Journal of Chinese Pharmaceutical Sciences

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2010, 19(5): 323-326.

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Synthesis and anti-tumor activities of 5-carbohydrate modified cyclophosphamide derivates

Yu Zheng, Xiang-Bao Meng, Shu-Chun Li, He-Qing Huang, Zhong-Jun Li^*, Qing Li^*

2010, 19(5): 327-340.

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Novel prodrugs of cyclophosphamide 1a and 1b, which comprised the galactosyl moiety, the key fraction of cyclophosphamide derivates, and the linker 4-hydroxy benzaldehyde, were synthesized. These compounds were anticipated to exhibit amplified anti-tumor activity and targeting ability.

Structure-based design of hexahydropyrimidin-5-ols as novel non-peptidic β-secretase inhibitors

Bo Zhou, Yan Niu, Xiao-Min Zou, Feng-Rong Xu, Yue Yuan, Chao Wang, Hai-Fei Gao, Peng Liu, Ping Xu^*

2010, 19(5): 341-345.

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Based upon the crystal structure of a previously reported fragment hit that binds to β-secretase, a novel series of non-peptidic small-molecule β-secretase inhibitors, namely hexahydropyrimidin-5-ols, along with two series of their analogues, were rationally designed through structural modification. The CADD study was performed and revealed good expectation. Inhibitory activities of the corresponding structural cores were tested, which provided further support for our design approach.

Modification of the alkylating agent chlorambucil with spiropiperazinium salts

Gong Li, Qi Sun*, Jing-Rong Cui, Run-Tao Li^*

2010, 19(5): 346-352.

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In order to improve the antitumor activity and reduce the toxicity of the alkylating agent chlorambucil, a series of spiropiperazinium salts of chlorambucil (8) were designed and synthesized. It was found that compound 8f exhibited potential in vivo activity against H22.

Preparation of lomustine loaded liposomes and studies of its pharmacokinetics and tissue distribution properties

Jin-Ping Wang, Xia-Li Zhu, Yan-Wei Xi, De-Feng Wang, Gui-Hua Huang^*

2010, 19(5): 353-362.

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Liposomes are used as carriers for targeted drug delivery by the intravenous route. The aim of our study was to prepare lomustine loaded liposomes (CCNU-Lips) and evaluate its physicochemical properties and the tissue targeting after intravenous (i.v.) injection. CCNU-Lips were prepared by film dispersion method. In vitro drug release was investigated in phosphate-buffered saline (pH 6.8) at 37 ºC. The concentrations of CCNU in selected organs were determined using reversed-phase high-performance liquid chromatography (HPLC) following i.v. administration of CCNU-Lips and inclusion complex solution of CCNU with hydroxypropyl-β-cyclodextrin (CCNU-Sol). CCNU-Lips had an average diameter of (189.8±28.5) nm with a zeta potential of (-19.13±0.12) mV and the in vitro drug release was monitored for up to 3 d, and the release behavior was in accordance with Weibull-equation. The CCNU-Lips exhibited a longer elimination half life (t1/2β) in vivo compared with CCNU-Sol after i.v. injection to New Zealand rabbits. The encapsulation of lomustine in liposomes also changed its biodistribution in mice. CCNU-Lips showed significant brain targeting with AUC, Te and Re of the brain all showing obvious elevation. These results indicated that CCNU-Lips were promising passive targeting formulation to the brain.

Octreotide modified PEGylated liposomes improved the anticancer efficacy of doxorubicin in somatostatin receptor II positive tumor model

Jun-Lin Zhang, Wu Jin, Xue-Qing Wang, Jian-Cheng Wang, Xuan Zhang, Qiang Zhang^*

2010, 19(5): 363-370.

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Active targeting drug delivery systems (TDDS), which could improve drug therapeutic efficacy and reduce toxicity, are still the focus of many scientific researches in cancer therapy. The drug circulation time and tumor accumulation could be significantly increased with the application of sterically stabilized liposome (SSL). SSL could also be modified easily with certain ligands to achieve targeting drug delivery. Because many tumors overexpress somatostatin receptors (SSTRs), octreotide (OCT) becomes a potential targeting ligand due to its high affinity to SSTRs, especially to subtype 2 (SSTR2). In this study, OCT was conjugated to methoxypolyethyleneglycol-distearoyl-phosphatidylethanolamine (DSPE-PEG2000), and doxorubicin (DOX)-loaded SSL with a variable percentage of octreotide-methoxypolyethyleneglycol-distearoyl-phosphatidylethanolamine (DSPE-PEG2000-OCT) were prepared (OCT-SSL-DOX). All liposomes were about 90 nm in diameter and negatively charged on the surface, with DOX encapsulation efficiency at above 95%. OCT modification exhibited little effect on the physicochemical properties of SSL. In this study, cellular delivery efficacy of all prepared liposomes was evaluated in SSTR2-positive cells in vitro by flow cytometry for the optimization of the OCT density on the surface of liposomes. Lipid formulation containing 1.5% DSPE-PEG2000-OCT exhibited the highest efficiency of intracellular drug delivery. The modification of OCT did not alter the release behaviors of liposomal DOX in vitro, but OCT-SSL-DOX increased the cytotoxicity and improved the anti-tumor effect of liposomal DOX in SSTR2-positive cells and tumor-bearing mice models. In summary, OCT-modified SSL succeeded in increasing intracellular delivery and enhancing therapeutic efficacy of encapsulated anticancer agent, suggesting that it might be a promising TDDS for the treatment of SSTR2-overexpressing cancers.

Synthesis and characterizations of naproxen intercalated Mg-Al layered
double hydroxides

Bao-Zhong Du^*, Ru-Min Wang

2010, 19(5): 371-378.

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Naproxen (Nap), a non-steroidal anti-inflammatory drug (NSAIDs), was intercalated into the gallery of Mg-Al layered double hydroxides (LDHs) by ion exchange and co-precipitation with different location of magnesium ion and aluminum ion solutions, respectively. The product was characterized with powder X-ray diffraction (XRD), Fourier Transform Infrared spectral (FT-IR) and Thermogravimetry (TG). The results showed an expanded LDH structure, indicating that the drug was successfully intercalated into LDH with the monolayer perpendicular to (along the short axis orientation in proper angle) Nap anion. As compared to the pure form of Nap, the thermal stability of the intercalated Nap was significantly enhanced due to the host-guest interaction involving hydrogen bond and electrostatic attraction. We further investigated the drug release characteristics of the pillared LDH materials by a dissolution test in simulation gastrointestinal and intestinal fluids under different pH values. The results indicated that the release percentages decrease upon increasing pH from 4.60 to 7.43, likely due to the dependence of release mechanism on pH. We have carried out a kinetic simulation to the release data and found that the dissolution mechanism was mainly responsible for the release behavior of Nap-LDHs at pH 4.60, while the ion-exchange mechanism was responsible for that at pH 7.43. In addition, the initial release rates and equilibrium percent releases of the nanohybrids depended significantly on the synthesis methods, from which we have proposed a schematic model. The current study clearly showed that this drug-inorganic layered material has prospective applications in drug delivery system.

A simple and robust HPLC-MS method for the quantitative determination of nimesulide in human plasma and its application to bioequivalence study in Chinese volunteers

Wen-Wen Yang, Li-Na Fang, Gui-Tong Hao, Li-Xia Liu, Hong-Ying Yang, Li-Xin Sun^*

2010, 19(5): 379-386.

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A rapid and sensitive high performance liquid chromatography-mass spectrometry (HPLC-MS) method for the quantification of nimesulide in human plasma was developed and validated. Sample aliquots of 100 µL were extracted by one-step liquid-liquid extraction after addition of hydrochlorothiazide as the internal standard (IS). Analytes were separated on a reverse phase C18 column using methanol-water (84:16, v/v) as the mobile phase and detected by a single quadrupole mass spectrometer in selected ion monitoring (SIM) negative mode. Monitored m/z values for nimesulide and IS were 307.00 and 295.90, respectively. The overall run time was 4.2 min. Validation experiments demonstrated good precision and accuracy over a wide concentration range of 20.0-7000 ng/mL with a lower limit of quantification (LLOQ) at 20.0 ng/mL. No interference by endogenous substances or matrix effect was observed. Average extraction recoveries for nimesulide and IS were all greater than 84.4%. The assay was successfully applied to a bioequivalence study of nimesulide dispersible tablets in Chinese male volunteers after oral administration.

Assignment of the absolute stereochemistry of an unusual diterpenoid from the mangrove plant Excoecaria agallocha L.

Zhen Liu, Wei Jiang, Zhi-Wei Deng, Wen-Han Lin^*

2010, 19(5): 387-392.

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An unusual diterpenoid excoagallochaol A (1), together with epi-β-amyrin (2), epitaraxerol (3), epi-α-amyrin (4), epilupeol (5), betulin (6), betulinic acid (7), lupenone (8), betulone (9), betulonic acid (10), (9Z,12Z,15Z)-2,3-dihydroxypropyl octadecatrienoate (11), and (9Z,12Z)-2,3-dihydroxypropyl octadecadienoate (12)were isolated from the stems of Excoecaria agallocha L. Their structures were elucidated by spectroscopic analyses, and the absolute stereochemistry of 1 was assigned using Mosher method. Compounds 4, 8, 10-12 were isolated from the genus Excoecaria for the first time.

Fast and simultaneous determination of ginsenosides by isocratic high-performance liquid chromatography

Da-Wei Lou^*

2010, 19(5): 393-399.

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A high-performance liquid chromatography method for the simultaneous determination of seven bioactive ginsenosides with diol stationary phase and isocratic elution was used to determin the ginsenosides in ginseng products. The optimization of the chromatographic separation was performed and the effect of temperature on separation was investigated. Using the validated procedure, the developed method was demonstrated to be more sensitive and effective than the conventional reversed-phase chromatography, where the chromatographic run is time-consuming to analyze a large number of ginsenosides. The results indicated that the developed method can be used for the quantitative determination of ginsenosides in complex ginseng samples.

A practical and efficient procedure for the α-bromination of arylethanones

Rui-Juan Xing, Li Pan, Xi Wen, Jian Wang, Mao-Sheng Cheng^*

2010, 19(5): 400-402.

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A series of α-bromoarylethanones were prepared in high yields by a practical and efficient method. The arylethanones were reacted with bromine to give a mixture of α- and α, α-dibromides, which were debrominated with diethylphosphite in the presence of triethylamine to give the desired α-monobromo products.

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Journal of Chinese Pharmaceutical Sciences

2010, 19(5): 403-403.

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