Table of Content

    29 June 2016, Volume 25 Issue 6
    Original articles
    Synthesis, anti-fibrosis activity, and quantitative structure-activity relationship studies of 1,3-disubstituted-pyridin-4(1H)-one derivatives
    Juan Peng, Qianbin Li, Honglin Xiang, Zeyu Wang, Gaoyun Hu
    2016, 25(6):  395-407.  DOI: 10.5246/jcps.2016.06.045
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    A series of 1,3-disubstituted-pyridin-4(1H)-one derivatives were synthesized. The results of a viability assay on NIH3T3 cells indicated that compound 3m potently inhibited the cell viability with an IC50 value of 2.0 μM. The 3D-quantitative structure-activity relationship analyses of 30 final molecules applying topomer CoMFA and AutoGPA methods gave two reasonable models with a cross-validated correlation coefficient q2 of 0.662 and 0.787, respectively. The achievement herein suggested the application of 3-hydroxypyridin-4(1H)-one as a novel scaffold for the discovery of anti-fibrosis agents. In addition, the QSAR and pharmacophore models established with the activity data may provide new insights into the structure optimization of pyridin-4(1H)-one derivative with potent anti-fibrotic effects.

    Study on the dipeptide vinyl sulfonamide derivatives as proteasome inhibitor
    Shuyang Yao, Yue Zhou
    2016, 25(6):  408-418.  DOI: 10.5246/jcps.2016.06.046
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    On the basis of the Michael-addition mechanism of classical proteasome inhibitors, six dipeptide vinyl sulfonamide and dipeptide vinyl sulfonate derivatives were designed and synthesized. Moreover, an efficient method for the synthesis of g-amino vinyl sulfonamides, key intermediates to the target molecules, was developed via the Wittig-Horner reaction of peptide aldehyde with Wittig reagents derived from methanesulfonamides.

    An efficient synthesis of polysubstituted tetrahydropyrimidines using acidic Al2O3 as solid media
    Tian Gao, Ling Ji, Xin Wang, Runtao Li
    2016, 25(6):  419-427.  DOI: 10.5246/jcps.2016.06.047
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    A series of polysubstituted tetrahydropyrimidines were synthesized in moderate to good yields via a one-pot,  four-componentreaction of an alkyne, formaldehyde, and amines in solid media acidic Al2O3. The advantages of this protocol include mild reaction conditions, broad substrate scope, and environmentally friendly reaction media.

    Molecular models of different states of the human multidrug resistance protein 4 (MRP4/ABCC4)
    Ya Chen, Hongwei Jin, Liangren Zhang, Zhenming Liu
    2016, 25(6):  428-437.  DOI: 10.5246/jcps.2016.06.048
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    ATP-binding cassette (ABC) transporter multidrug resistance protein 4 (MRP4, ABCC4) is involved in multidrug resistance (MDR), which is an increasing challenge to the treatment of cancers and infections. MRP4 is overexpressed in several types of cancers, and MRP4 inhibition shows striking effects against cancer progression and drug resistance. However, the structuralknowledge of this protein remains unclear due to lack of an MRP4 X-ray structure, and homology modeling approach is an effectiveway to obtain three-dimensional structure of MRP4. We constructed three molecular models of human MRP4 mainly based on the inward facing Caenorhabditis elegans P-glycoprotein (P-gp), the Thermotoga maritima heterodimeric ABC transporter TM287-TM288 (TM287/288) and the outward facing Staphylococcus aureus Sav1866 crystal structures, which represented substrate uptake, transport and release state, respectively. The structures were further energy minimized and optimized by molecular dynamic simulations (MDS). All the models were validated by various tools and servers, and the results showed that the quality of the models was reasonable and acceptable. These MRP4 models could be used as working tools for experimental studies on the structure and functions of MRP4 and designing more specific membrane transport modulating agents (MTMA).

    Augmented efficacy and the mechanism of a combined use of daunorubicin with rofecoxib in treatment of triple-negative breast cancer
    Yao Zhao, Jingying Zhang, Yingjie Hu, Jiashuan Wu, Yingzi Bu, Wanliang Lu
    2016, 25(6):  438-447.  DOI: 10.5246/jcps.2016.06.049
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    Triple-negative breast cancer is the tumor that lacks expressions of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor-2 (HER2). A regular chemotherapy cannot eradicate triple-negative breast cancer. In the present study, we aimed to develop a combined use of daunorubicin and rofecoxib to treat triple-negative breast cancer, and reveal the underlying mechanisms. A gradient elution HPLC-UV method was developed for quantification, and the evaluations were performed on the triple-negative breast cancer MDA-MB-231 cells using a high content screening system. The results demonstrated that daunorubicin alone was insensitive to the triple negative breast cancer cells, while the combined use of daunorubicinand rofecoxib was able to effectively kill these triple-negative cancer cells, exhibiting a rofecoxib concentration-dependent manner. The mechanism revealed that the augmented anticancer efficacy was associated with direct killing effect, inducing apoptosis and inducing autophagy by the combination treatment. Besides, the apoptosis signaling pathways were correlated to a cascade of reactions by activating apoptotic enzyme caspase family and by suppressing anti-apoptotic gene expressed protein Bcl-2 family. In conclusion, this study provided a fundamental evidence for further developing the combined use of daunorubicin and rofecoxib formulation, hence offering a promising strategy for eradicating the triple negative breast cancer.

    Regulatory effects of coenzyme Q10 on the immunological activity of mice
    Yingjie Xu, Li Shuai, Jiang Hu, Delin Duan
    2016, 25(6):  448-457.  DOI: 10.5246/jcps.2016.06.050
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    To examine how coenzyme Q10 (CoQ10)regulates immunity, experiments using low, middle and high doses of CoQ10were conducted in mice to confirm its non-toxicity and non-genotoxicity. Delayed type hypersensitivity (DTH) and MTT assays were used to to examine various lymphocyte transformations, the proliferation of antibody-producing cells, the phagocytotsis activity of macrophages, and the activity of nature killer cell (NK). High-dose (0.50 g/kg.bw) CoQ10 increased DTH levels and promoted the proliferation of antibody-producing cells and levels of red blood cell hemolysis. Medium and high doses enhanced the phagocytic ratio of macrophages but didnot influence other indexes. These results showed that the applied CoQ10 did not exhibit any toxicity or genotoxicity, and CoQ10 can actually improve immunologic function in mice.

    Sini Powder extract produces antidepressant-like effects in a chronic social defeat stress model of depression in tree shrews
    Shanshan Wei, Hejin Yang, Jiawen Huang, Xueping Lu, Lingfang Peng, Qingguo Wang
    2016, 25(6):  458-465.  DOI: 10.5246/jcps.2016.06.051
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    Sini Power (SP) is a famed traditional Chinese formula that has long been used to treat depression. Here, we investigated the effects and possible mechanisms of SP extract on an established model of depression: chronic stressed tree shrew, which mimics the human condition of social stress. The animals were divided into 4 groups. Except for the naïve group, the other animalswere subjected to daily social defeat stress for 5 weeks, and during the last 4 weeks treated with SP extract (3.6 g/kg/d), fluoxetine (15 mg/kg/d), and vehicle, respectively. The results showed that SP extract could reverse body weight loss to a certain extent and reduce the levels of urine/serum cortisol that were initially increased by chronic social defeat. In addition, SP extract increased hippocampus norepinephrine concentrations. Our data suggested that SP extract had positive effects on the main depression symptoms in the chronic stressed tree shrew model and that it may be used to help control hypothalamic-pituitary-adrenal axis hyperactivity.

    Short review
    Research progress on the antioxidant therapy for gastric cancer
    Lina Yu, Caixia Gao, Jun Ma, Wenjin Hao, Qiusheng Zheng
    2016, 25(6):  466-476.  DOI: 10.5246/jcps.2016.06.052
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    Gastric cancer is one of common malignant tumors from a global perspective, and its morbidity ranks the forth and also the second largest cause of cancer-related death worldwide. Many factors can cause gastric cancer, including helicobacter pylori infection, chronic inflammation, genetic factors et al. Among all of these, helicobacter pylori infection can significantly increase the production of reactive oxygen species (ROS) and reactive nitrogen species (RNS) in human stomach, which can cause the oxidative stress. Oxidative stress plays an important role in the pathogenesis of gastro-intestinal diseases such as mucosal damage, gastro-intestinal ulcers and cancer. Modern therapeutic treatments such as surgery and chemotherapy have undesired side effects, so the antioxidant therapy gains more and more attentions. Antioxidant therapy system comprises of various antioxidants (SOD, catalase, glutathione peroxidase and carnosine) and Chinese herbal medicine, which is mainly focused on the chemoprevention. Natural products and their derivatives, such as tea polyphenol, resveratrol and vitamins, have some potential benefits on their chemoprevention. Besides, much work has been done to understand the role of dietary factors playing in the prevention of gastrointestinal cancers. In this review based on some valuable studies, we aim to make some brief summaries about risk factors, pathogenic mechanism of oxidative stress and antioxidants therapy in gastric cancer.