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Table of Content

    30 September 2017, Volume 26 Issue 9
    Review
    PI3K signaling pathway targeting by using different molecular approaches to treat cancer
    Mohammad Rashid, Shahid Karim, Babar Ali, Shamshir Khan, Makhmur Ahmad, Asif Husain, Ravinesh Mishra
    2017, 26(9):  621-634.  DOI: 10.5246/jcps.2017.09.070
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    Recent evidence of research has been proposed that the phosphoinositide 3-kinase (PI3K) pathway is noticeable target for searching novel anticancer agents. The phosphoinositide 3-kinase (PI3K) is accountable for harmonizing a diverse range of cell functions, such as transcription, proliferation, cell survival, cell growth, degranulation, vesicular trafficking and cell migration, which are mostly involved in carcinogenesis. Particularly, PI3K-mediated signaling molecules and its effects on gene expression contribute to tumorigenesis. PI3Ks generally are grouped into three distinct classes: I, II and III according to their structure and function. The class IA of PI3K includes an alpha, beta or delta p110 catalytic subunit (p110α, p110β, or p110γ), which are associatedwith the activation of RTKs. Mutations in PIK3CA, the gene encoding the p110α catalytic subunit of PI3K, have just been recognizedas novel mechanisms of inducing oncogenic PI3K signaling. Therefore, the class IA PI3K is the only one of most evidently implicated in cancer. The PI3K pathway is mostly mutated in more cancer patients compared with normal person, making it an eye-catching molecular target for analyses based on inhibitor molecule. In this article, we highlighted the signaling effects and regulation pathway of PI3K involved in the development and survival of tumor cells. The consequence and intricacy of PI3K pathway made it an essential beneficial target for cancer treatment.

    Original articles
    Cheminformatics analysis of natural products and indication distribution prediction
    Xin Zhou, Yibo Li, Chuanyu Lv, Zhenming Liu, Liangren Zhang
    2017, 26(9):  635-641.  DOI: 10.5246/jcps.2017.09.071
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    As a valuable resource for drug discovery, natural products remain largely unexplored. The cheminformatics analysis of natural product databases could help us know better about natural products, providing valuable information in drug design. In this study, we collected an in-home natural product library consisting of more than 220 000 molecules. The results showed that natural products were distributed more diversely than synthetic compounds and approved drugs in chemical space, and natural products still possessed better scaffold diversity. Besides, natural product scaffolds had more potential in some specific indications, such as antiarthritic, antihypertensive, antiallergic and analgesic. However, the utilization rate of natural product scaffolds is relatively low, especially in terms of potential indications. Therefore, we recommend the greater use of natural products while designing lead libraries.

    The glycosylation-oriented engineering of human vasopressin
    Hongxing Li, Ning Yuan, Suwei Dong
    2017, 26(9):  642-649.  DOI: 10.5246/jcps.2017.09.072
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    A glycosylamino acid “cassette”-based synthetic route has been developed for the preparation of vasopressin analogues with glycosylation. This efficient protocol may be utilized in the synthesis of other novel cyclic glycopeptide structures and derivatives.

    Design and synthesis of 2-aminobenzimidazoles as potential BACE1 inhibitors
    Jiapei Yu, Yan Niu, Qi Sun, Fengrong Xu, Lei Liang, Chao Wang, Ping Xu
    2017, 26(9):  650-659.  DOI: 10.5246/jcps.2017.09.073
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    Fragment-based drug discovery (FBDD) has been widely applied in the research of aspartyl protease inhibitors. In the present study, we reported our work on 2-aminobenzimidazole as the original fragment, which was predicted to bind with the catalytic aspartyl dyad (Asp228 and Asp32) of β-site amyloid precursor protein cleaving enzyme 1 (BACE1). A series of novel 2-aminobenzimidazole derivatives were designed and synthesized. The results from FRET assay revealed that three out of the 12 designed 2-aminobenzimidazoles could inhibit more than 50% of the enzymatic potency of BACE1 at 10 μM. Docking study showed that 2-aminobenzimidazole could form multiple hydrogen bonds and occupy S1/S2’ pockets well.

    Synthesis and cytotoxicity of kaempferol derivatives
    Yajing Ma, Huan Liu, Shunan Tang, Siwang Yu, Mingying Shang, Shaoqing Cai
    2017, 26(9):  660-665.  DOI: 10.5246/jcps.2017.09.074
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    In the present study, we developed a simple approach for the structural modifications of kaempferol (1). A new compound, 3,5-dihydroxy-2-(4-hydroxyphenyl)-6,8,8-tris(3-methylbut-2-en-1-yl)-4H-chromene-4,7(8H)-dione (5) together with three known compounds, 8-prenylkaempferol (2), 6-prenylkaempferol (3) and 6,8-diprenylkaempferol (4), were synthesized under different reaction conditions. All of derivatives were synthesized in a structural modification way for the first time. Their structures were primarily elucidated by NMR and MS analyses. Compounds 2, 3 and 5 exhibited prominent cytotoxic activity against MDA-231 (IC50 values were 9.45±0.20μM, 7.15±0.37 μM and 6.92±0.30 μM, respectively) and MCF-7 (IC50 values were 10.08±0.57μM, 10.04±0.23 μM and 2.15±0.20 μM,respectively) breast cancer cells.

    Preparation, characterization and evaluation of liposomal doxorubicin and harmine that show synergistic activity in vitro
    Jiongxi Lei, Shuangchen Cong, Maoyuan Song, Wenxi Zhang, Guanghua Peng, Yuanyuan Zhang, Mengya Yin, Jiaxing Wang, Jiajia Li, Xinru Li
    2017, 26(9):  666-674.  DOI: 10.5246/jcps.2017.09.075
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    A combinatory therapeutic system that simultaneously targets several independent pathways is preferred for the treatment of cancer. In our study, a combinatory liposomal delivery system containing doxorubicin (Dox) and harmine (HM) was constructed by thin film dispersing method together with pH gradient method. A simple, precise and accurate spectrophotometric method for the determination of Dox and HM in liposomal formulation was established and validated. A drug HSPC ratio of 1: 20, loading time of 30 min and loading temperature of 50 °C were the optimal conditions for the preparation of drug loaded liposomes, which exhibited excellent physicochemical properties such as average particle size of ~100 nm, low polydispersity index below 0.2 and high entrapment efficiency above 93%. Sustained release of drug from liposomes at pH 7.4 showed good biological safety. The synergetic cytotoxic effect for these two drugs was evaluated in MCF-7 cells. The in vitro antitumor studies demonstrated the superior anti-proliferation activity of the liposomal Dox and HM with a combination index of 0.81, which indicated great synergistic effect and increased anti-proliferation efficiency. The experimental data suggested that combinational liposome therapy could be an effective way to develop efficient treatment of cancers.

    Development of a cell-based HTS adaptable calcium fluorescent assay in FlexStation3 for the screening of TRPV3 inhibitors
    Xiaomei Sun, Ningning Wei, Xiaoying Sun, Kewei Wang
    2017, 26(9):  675-683.  DOI: 10.5246/jcps.2017.09.076
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    To develop a cell-based high-throughput calcium fluorescent assay for screening of TRPV3 channel modulators, we employed the FlexStation3 microplate reader and optimized conditions of the high-throughput screening (HTS) adaptable calcium fluorescent assay, such as cell density, incubation time and concentration of Cal-520 calcium fluorescent dye. The optimized FlexStation3 assay included the cell density of 40 000 cells per well, 5.0% of Cal-520 calcium fluorescent dye and 1.5 h of incubation time. Using the FlexStation3 assay in a 96-well format, we screened and identified a natural neferine from Nymphaeaceae plant that inhibited TRPV3 channel. To further confirm the inhibitory effect of neferine on TRPV3, we utilized the whole-cell patch clamp recordings and determined the dose-dependent inhibition of TRPV3 current by neferine with an IC50 at 24.5±4.1 μM (n = 6) without inhibition of TRPV1 or TRPV4 channels. Taken together, our data showed that this validated HTS adaptable calcium fluorescent assay in FlexStation3 format could be used for screening and identification of modulators for either TRPV3 channel or other calcium permeable TRP channels. The identified natural neferine could be used as a tool for pharmacological investigations of TRPV3 channel function. 

    Neuroprotective effect of dioscin on cerebral ischemia/reperfusion mice by reducing glial cell activation and maintaining the levels of SODs
    Cheng Yin, Jie Wang, Pei Xu, Bingchun Yan
    2017, 26(9):  684-691.  DOI: 10.5246/jcps.2017.09.077
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    In the present study, we aimed to explore the neuroprotective effect of dioscin, a natural steroid saponin, on transient focal cerebral ischemia induced by middle cerebral artery occlusion (MCAO) in mice and its related mechanism. We observed that dioscin (1.5 mg/kg, intracerebroventricular injection 30 min before MCAO) dramatically reduced the cerebral infarct volume, leading to improved neurological symptoms and reduced death of neuron, astrocytes and microglia in the infarct region. The gliosis and the reduced expressions of SOD1 and SOD2 by MCAO in the hippocampal CA1 region were significantly elevated by 1.5 mg/kg dioscin administration. These findings suggested that pretreatment of dioscin had a neuroprotective effect on mice transient focal cerebral ischemia via inhibiting the gliosis and elevating the SOD levels.

    The others
    2017 Chinese Medicinal Chemistry Symposium——The speakers from School of Pharmaceutical Sciences, PKU
    Xin Liu
    2017, 26(9):  692-696.  DOI: 10.5246/jcps.2017.09.078
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    The 2017 Chinese Medicinal Chemistry Symposium was successfully held on Aug. 27-30 at the Beijing National Conference Center. The theme of this conference is Global New Drug Research and Development: New molecules, New Technologies, and New Therapies. This symposium collected a very impressive list of scientists who are highly active in drug discovery. The symposium delivered 179 presentations and 135 posters on the topics of 1) Progression of cell therapy research (including immune, stem cells, etc.); 2) New frontiers and trends in medicinal chemistry; 3) Latest developments in critical diseases; 4) New theories and methods of drug molecular design; 5) New methods and technologies in medicinal materials and drug synthesis; 6) Chemical biology and related fields; 7) Frontiers of natural medicine and traditional Chinese medicine. Among them, 11 invited speakers are come from School of Pharmaceutical Sciences, PKU.