered as a useful approach for detecting and characterizing focal liver lesions. However, the sensitivity and specificity of conventional MRI contrast agents are far from satisfaction for the detection and characterization of benign and malignant focal liver lesions in the early stage. The novel molecular contrast agents special for liver with relatively longer metabolic time and stable contrast effect in liver tissue are highly desired. The development of nanotechnology provides an unprecedented opportunity for the diagnostic detection rate of HCC and cell-surface receptor-targeted nanotechnology improves the specificity of the detection of focal liver lesions. In order to maximize lesion detection and characterization, novel gadolinium chelates loaded nanovectors including the solid lipid nanoparticles, nanocomplexes and polymeric nanoparticles have been used as biocompatible molecular MRI contrast agent. In this review, the characterization and the advantages/disadvantages of these Gd-loaded novel nanovectors used as molecular MRI contrast agents were discussed. Furthermore, liver target nanovectors aimed at improving the diagnostic accuracy of liver MRI by targeting additional features of focal liver lesions were highlighted.

Full Papers

Synthesis and molecular docking study of (E)-4-(6,7-dimethoxyquinazolin-4-ylamino)phenyl-3-(4-chlorophenyl)acrylate as a JAK3 inhibitor

Xiao-Hua Guo, Yu-Zhuo Ma, Yang Zhang, Ying-Xiang Liu^*

2011, 20(2):  118-124.  DOI: 10.5246/jcps.2011.02.014

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A 4-anilinoquinazoline derivative (1) designed as a JAK3 inhibitor was synthesized in high yield by a practical and efficient method. The molecular docking study was also performed to elucidate the molecular mechanism of the JAK3 inhibitory potency of compound 1. The results indicated that compound 1 had various interactions with the key amino acid residues at the ATP-binding cavity of JAK3 protein and presented high affinity to JAK3 protein, which was even higher than JANEX-1 and Tasocitinib.

Application of the HSAB principle for the quantitative analysis of nucleophilicity/basicity of organic compounds with lone-pair electrons

Zheng Zheng, Zhen-Ming Liu^*

2011, 20(2):  125-132.  DOI: 10.5246/jcps.2011.02.015

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Based on the density functional theory, we described here a method to investigate the quantitative relationship between nucleophilicity/basicity and HSAB-theory-based properties of compounds with lone-pair electrons. Descriptors including global softness, Fukui function, local softness and local mulliken charge were calculated at SVWN/DN* level of DFT with PC Spartan Pro. Nucleophilicity and basicity of 28 selected compounds were classified based on intensity. BP algorithm of artificial neural network (ANN) was employed to study the relationship between the descriptors and nucleophilicity/basicity. Cross-validation was carried out to avoid the over-fitting in training of ANN. A BP network was trained to quantify the relationship between HSAB-theory-based properties and nucleophilicity/basicity of compounds with lone-pair electrons. The results show that the prediction based on the network matches with the experimental results well. The local softness and Fukui function have a better relationship with nucleophilicity and local mulliken charge than with the basicity. The trained BP network could be utilized for predicting the nucleophilicity/basicity of compounds or functional groups with lone-pair electrons.

Synthesis of a series of guanidine substituted derivatives of aminoglycosides

Bo Peng, Gui-Hui Chen, Pan Pan, Xiang-Bao Meng, He-Qing Huang^*, Shu-Chun Li, Zhong-Jun Li^*

2011, 20(2):  133-138.  DOI: 10.5246/jcps.2011.02.016

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A novel method to prepare guanidine substituted aminoglycoside derivatives was developed. Free guanidine reacted with Cbz-protected aminoglycosides to produce guanidinylcarbonyl substituted derivatives. A methoxycarbonyl-protected intermediate was isolated, and the mechanism of guanidinylcarbonyl modification was proposed. With this method, six per- or part- guanidylcarbonyl substituted aminoglycosides were successfully obtained in good yields. Their in vitro antibacterial activities were essayed.

Stereoselective synthesis of 2-deoxy-pyranosides via the Lewis acid-promoted rearrangement of 2,3-anhydrothiosugars

Chao Gao, De-Cai Xiong, Yuan Wang, Xin-Shan Ye^*

2011, 20(2):  139-145.  DOI: 10.5246/jcps.2011.02.017

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An efficient method for the preparation of 2-deoxy-glycopyranosides was developed by using 2,3-anhydrothioglycosides as the glycosylating agents. The reaction proceeded by the Cu(OTf)2-mediated rearrangement of 2,3-anhydrothiosugars. And high anomeric stereoselectivity was achieved. The disclosed methodology may find applications in the preparation of many biologically important 2-deoxy-glycosides.

Synthesis and anti-HIV-1 activity evaluation of N-1-alkyl-5-halogeno-6-alkylamino uracils as novel non-nucleoside HIV-1 reverse transcriptase inhibitors

Han Yan, Xiao-Wei Wang^*, Ying Guo, Zhi-Li Zhang, Jun-Yi Liu^*

2011, 20(2):  146-153.  DOI: 10.5246/jcps.2011.02.018

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N-1-alkyl-5-halogeno-6-alkylamino uracils, which are novel 1-[(2-hydroxyethoxy) methyl]-6-(phenylthio) thymine (HEPT) analogues, were synthesized as the selective and potent non-nucleoside human immunodeficiency virus (HIV)-1 reverse transcriptase inhibitors. Some of the compounds showed potent inhibitory activity against HIV-1 reverse transcriptase. For instance, compounds 1d, 1m and 1n exhibited potent anti-HIV-1 activity with the IC50 values of 13.3, 11.7 and 3.15 µM, respectively, which are comparable to that of nevirapine (IC50 8.38 µM).

Chemical constituents of Rhodiola kirilowii Maxim.

Lian-Mei Yang, Rong Hu, Wen Qi, Peng Xing, Hong-Zheng Fu^*

2011, 20(2):  154-158.  DOI: 10.5246/jcps.2011.02.019

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Chemical constituents of the whole herb of Rhodiola kirilowii (Regl) Maxim. were investigated. The separation of the constituents was achieved by using a combination of various chromatographic techniques including column chromatography over silica gel, ODS, Sephadex LH-20 and reversed-phase HPLC. Their structures were elucidated by spectroscopic techniques including 1D and 2D NMR spectroscopy. Eleven compounds were obtained and identified as 4-[2-[(4-methoxyphenyl)ethoxy]ethyl]phenol (1), 1-(2-hydroxy-2-methylbutanoate)-β-D-glucopyranose (2), 4-ethoxy-phenylethanol acetate (3), p-hydroxyacetophenone (4), p-hydroxy-benzoic acid ethylester (5), 4-hydroxybenzoic acid (6), 4-hydroxybenzaldehyde (7), R(-)-mellein (8), stigmasterol (9), 4-methoxy-phenylethanol (10), and methylgallate (11). Among them, 1 and 2 are new compounds; compounds 3, 5, 7, 8, and 10 were isolated from Rhodiola genus for the first time; and compounds 4, 6, 9, and 11 were isolated from Rhodiola kirilowii (Reg1) Maxim. for the first time.

Optimization for supercritical CO₂ extraction of icariin by response surface method

Ya-Qiong Guan, Yao-Wu Zhang^*, Long Zhang

2011, 20(2):  159-163.  DOI: 10.5246/jcps.2011.02.020

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The aim of the present study was to optimize the supercritical CO2 extraction conditions of icariin from Herba Epimedii by response surface method (RSM) and central composite design (CCD). A 3-factor, 5-level CCD was used for the optimization. Independent variables were extraction temperature, extraction pressure and entrainer flow rate. Dependent variable was yield ratio of icariin from Herba Epimedii. A two-order polynomial equation was fitted to the data. The results showed that the optimum extraction conditions were as follows: extraction temperature 46.5 ºC, extraction pressure 30.6 MPa, entrainer flow rate 3.3 mL/min. CCD/ RSM is convenient and highly predictive for optimizing the extraction process of icariin from Herba Epimedii.

Preparation of sorafenib self-microemulsifying drug delivery system and its relative bioavailability in rats

Ya-Ou Liu, Jie-Ming Fan, Xue-Qing Wang^*, Qiang Zhang

2011, 20(2):  164-170.  DOI: 10.5246/jcps.2011.02.021

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Sorafenib is a novel antitumor drug, which is poorly absorbed in the gastrointestinal tract due to its low solubility in water. To improve the bioavailability of sorafenib, a self-microemulsifying drug delivery system (SMEDDS) formulation of sorafenib was prepared and its relative bioavailability in rats was evaluated. The blank SMEDDS was prepared from a mixture of ethyl oleate (oil phase, 20%, w/w), Cremophol EL (surfactant, 48%, w/w), PEG-400 (co-surfactant, 16%, w/w) and ethanol (co-surfactant, 16%, w/w). Sorafenib was subsequently dissolved in the blank SMEDDS to obtain a sorafenib SMEDDS formulation with a final sorafenib concentration at 20 mg/mL. The particle size of the emulsified sorafenib SMEDDS was about 20-25 nm. Compared with sorafenib suspension, the prepared SMEDDS formulation exhibited no effect on the Tmax, significantly increased the AUC, Cmax and MRT and decreased the drug clearance. Most importantly, the oral bioavailability based on AUC0-72 h increased about 25 times after formulating sorafenib in SMEDDS. We concluded that SMEDDS could be a promising vesicle for the oral delivery of the poorly soluble antitumor drug sorafenib.

Establishment of an HPLC method for the analysis of biapenem and its impurities

Nan Wang, Chun-Feng Li, Dou-Sheng Zhang, Chang-Qin Hu^*

2011, 20(2):  171-180.  DOI: 10.5246/jcps.2011.02.022

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An HPLC method for routine quality control of biapenem was established. A Dikma Diamonsil C18 column (250 mm×4.6 mm, 5 µm) was used with diode array detection and single wavelength detection at 220 nm. The mobile phase was consisted of acetonitrile-0.1% triethylamine water (1:99, v/v). The liner range for biapenem quantification was 0.05-10.0 mg/mL (r² = 0.999). The LOD and LOQ of impurity were 4.8 ng (S/N = 3) and 18.5 ng (S/N = 10), respectively. Intra-day RSD of main impurity and total impurity were 1.84% and 3.37% (n = 3); inter-day RSD of main impurity and total impurity were 4.84% and 7.58% (n = 9). The test solution was stable when stored at 4 ºC for 6 h. The impurity peaks of biapenem can be identified by chromatographic spectral correlation analysis using high-performance liquid chromatography-diode array detection data from the quality control method by calculating correlation coefficients without reference standards. Two hydrolysis degradation products with relative retention times (RRTs) of 0.528 and 0.743, two dimers with RRTs of 1.062 and 2.817 were identified in the quality control chromatogram. It provides a new way to identify impurity peaks by the routine HPLC-UV method.

Calf spleen extract alleviates cyclophosphamide-induced leucopenia in mice and inhibits the glycolysis of HL60 cells

Zhen-Yu Hu, Xiao-Yan Liu, Xiu-Mei Liu, Zhen-Jun Yang^*, Yin-Ye Wang^*

2011, 20(2):  181-187.  DOI: 10.5246/jcps.2011.02.023

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Calf spleen extract (CSE) has been clinically used as an adjuvant agent in malignant tumor therapy. It can improve the physical status of patients. However, its mechanism of action remains relatively unclear. In this study, we investigated the effect of CSE on leucopenia in mice and on promyelocytic leukemia cells (HL60). CSE in 10 mL/kg (2.5 mg bioactive polypeptides and 190 μg ribose/mL) significantly increased leukocyte numbers in leucopenia mice. The effect on neutrophil numbers, among all leukocytes, was the most evident. CSE stimulated the proliferation of bone marrow cells in vitro and decreased the GM-CSF level in serum. In addition, CSE significantly reduced the viability of HL60 cells, decreased the production of lactate and adenosine triphosphate (ATP) of these cells. CSE induced the apoptosis and S-phase arrest in HL60 cells. In conclusion, CSE can enhance leukocyte numbers, which may be attributed to its direct stimulatory effect on bone marrow cells. CSE is an inhibitor of promyelocytic leukemia cell viability, which may be attributed to the induction of the apoptosis, the arrest of cell cycle and the inhibition of the glycolysis of cells.

Glucosamine reduces blood-brain barrier disruption by inhibiting the expression of matrix metalloproteinase-9 in experimental autoimmune encephalomyelitis rats

Chun-Yun Liu, Ling Feng, Jie-Zhong Yu, Min-Fang Guo, Yong-Sheng Sun, Ning Ji, Jian Meng, Li-Yun Liang, Cun-Gen Ma^*

2011, 20(2):  188-194.  DOI: 10.5246/jcps.2011.02.024

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We investigated the effects of glucosamine (GS) on blood-brain barrier (BBB) function and matrix metalloproteinase-9 (MMP-9) expression in rats with experimental autoimmune encephalomyelitis (EAE). Animals were randomly divided into three groups, among which the EAE and GS groups were immunized with complete antigen and pertussis toxin, and the adjuvant group was immunized with complete Freund’s adjuvant and pertussis toxin. Rats were treated by peritoneal injection of GS 180 mg/(kg·d) in the GS group and peritoneal injection of phosphate-buffered saline 4.5 mL/(kg·d) in the EAE and adjuvant groups. We proposed to assess the integrity of BBB by calculating cerebrospinal fluid to serum albumin quotient (QA) on days 6, 8, 10, 12, 14, 16 and 18 post-immunization. At the same time, the brains and spinal cords were removed for MMP-9 immunohistochemical staining. Experiments demonstrated that in the EAE group, QA value and MMP-9 expression were highly elevated and up-regulated and correlated to disease severity. Moreover, there was statistically significantly positive correlation between QA value and MMP-9 expression. In the GS group, we observed that the mean disease onset date was delayed, the incidence and mean score of symptom were suppressed at the peak phase of disease (P<0.05). Furthermore, QA value and MMP-9 expression in the GS group showed stronger inhibition when compared with those of the EAE group (P<0.05). Our study showed that GS would reduce the BBB breakdown and leukocyte trafficking by inhibiting the production of MMP-9 and mitigate EAE.

Note

Synthesis of functional amino acids bearing 1,3-dithiane modification

Ying Yang, Chao Wang^*

2011, 20(2):  195-198.  DOI: 10.5246/jcps.2011.02.025

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Two protected single amino acid chelates, N^α-Fmoc-N^ε, N^ε-di((2,2-dimethyl-1, 3-dithian-5-yl)methyl)-L-lysine (7) and N^α-Fmoc-N^ε-(2,2-dimethyl-1,3-dithian-5-yl)methyl, N^ε-Boc-L-lysine (9), were synthesized by modifying the side chain of lysine with 1,3-dithiane through direct reductive N-alkylation protocol. These amino acids have potential uses in peptide chemistry.