Table of Content

15 September 2012, Volume 21 Issue 5

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Contents

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Journal of Chinese Pharmaceutical Sciences

2012, 21(5):  365-368. 

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Reviews

Discovery and early evaluation of new chemical entities

Jing Deng, Fei Zhao, Jian Li, Hong Liu, Hualiang Jiang^*

2012, 21(5):  369-387.  DOI: 10.5246/jcps.2012.05.051

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Drug discovery is a costly and time-consuming process, with very few novel molecular entities approved for clinical use today. With the advancement of computational chemistry, integrated X-ray crystallography and nuclear magnetic resonance spectroscopy technology, more and more potential therapeutic agents for the treatment of human diseases are discovered. Furthermore, multiple medicinal chemistry approaches have been developed in support of early drug discovery. However, there is still much can be done in the early phase of drug discovery to improve the chances of success of a drug candidate. This paper reviews the discovery and evaluation of new chemical entities in the early stages of drug development.

Hypericin in hypericum: chemistry, botanical sources and biological activities

Linfang Huang, Shilin Chen^*

2012, 21(5):  388-400.  DOI: 10.5246/jcps.2012.05.052

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Hypericin, a secondary metabolite first reported in 1830, is a natural photosensitizing naphtodianthrone and is mainly from the natural plant sources of genus Hypericum. Hypericin exhibits a wide variety of biological and pharmacological activities, such as antiviral, antidepressant, antitumor, antimicrobial, and antioxidant activity. Hypericin can also be utilized in photodynamic diagnosis. Accumulating evidence is pointing to the effects of hypericin with potential pharmaceutical and clinical interests in the past decades. The present review gives a comprehensive outline of the chemistry, botanical occurrence and biological activities of this powerful compound.

Original articles

Novel inhibitors for p90 ribosomal S6 protein kinase 2: design, synthesis and SAR

Mengzhu Xue, Jun Yuan, Bin Wu, Xue Zhao, Xiaofeng Liu, Jin Huang, Zhenjiang Zhao^*, Honglin Li^*, Yufang Xu

2012, 21(5):  401-408.  DOI: 10.5246/jcps.2012.05.053

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A series of benzohydrazide derivatives as novel ribosomal S6 kinase 2 (RSK2) inhibitors were designed and synthesized from a hit compound previously discovered by ligand-based virtual screening. Biological assays showed that these compounds possessed moderate inhibitory activities towards RSK2. The structural activity relationships (SAR) were elucidated by molecular docking and further optimization was performed.

Oxidative coupling of α–bromoarylacetonitriles and oxidative decyanation of diarylacetonitriles catalyzed by solid-liquid phase transfer

Xin Zhang^¶, Xueling Hou^¶, Fangbin Han, Zemei Ge^*, Tieming Cheng, Runtao Li^*

2012, 21(5):  409-415.  DOI: 10.5246/jcps.2012.05.054

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Oxidative coupling of α-bromoarylacetonitriles and oxidative decyanation of diarylacetonitriles are efficiently realized by solid-liquid phase transfer catalysis using anhydrous K₃PO₄ as base and TBAB as catalyst in acetone at room temperature. In this mild and convenient method, α,β-dicyanostilbenes and diarylketones were prepared in good to excellent yields.

Synthesis and evaluation of tetrahydro β-carboline derivatives as anticancer agents

Hongrui Liu^¶, Guangzhi Bao^¶, Suna Yang, Lixin Wu, Xianfeng Gu^*, Yizhun Zhu^*

2012, 21(5):  416-420.  DOI: 10.5246/jcps.2012.05.055

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A series of β-carboline derivatives (1-6) have been synthesized and evaluated for their anticancer activities. We observed that compound 5 exhibited significant anticancer activities over both human gastric cancer and human hepatic cancer cell lines, and compound 6, which is slightly different from 5 in its structure, showed good anticancer activity over human colorectal cancer cell line.

Anomalusins A and B, two new ent-rosane diterpenoids from Mallotus anomalus

Gang Ni, Shengping Yang, Jianmin Yue^*

2012, 21(5):  421-427.  DOI: 10.5246/jcps.2012.05.056

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Two new ent-rosane type diterpenoids, anomalusins A (1) and B (2), together with ten known compounds were isolated from the plants of Mallotus anomalus Meer et Chun. The structures of compounds 1 and 2 were fully elucidated on the basis of spectroscopic evidence, and CD analysis.

Chemical constituents of Pseudolarix kaempferi Gord

Tianzhi Cai, Wen Qi, Lianmei Yang, Guangzhong Tu, Rong Yang, Kehui Xie, Hongzheng Fu^*

2012, 21(5):  428-435.  DOI: 10.5246/jcps.2012.05.057

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Phytochemical investigations of Pseudolarix kaempferi Gord led to the isolation of 26 known compounds. They were identified as follows: pseudolaric acid D (1), pseudolaric acid A (2), pseudolaric acid B (3), pseudolaric acid C (4), oleana-∆^11,13(18)-dien-3β-O-acetyl (5), oleana-∆^9(11),12-dien-3β-O-acetyl (6), oleana-∆^11,13(18)-dien-3β-hydroxyl (7), oleana-∆^9(11),12-dien-3β-hydroxyl (8), celangulatin C (9), celangulatin E (10), 17β-tenacigenin B (11), 11α-O-2-methyl butyryl-12β-O-acetyl tenacigenin B (12), 11α-O-2-methyl butyryl-12β-O-tigloyl tenacigenin B (13), β-sitosterol acetate (14), umbelliferone (15), 5,7-dihydroxyl coumarin (16), xanthotoxin (17), isopimpinellin (18), formononetin (19), calycosin (20), cnidimol B (21), thymine (22), 3-furoic acid (23), 2-furoic acid (24), vanillic acid (25), protocatechuic acid (26). Compounds 5–24 were isolated from P. kaempferi for the first time. And the ¹H and ¹³C NMR spectra of compound 1 were completely assigned for the first time.

Comprehensive study of rutaecarpine on vascular constriction relative to RhoA/MLCP-MLC signaling

Xiukun Wang, Yugang Wang, Yushuang Chai, Jun Hu, Honglei Zhan, Dongming Xing, Xuefu You, Zhimin Wang, Xiuwei Yang, Fan Lei, Lijun Du^*

2012, 21(5):  436-447.  DOI: 10.5246/jcps.2012.05.058

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The aims of the present study are to investigate the effect of vasoconstriction and to explore the mechanism of rutaecarpine. The research findings showed that rutaecarpine could induce contractions of the rat thoracic aorta in vitro. The inhibitors of Rho-kinase and inositol 1,4,5-triphosphate receptor (IP₃R) could suppress the effect of rutaecarpine-induced vasoconstriction. In the study of A7r5 cells (a line of smooth muscle cells), 300 μg/L rutaecarpine promoted the concentration of intracellular Ca²⁺ and enhanced the IP₃R expression, which connects with 1,4,5-triphosphate to evoke the release of Ca²⁺ from the intracellular stores. Rutaecarpine increased the RhoA mRNA expression when the cells were pretreated with inhibitor H-1152, and improved the levels of phosphorylation of myosin light chain phosphatase (MLCP) and myosin light chain (MLC). These results suggest that rutaecarpine plays a role in vasoconstriction relative to the RhoA/MLCP-MLC signaling pathway, which denotes a new field of rutaecarpine in pharmacology.

Cell cycle arrest effect of compound YSY-01A, a new proteasome inhibitor, on HT-29 cells in vitro

Kan Tong, Jingtao Liu, Xia Yuan, Bo Xu, Wei Guo, Liqiang Han, Shuyang Yao, Zemei Ge, Runtao Li^*, Jingrong Cui^*

2012, 21(5):  448-458.  DOI: 10.5246/jcps.2012.05.059

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Compound YSY-01A, a recently synthesized proteasome inhibitor, has shown potent growth-inhibitory effect on tumor cells in previous researches. However, the mechanism of its inhibitory effects, especially on cell cycle, remains largely unclear. This study aims to evaluate the correlation between cell cycle arrest effect of YSY-01A and its anti-cancer effect, and to probe the possible molecular mechanisms for its effects on human colorectal adenocarcinoma cells HT-29. The results suggested that YSY-01A significantly (P<0.05) inhibited cellular proliferation of HT-29 cells in a time and concentration-dependent manner. Furthermore, YSY-01A suppressed the G₂/M transition of HT-29 cells, whereas the mitotic inhibitor paclitaxel induced M phase accumulation. Further investigation revealed that YSY-01A significantly (P<0.05) up-regulated the expression levels of a series of cell cycle related protein, such as cyclin B1, Wee1, p-cdc2 (Tyr15), p53, p21, and p27. The HT-29 cells only exhibited typical cytotoxic symptom when YSY-01A concentration reached 0.5 μM (P<0.05), which was above the dose we used in the mechanism research. In conclusion, YSY-01A showed remarkable anti-cancer activity on HT-29 cells, and its molecular mechanisms are related to G₂/M cell cycle transition arrest.

Construction of a universal quantitative model for the determination of azithromycin in granules using near-infrared diffuse reflectance spectroscopy

Wenbo Zou, Yanchun Feng, Danqing Song, Changqin Hu^*

2012, 21(5):  459-467.  DOI: 10.5246/jcps.2012.05.060

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A universal quantitative model was developed to determine the azithromycin content in granules using near infrared (NIR) diffuse reflectance spectroscopy. The diffuse reflection spectra were recorded with the integrating sphere at 8 cm^-1 resolution in 4000-12 000 cm^-1 spectral range. During each measurement, 32 co-added scans were performed. This quantitative model was constructed with 103 batches of azithromycin granules from 21 different manufacturers. The azithromycin content ranges from 3.0% to 24.5%. The root mean square error of prediction (RMSEP) of model was 0.613. In addition, the quantitative model was evaluated in terms of specificity, linearity, accuracy, and precision according to ICH guidelines. In conclusion, it is feasible to construct a universal quantitative model for azithromycin granules by choosing suitable training set samples and selecting an appropriate wavelength range. The quantitative model could be applied in the quick assay of azithromycin granules produced by domestic manufacturers (content: 3.0%-24.5%).

Short communications

Direct chiral separation of azelnidipine by HPLC with Pirkle-type column

Xiaoxia Ye, Xu Xu^*

2012, 21(5):  468-471. 

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Direct chiral separation of azelnidipine enantiomers with Pirkle-type Sumichiral OA-2500 column was studied by normal phase and reserve phase conditions. By normal phase, azelnidipine enantiomers were well separated with Rs as 4.0 using hexane-ethanol (90:10, v/v) as mobile phase, and Rs as 2.7 in shorter time (no more than 13 min) using hexane-ethanol (60:40, v/v) as the recommended mobile phase. They were only partially separated by reverse phase using methanol or methanol containing 0.05 mol/L ammonium acetate. Using same chiral column, the chiral separation of other dihydropyridine calcium antagonist analogues almodipine and nimodipine were also studied and showed partial chiral separation in normal phase.

A new synthesis route of cabazitaxel

Guoning Zhang, Weishuo Fang^*

2012, 21(5):  472-476.  DOI: :10.5246/jcps.2012.05.062

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A new route for the synthesis of cabazitaxel (Javanta^®) starting with 10-deacetylbaccatin III was developed. In this new procedure, a mild condition for the methylation of 7-OH was applied, thus the epimerization of 7β-OH under basic conditions was reduced. The total yield of this 6-step synthesis is 20%.

Acute toxicity and genotoxicity evaluation of hyperoside extracted from Abelmoschus manihot (L.) Medic

Guo Ai, Zhengming Huang^*, Dewen Wang, Haiting Zhang

2012, 21(5):  477-482.  DOI: 10.5246/jcps.2012.05.063

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To further assess hyperoside as a potential new anti-hepatitis B virus (HBV) drug, the safety of hyperoside extracted from Abelmoschus manihot (L.) Medic was evaluated by testing its acute toxicity and mutagenic risk. To test the acute toxicity of hyperoside, we determined the median lethal dose (LD₅₀) in mice. Forty healthy BALB/c mice (20 per sex) were administered a single oral dose of 5000 mg/kg hyperoside via the intragastrical route. The number of animals poisoned and died was noted daily for 14 consecutive days. All animals survived and appeared active and normal, indicating that the LD₅₀ of hyperoside was more than 5000 mg/kg. Potential genotoxicity of hyperoside was investigated using a bacterial reverse mutation assay (Ames test), a chromosome aberration test in Chinese hamster lung (CHL) fibroblasts, and an in vivo micronucleus test in rat bone marrow cells. In the bacterial reverse mutation assay, we observed no increases in the number of revertant colonies at any concentrations of hyperoside regardless of metabolic activation (S9) in all tester strains (TA97, TA98, TA100 and TA102) compared to the vehicle control (P>0.05). Hyperoside did not cause significant structural aberration in CHL cells in the presence or absence of S9 (P>0.05). The micronuclei rates of mice bone marrow cell in all groups showed no significant difference when compared with the negative control (P>0.05). In summary, hyperoside showed no genotoxicity in our experimental conditions.

Special subject

Establishment of an internationally recognized platform for the communication of pharmaceutical researches supported by the National New Drug Innovation Programs

Heqing Huang^*, Jian Han, Jingjing Zhang

2012, 21(5):  483-490.  DOI: 10.5246/jcps.2012.05.064

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The initiation of the National New Drug Innovation Key Technology Program marked a strategic shift of new drug discovery in China, which will greatly enhance the new drug discovery research activities. It presents a valuable opportunity for the growth and quality advancement of pharmaceutical science journals. As the only comprehensive English journal of the Chinese Pharmaceutical Association, In the new situation, Journal of Chinese Pharmaceutical Sciences (JCPS) plays a critical role in the communication of new discoveries in pharmaceutical researches to the scientific community. To fulfill the roles as an internationally recognized platform for the communication of the new drug discoveries supported by the National New Drug Innovation Programs, the JCPS editorial office will take advantage of its English language specialty, emphasize quality and digital access, and promote the advancement of the journal.

The 8th International Symposium for Chinese Medicinal Chemists and the 9th IUPAC international Symposium on Biomolecular Chemistry were held in Beijing

Yingbo Li

2012, 21(5):  491-491. 

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The 8^th International Symposium for Chinese Medicinal Chemists (ISCMC2012) and the 9^th IUPAC international Symposium on Biomolecular Chemistry (ISBOC-9) were held at Beijing Conference Center, on August 25-29, 2012, Beijing, China.

The symposiums were hosted by the Division of Medicinal Chemistry, Chinese Pharmaceutical Society and IUPAC Biomolecular Chemistry Division, organized by the State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University. In the symposiums, two Nobel Prize winners, Prof. Ada Yonath from Weizmann Institute of Science (Israel) and Prof. Robert Huber from Max Planck Institute of Biochemistry (Germany), were invited to give Nobel Laureate Lectures. There were more than 140 distinguished scholars across the world delivered keynote lecture and oral presentation, and nearly 150 posters spread over plenary lectures and 5 parallel sessions. Over 700 representatives from 21 countries and regions attended the event. Journal of Chinese Pharmaceutical Sciences also attended the poster exhibition.

The main subjects for this year’s symposiums were: modern drug design and development of methodology, novel strategy and approach for drug discovery, lead discovery and optimization, optimizing the drug-like properties of leads, natural products based drug discovery, biological science driven drug discovery, synthetic methods and the process studies and new developments in the treatment for cancer and infectious disease. The ISCMC2012 and ISBOC-9 achieved the goal of providing a platform for communicating the forefront progress of drug discovery and development, and further improved the research on medicinal chemistry in China and expand Chinese scholars’ influences on the world stage.

Call for Papers: A Special Issue of Medicinal Chemistry and Biomolecular Chemistry

Committee of ISBOC-9 & ISCMC-8; Editorial Office of Journal of Chinese Pharmaceutical Sciences

2012, 21(5):  492-492. 

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After 9^th IUPAC International Symposium on Biomolecular Chemistry & 8^th International Symposium for Chinese Medicinal Chemists (ISCMC-8) finished successfully, a special issue of the Journal of Chinese Pharmaceutical Sciences (JCPS) is being planned for publication in the year 2013 by the International Advisory Committee and the JCPS editorial office. We hope that it will promote international academic exchange and establish a platform for communication among medicinal chemists and biomolecular chemists. All manuscripts submitted must meet the publication standards of JCPS and will be peer-reviewed through the “Rapid Track”. The journal editorial office will select the qualified manuscripts to appear on the special issue, with the remaining manuscripts being considered for publication on a regular issue of the journal. The deadline for submission of manuscripts is February 15, 2013.

Scope of the special issue

The special issue will cover all areas of modern drug design and its development of methodology, the novel strategy and approach for drug discovery, lead discovery and optimization, synthetic method and the process studies, structure, function and interaction of biomolecular, biological sciences driven drug discovery, chemical questions in the life process, and chemical genomics.

Guide for authors

Please send your submission as word document by email to jcps@bjmu.edu.cn. Be sure to include authors' name, affiliation, post address, E-mail address, and telephone number. Please also mark your mail with "Special Issue of Medicinal Chemistry and Biomolecular Chemistry". The detailed guide for manuscript preparation and free manuscript samples are available at http://www.jcps.ac.cn.

A manuscript submitted to JCPS must be based on original research by the authors and must not have been published elsewhere. No manuscript reporting the same results may be under simultaneous consideration by another journal.

Manuscript charge

After the paper is accepted, page charges and copyright transfer agreement should be returned to the editorial office within 2 d. Authors will be presented with two copies of the current issue and a PDF file at no cost. The fee for copyright and payment for the article will be paid at one time.

Tel./Fax: 010-82801713, 82805496 E-mail: jcps@bjmu.edu.cn

Address: Editorial Office of Journal of Chinese Pharmaceutical Sciences, School of Pharmaceutical Sciences, Peking University, 38 Xueyuan Road, Beijing 100191, China