Table of Content

28 July 2017, Volume 26 Issue 7

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Reviews

Research progress of synthetic lactacystin and its analogs as β-lactone proteasome inhibitors

Yuping Wang, Xiaowei Zhu, Jian Xin, Yanyan Guo, Xiangnan Xu, Yuheng Ma

2017, 26(7):  467-478.  DOI: 10.5246/jcps.2017.07.052

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As Bortezomib and Carfilzomib are approved to treat refractory multiple myeloma, 20S proteasome has become a highly interested tumor therapeutic target. Because of drug resistance of Bortezomib and Carfilzomib, β-lactone natural products are used to treat cancer, arthritis, asthma, and Alzheimer’s diseases. Now the second generation drug candidates are developed, eg. Salinosporamide A (1). This review is aiming to encapsulate the synthetic methods of β-lactone proteasome inhibitors, lactacystin (3) and its analogs.



Research and development of alginate-based raft forming system

Yaxian Lin, Zhao Yang, Nan Yang, Yamei Cai, Tiantian Yu, Ying Fan

2017, 26(7):  479-487.  DOI: 10.5246/jcps.2017.07.053

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Formulations of Gaviscon based on novel alginate raft forming system have been developed to prevent gastroesophageal reflux disease (GERD) symptoms. Alginate gel becomes buoyant and CO₂-aerated as soon as Gaviscon comes into contact with gastric contents. This system can be characterized by several indicators, such as strength or coherence, volume, buoyancy, reflux resistance and resilience. In addition, the strength of the raft is influenced by many factors, such as molecular weight and the ratio of D-mannuronic and L-guluronic acid residues (M/G), which are intrinsic factors in this formulation. Besides, there are several extrinsic factors, such as the presence of specific cations, the amount of carbon dioxide generated and entrapped in the raft. This review focused on how to evaluate the raft, introduced some factors that impact the raft and summarized the degradation of alginate and future advance.



Original articles

Dnmt1 regulates adipogenesis by Cdkn1a methylation

Yi Yang, Fan Yi, Pei Zhang, Hua Li, Quan Du

2017, 26(7):  488-495.  DOI: 10.5246/jcps.2017.07.054

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Obesity has recently become a major healthy concern in developed countries. This leads to intensive interest in the mechanism study of adipogenesis, in which epigenetic mechanisms are speculated to play an essential role. To explore the function of Dnmt1, its expression was first profiled during the course of adipocyte differentiation of 3T3-L1 cells. The results revealed a dynamic regulation of its expression at the initiation stage. Knockdown of Dnmt1 compromised the differentiation process and decreased lipid production within the cells. To the aspect of epigenetic regulation, promoter methylation of Cdkn1a was significantly increased at the initiation stage of the differentiation, accompanied by decreased Cdkn1a expression. Furthermore, knockdown of Dnmt1 led to an increased Cdkn1a expression, indicating that Dnmt1 inhibits Cdkn1a expression by promoter methylation. Furthermore, we found that knockdown of Cdkn1a up-regulated the expression of PPARγ and resulted in enhanced adipocyte differentiation. In summary, our results demonstrated that Dnmt1 regulated the process of adipogenesis by methylation of Cdkn1a promoter, suggesting that Cdkn1a played a fundamental role in the prevention of adipocyte hyperplasia.



Synthetic study toward the total synthesis of fumigaclavines A–D

Yongfan Ma, Yanxing Jia

2017, 26(7):  496-503.  DOI: 10.5246/jcps.2017.07.055

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In the present study, we developed a novel approach for the synthesis of the tetracyclic core of fumigaclavines A–D. A palladium-catalyzed intramolecular Larock indole synthesis was utilized to assemble the B/C rings of the tetracyclic core in one step. Although all attempts to convert compound 18 to fumigaclavine B failed, this study provided useful information for the total synthesis of fumigaclavines A–D.



Design, synthesis and bioevaluation of isoflavone derivative as a novel CLR/RAMP1 antagonist

Junjie Wang, Chao Wang, Peng Lü, Yan Niu, Hongyue Li, Wenhui Huang, Can Li, Fengrong Xu, Lei Liang, Ping Xu

2017, 26(7):  504-511.  DOI: 10.5246/jcps.2017.07.056

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CGRP receptor (CLR) is a B class GPCR that functions only when combined with RAMPs. CLR/RAMP1 has been regarded as a promising target for migraine treatment, as its antagonists have been proved to be effective recently. In the present study we designed and synthesized small molecular antagonists against CLR/RAMP1, resulting in a novel type of structure with acceptable high potency. The molecules were designed via virtual screening. Afterwards, a series of modification were conducted on the hit compounds, resulting in compound 8 as the best scored compound in docking, which was further validated in vitro by cell-based functional assay. 



Docking and field-based QSAR studies of S-DABOs as HIV-1 reverse transcriptase inhibitors

Ningning Fan, Zhenming Liu, Xiaowei Wang, Junyi Liu

2017, 26(7):  512-520.  DOI: 10.5246/jcps.2017.07.057

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HIV-1 reverse transcriptase (RT) inhibitors are major components of HAART (highly active antiviral therapy). The S-DABOs (dihydro-alkylthio-benzyl-oxopyrimidines) series and their similar skeletons have exhibited preferable activities to inhibit HIV-1 RT. In the present study, we generated field-based QSAR models using common structure alignment, which was characterized by Gaussian steric, electrostatic, hydrophobic, hydrogen bond donor, hydrogen bond acceptor and aromatic ring fields (R² = 0.8421, R²_CV = 0.5949 for the training set, Q² = 0.5486, Pearson-r = 0.7460 for the test set). Docking, pocket surface and contourmap analyses were carried out. Key pharmacophore features were investigated, including (i) π-π interaction with residue Tyr181, Tyr188 and Trp229, σ-π interaction with His236, (ii) hydrogen bond with residue Lys101 and halogen bond with residue Tyr188. The docking analysis and field-based QSAR models could provide reasonable guidance in the rational design of potent HIV-1 RT inhibitors.



Characterization of amphiphilic dendrimer modified PEG-PLA nanoparticles prepared by a double emulsion-solvent evaporation method

Xin Li, Ning Pang, Ji Li, Xianrong Qi

2017, 26(7):  521-527.  DOI: 10.5246/jcps.2017.07.058

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Drug delivery by nanocarriers requires characterizations of suitable particle size, high drug loading and safety. In this work, we prepared an amphiphilic dendrimer modified PEG-PLA mixed nanoparticles (NPs) by a double emulsion-solvent evaporation (DESE) method. The particle size and drug encapsulation efficacy (EE) were compared to evaluate and optimize the preparation parameters. The mixed NPs had average size ranging from (102±1) nm to (137±5) nm, and the zeta potential turned to positive with incorporation of the amphiphilic dendrimer. The NPs showed different EE of docetaxel (DTX) and paclitaxel (PTX) with higher affinity to more lipophilic PTX. The blank mixed NPs showed little cytotoxicity, and the DTX-loaded NPs could effectively facilitate the antiproliferation activity on PC-3 cells. The NPs could be used as an effective drug delivery system, and its anti-tumor effect is worthy of further study.



Drug administration and clinical pharmacy column

A novel drug of elotuzumab for treatment of refractory/relapsed multiple myeloma: a meta-analysis of eight trials

Lin Zhang, Jiewei Ding, Yang Wang, Xiaoxuan Jin, Weidong Ge, Shuting Huang, Yuting Li

2017, 26(7):  528-533.  DOI: 10.5246/jcps.2017.07.059

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Elotuzumab was approved by the US FDA in 2015 as a new drug for the treatment of multiple myeloma (MM), and it became a new choice for MM patients. The drug is the first immunostimulatory drug to treat MM and used to treat recurrent/refractory multiple myeloma (R/RMM) in combination with lenalidomide and dexamethasone. Therefore, we collected the reports from existing clinical trials to analyze the efficacy of the drug in clinical applications to better evaluate the effects of the drug on R/RMM. The search strategy used “elotuzumab” and “multiple myeloma” as keywords to search from the database of Cochrane, Embase, PubMed and Medline. The heterogeneity among the studies was assessed using the Cochrane χ² test, and its extent was evaluated using I² statistics. A P value of less than 0.05 was considered as statistically significant. All meta-analyses were conducted with R Software 3.3.2. We identified eight prospective studies consisting of 608 MM patients. The meta-analysis showed that the overall response rate (ORR) was 63%, 162 patients (26.6%) achieved a very good partial response rate (VGPR), and 34 patients (5.59%) achieved complete response rate (CR). The most common adverse effects of the drug included anemia, lymphopenia, thrombocytopenia, neutropenia and fatigue. Therefore, elotuzumab combination regimens offered clinical benefits to R/RMM patients, and such a combination therapy was a suitable option for continuous treatment for R/RMM patients. 



A general introduction to the development of Good Laboratory Practice in China

Jing Zhang, Xiaoyu Fan, Hongtao Jin, Xingchao Geng

2017, 26(7):  534-544.  DOI: 10.5246/jcps.2017.07.060

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Good laboratory practice (GLP) plays an important role in pre-clinical studies, which are a key stage in new drug research and development (R&D). The development of GLP in China started in the late 1990s. Following 20 years of developments, GLP system has already been established in this country. This review firstly evaluated all the institutions in this field, and described the annual number and total number of institutions, the distribution of GLP institutions, the types of GLP institutions, and the service provided by these GLP institutions. Since the initiation of the National Key Technology R&D Program during the 11^th Five-Year Plan, it had a significant effect on the development of GLP. Therefore, the institutions which have undertaken projects from this program will be introduced later. We also described the infrastructure of hardware and software in GLP institutions along with their faults, such as variation in development and the lack of innovation.