Journal of Chinese Pharmaceutical Sciences

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2012, 21(6): 495-498.

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Modification of oligonucleotides by isonucleosides incorporation and peptides conjugation

Ye Huang, Xiaofeng Wang, Zhenjun Yang^*, Lihe Zhang

2012, 21(6): 499-508. DOI: 10.5246/jcps.2012.06.065

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Synthetic oligonucleotides including antisense oligonucleotides and siRNA have shown promising therapeutic potential. However, to realize the therapeutic potential of synthetic oligonucleotides, many obstacles have to be overcome, such as their poor biological stability, non-specific activity and inadequate cell membrane permeability. In this paper, the achievements by Lihe Zhang's group in the study of isonucleotide modified oligonucleotides and oligonucleotides conjugated with cell penetrating peptides are summarized.

A perspective on picornavirus inhibitors and concrete evolution of WIN compounds

Long Ren, Ning Jiao^*

2012, 21(6): 509-525. DOI: 10.5246/jcps.2012.06.066

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The family Picornaviridae is one of the largest families of human viral pathogens, causing an extensive range of clinical manifestations from mild fever, common cold to serious paralytic poliomyelitis, COPD, etc., some of which can even be life-threatening. Picornaviruses also cause zoonotic epidemics that result in dramatic social and economical losses. Although no efficient antivirus agent for prophylaxis or treatment of picornarivus infections has been officially approved yet, a large number of anti-picornavirus compounds with potent activity have been developed and investigated, through which further information about picornavirus has been revealed as well. Viral mRNA translation, viral mRNA replication and especially the viral capsid are the three main targets of these compounds having been extensively studied. The typical one is the WIN series of compounds that bind to the viral capsid and inhibit rival attachment or uncoating. Herein, a perspective on picornavirus inhibitors and a concrete evolution of WIN compounds will be presented in this paper.

SecA inhibitors: next generation antimicrobials

Weixuan Chen, Arpana Chaudhary, Jianmei Cui, Jinshan Jin, Yinghsin Hsieh, Hsiuchin Yang, Yingju Huang, Phang C. Tai^*, Binghe Wang^*

2012, 21(6): 526-530. DOI: 10.5246/jcps.2012.06.067

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Health problems caused by bacterial infection have become a major public health concern in recent years due to the widespread emergence of drug-resistant bacterial strains. Therefore, the need for the development of new types of antimicrobial agents, especially those with a novel mechanism of action, is urgent. SecA, one of the key components of the secretion (Sec) pathway, is a new promising target for antimicrobial agent design. In recent years, promising leads targeting SecA have been identified and the feasibility of developing antimicrobial agents through the inhibition of SecA has been demonstrated. We hope this review will help stimulate more research in this area so that new antimicrobials can be obtained by targeting SecA.

Allosteric kinase inhibitors: a new paradigm for effective and selective modulation of kinase activities

Hongliang Yang, Ting Chen, Xu Bai, Yazhong Pei^*

2012, 21(6): 531-543. DOI: 10.5246/jcps.2012.06.068

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Dysregulation of kinases has been proven to be one of the main causes of abnormal growth and survival of cancer cells. Selective modulations of kinase activities have become the focus of many research programs for the development of safe and effective chemotherapy for cancers. So far, fifteen kinase inhibitors have received FDA approval for the treatment of various forms of cancers. Among them, the allosteric kinase inhibitors have been shown to have superior clinical profile in terms of safety and efficacy. In this review, we summarize the allosteric conformations of kinases, their corresponding inhibitors and the modes of their interactions.

Drug design based on the function of membrane transporters in drug absorption, distribution, metabolism and excretion

Dongli Sun, Huidi Jiang^*, Su Zeng^*

2012, 21(6): 544-552. DOI: 10.5246/jcps.2012.06.069

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Membrane transporters mediate the influx and efflux of various drugs, and play essential roles in drug absorption, distribution, metabolism and excretion (ADME). The unique characteristics of membranes transporters potentiate them as targets for developing drugs with ideal pharmacokinetics profiles, including targeted distribution, improved clinical efficacy and low adverse reaction. In this review, we summarize the tissue-specific expression, transport functions and substrates profiles of the major influx and efflux transporters, including solute carrier (SLC) superfamily and adenosine triphosphate (ATP)-binding cassette (ABC) superfamily. Moreover, we describe examples of successful drug or prodrug design based on the function of transporters that yielded drugs with excellent ADME properties. Lastly, we discuss the in vitro and in vivo methods that are broadly applied in the drug designing process to study the interactions between the drugs and the transporters.

Discovery of benzamide derivatives as potent Kv1.5 inhibitors

Xiaoke Guo, Zheng Shen, Peng Yu, Hongxi Chu, Yiqun Tang, Qidong You*

2012, 21(6): 553-560. DOI: 10.5246/jcps.2012.06.070

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Kv1.5 potassium channel is reported as a potent and safe target for atrial fibrillation. CPUY11018 was proved it had moderate inhibition of Kv1.5. In order to improve the stability of CPUY11018, and investigate the structure-activity relationship, 4 series of benzamide derivatives were synthesized and evaluated. Among them, 8c is a most potent inhibitor of Kv1.5.

Synthesis of α-substituted β-amino acids via the Ni(II) complex through the Suzuki coupling reaction

Li Lv, Jiang Wang, Xiao Ding1, Daizong Lin1, Linxiang Zhao2, Hualiang Jiang, Hong Liu^*

2012, 21(6): 561-568. DOI: 10.5246/jcps.2012.06.071

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A convenient and efficient method for the preparation of α-substituted β-amino acids has been developed by reacting compound 2 with various boric acid/borate 3 through Suzuki coupling reaction, which gave multiple structure types of substituted Ni(II) complexes 4 in high yields. Hydrogenation and hydrolysis of complexes 4 led to the corresponding α-substituted β-amino acids.

Characterization of chemical constituents and in vivo metabolites of Kai-Xin-San prescription by HPLC/DAD/ESI-MSn

Chunfang Liu, Wenzhi Yang, Kedi Liu, Xue Qiao, Yang Liu, Yanyan Jiang, Renbing Shi*, Tao Bo, Xiuwei Yang, Min Ye^*

2012, 21(6): 569-576. DOI: 10.5246/jcps.2012.06.072

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This work aims to elucidate the chemical constituents of Kai-Xin-San (KXS) and its metabolites in rat plasma. KXS extracts were separated on an Agilent HPLC SB-C₁₈ column, analyzed by ion-trap tandem mass spectrometry and high-accuracy qTOF mass spectrometry in negative ion mode. A total of 39 compounds, including 11 ginsenosides, 14 Polygala saponins, 5 sucrose esters, 8 oligosaccharide esters and 1 xanthone were characterized from KXS. Fifteen of them were confirmed by reference standards. No constituents were detected from Poria or Acori Tatarinowii Rhizoma. After oral administration of KXS (7 g/kg), 10 ginsenosides and 18 Polygala compounds were detected in rat plasma. This study indicates that ginseng saponins, Polygala saponins and saccharide esters could be the major effective components of KXS prescription.

Anti-complement constituents of Commelina communis and their targets in complement activation cascade

Jiahong Jin, Zhihong Cheng, Daofeng Chen^*

2012, 21(6): 577-581. DOI: 10.5246/jcps.2012.06.073

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Anti-complement activity guided fractionation led to the isolation of 24 compounds from Commelina communis. Bioassay showed that six compounds inhibited the classical pathway and alternative pathway with CH₅₀values of 0.12-1.44 mM and AP₅₀ values of 0.28-7.05 mM, respectively. Preliminary mechanism studies demonstrated that quinovic acid acted on C1q, C2, C3, C4, C5 and C9 components of the complement system, β-sitosterol interacted with C3 and C4, (+)-catechin-3-O-β-D-gluco(2-cinnamoyl)-pyranoside, p-cresol and 6-methoxy-3-methylbenzene-1,2,4-triol blocked C1q, C2, C3, C5 and C9.

Extracts of Zanthoxylum bungeanum regulate cholesterol accumulation induced by sterols and LPS in vitro and in vivo

Tingting Wu, Aijun Hou, Zhenyi Hong, Yizhun Zhu^*

2012, 21(6): 582-590. DOI: 10.5246/jcps.2012.06.074

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In this investigation, the effects of PE, EtOAc, and BuOH fractions from Zanthoxylum bungeanum on cholesterol accumulation induced by sterols and LPS were determined in vitro and in vivo. HepG2 cells induced by 25-hydroxychoelsterol and cholesterol were employed as cell model. After treatment with PE, EtOAC, or BuOH fractions, cellular total cholesterol and apolipoprotein B secretion were significantly reduced. In addition, compared with control group, expressions of SREBP2, HMGCR, and ACAT decreased, while CYP27A1, ABCA1, and LDLR levels increased. Cholesterol accumulation was also induced in C57BL/6 mice by LPS and the mice were used as the animal model. Determination of serum TNF-α level and hepatic mRNA expression of TNF-α, IL-6, iNOS, COX-2 revealed that EtOAc and BuOH fractions had anti-inflammatory effects. Furthermore, hepatic total cholesterol was reduced, accompanied by the elevation of LXR-α and ABCA1 gene expression in BuOH fraction treated mice. Since EtOAc and BuOH fractions were found active, bioassay-guided isolation was performed and β-sitosterol, eudesmin, sesamin and syringaresinol-β-D-glucoside were isolated from the fractions.

PEG-PCL nanomicelles for cancer theranosis: targeted imaging and drug delivery

Hua Zheng, Wenjie Hou, Jiancheng Wang^*, Qiang Zhang

2012, 21(6): 591-597. DOI: 10.5246/jcps.2012.06.075

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Nanomicelles, self-assembling nanosized particles with a hydrophobic core and hydrophilic shell, are currently successfully used as carriers for targeted drug delivery systems via the enhanced permeability and retention (EPR) effect at the tumor sites. In this study, a near-infrared fluorescent cyanine dye (Cy7-NHS) was conjugated to poly (ethylene glycol)-block-poly (ε-caprolactone) (NH₂-PEG-b-PCL), and the resulting Cy7-PEG-PCL was further mixed with mPEG-b-PCL to form nanomicelles as carriers for paclitaxel (PTX) delivery. Our results showed that the selected mPEG₄₀₀₀-b-PCL₂₅₀₀copolymers self-assembled to form stable micelles with an average size of 30 nm in diameter and a zeta potential of approximately –3 mV. The micelles also exhibited more than 95% encapsulation efficiency of PTX when the molar ratio between paclitaxel and copolymers was 1/4. In vitro cytotoxicity study showed that the PTX-loaded nanomicelles had a similar cell growth inhibition efficacy to that of Taxol^® against human breast cancer MCF-7 cells. In vivo imaging showed that the Cy7-labeled nanomicelles could be passively targeted to tumor sites effectively after intravenous injection via the tail vein. Also, a strong anti-tumor activity was observed in the nude mice xenografted MCF-7 breast tumor after treatment with PTX-loaded micelles, similar to that of Taxol^®. As a result, the micelle drug delivery system designed in this paper has great potential in targeted imaging of tumors and chemotherapy.

Contents of Volume 21

Keywords Index of Volume 21

Author Index of Volume 21

Journal of Chinese Pharmaceutical Sciences

2012, 21(6): 598-609.

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Table of Content