Showing papers by "Kaixian Chen published in 2012"

Diverse Mechanisms of Antidiabetic Effects of the Different Procyanidin Oligomer Types of Two Different Cinnamon Species on db/db Mice

Abstract: The procyanidin oligomers are thought to be responsible for the antidiabetic activity of cinnamon. To investigate the hypoglycemic effects of different procyanidin oligomer types, the procyanidin oligomer-rich extracts were prepared from two different cinnamon species. Using high-performance liquid chromatography with purified procyanidin oligomers as reference compounds, we found that the Cinnamomum cassia extract (CC-E) and Cinnamomum tamala extract (CT-E) were rich in B- and A-type procyanidin oligomers, respectively. In the experiment, 8-week-old diabetic (db/db) mice were gavaged with CC-E and CT-E (both 200 mg/kg per day) for 4 weeks. Both CC-E and CT-E exhibited antidiabetic effects. Moreover, histopathological studies of the pancreas, liver, and adipose tissue showed that CC-E promoted lipid accumulation in the adipose tissue and liver, whereas CT-E mainly improved the insulin concentration in the blood and pancreas.

Pyrene Excimer‐based Bis‐triazolyl Pyranoglycoligands as Specific Mercury Sensors

Abstract: New C3,4-disubstituted bis-triazolyl glycoligands that feature a glucosyl or galactosyl scaffold incorporating two pyrenyl groups were synthesized via the CuI-catalyzed azide-alkyne 1,3-dipolar cycloaddition reaction (Cue-AAC). These compounds exert a major emission band corresponding to that of pyrene excimer and respond specifically to mercury with a markedly quenched fluorescence. The epimeric nature of the pyranoglycosyl scaffold is determined influential toward the selectivity of the sensors.

Estimation of carcinogenicity using molecular fragments tree.

Abstract: Carcinogenicity is an important toxicological endpoint that poses high concern to drug discovery. In this study, we developed a method to extract structural alerts (SAs) and modulating factors of carcinogens on the basis of statistical analyses. First, the Gaston algorithm, a frequent subgraph mining method, was used to detect substructures that occurred at least six times. Then, a molecular fragments tree was built and pruned to select high-quality SAs. The p-value of the parent node in the tree and that of its children nodes were compared, and the nodes that had a higher statistical significance in binomial tests were retained. Finally, modulating factors that suppressed the toxic effects of SAs were extracted by three self-defining rules. The accuracy of the 77 SAs plus four SA/modulating factor pairs model for the training set, and the test set was 0.70 and 0.65, respectively. Our model has higher predictive ability than Benigni’s model, especially in the test set. The results highlight that this meth...

Discovering potent inhibitors against c-Met kinase: molecular design, organic synthesis and bioassay

Abstract: The receptortyrosine kinase c-Met is an attractive target for therapeutic treatment of cancers nowadays. The discovery of small molecule inhibitors is of special interest in the blockade of the c-Met kinase pathway. Here, we initiated our study from compound 1a, a novel inhibitor against c-Met kinase. A substructure similarity search against the SPECS database and chemical synthesis methods were performed to obtain a series of pyrazolidine-3,5-dione derivatives. Through the enzyme-based assay against c-Met kinase, 4 compounds (1c, 1e, 1m and 1o) showed potential inhibitory activity, with IC50 values mostly less than 10 μM. Based on the structure–activity relationship (SAR) and binding mode analysis, a focused combinatorial library was designed by the LD1.0 program. Taking into account ADMET properties and synthesis accessibility, seven candidate compounds (5a–g) were successfully synthesized. The activity of the most potent compounds 5b (IC50 = 0.46 μM) was 20 fold higher than that of the lead 1a. Taken together, our findings identified the pyrazolidine-3,5-dione derivatives as potent inhibitors against c-Met kinase and demonstrated the efficiency of the strategy in the development of small molecules against c-Met kinase.

Thienyl [3, 2-d] pyrimidin-4-one compounds, preparation method, pharmaceutical compositions and use thereof

Abstract: Disclosed are new thienyl [3, 2-d] pyrimidin-4-one compounds shown as the general formula (I), preparation method, pharmaceutical compositions and pharmacological use thereof. The compounds are strong DPPⅣ (dipeptide peptidase Ⅳ) inhibitors and can treat type II diabetes through well inhibiting DPPⅣ, indirectly increasing the content of GLP-1 in vivo and inducing a series of physiological actions in vivo. Therefore, the compounds could be developed as new promising drugs for treating diabetes.

Advances in Cancer Chemotherapeutic Drug Research in China

Abstract: In this chapter, the history of cancer chemotherapy discipline in China is briefly reviewed

Hexahydro dibenzo [a,g] quinolizidine compound and preparation method, medicinal composition and application thereof

Abstract: The invention relates to a novel hexahydro dibenzo [a,g] quinolizidine compound shown as a general formula (I) and a derivative, an enantiomer, a diastereoisomer, a racemate, an enantiomer, diastereoisomer and racemate mixture, pharmaceutically acceptable salt and a preparation method thereof. In addition, the compound has a good effect of preventing and treating nervous system diseases, particularly diseases related to a dopamine receptor and a serotonin receptor. Biological activity experiments show that the compound is expected to be developed into a powerful new chemical entity for treating diseases related to the dopamine receptor and the serotonin receptor, particularly schizophrenia, Parkinson's disease, drug addiction, migraine and the like.

Novel pyrazole 5-lipoxygenase small molecule inhibitors, preparation method, pharmaceutical composition and application thereof

Abstract: The invention relates to novel pyrazole 5-lipoxygenase small molecule inhibitors shown in a general formula (I), enantiomers, diastereoisomers, racemic modifications, mixtures, and pharmaceutically acceptable salts thereof. The invention also relates to a method for preparing the pyrazole compounds. In addition, the pyrazole compounds have better prevention and treatment effect on diseases related to leukotriene produced by an experimental 5-lipoxygenase (5-LOX) metabolic pathway. The biological experimental activity shows that the compounds are effective 5-LOX small molecule inhibitors with novel structures. Therefore, the compounds expect to be developed into novel powerful chemical entities for treating diseases such as inflammation, cancer, asthma and atherosclerosis related to 5-LOX and the leukotriene.

The essential role for aromatic cluster in the β3 adrenergic receptor

Abstract: To explore the function of the conserved aromatic cluster F2135.47, F3086.51, and F3096.52 in human β3 adrenergic receptor (hβ3AR). Point mutation technology was used to produce plasmid mutations of hβ3AR. HEK-293 cells were transiently co-transfected with the hβ3AR (wild-type or mutant) plasmids and luciferase reporter vector pCRE-luc. The expression levels of hβ3AR in the cells were determined by Western blot analysis. The constitutive signalling and the signalling induced by the β3AR selective agonist, BRL (BRL37344), were then evaluated. To further explore the interaction mechanism between BRL and β3AR, a three-dimensional complex model of β3AR and BRL was constructed by homology modelling and molecular docking. For F3086.51, Ala and Leu substitution significantly decreased the constitutive activities of β3AR to approximately 10% of that for the wild-type receptor. However, both the potency and maximal efficacy were unchanged by Ala substitution. In the F3086.51L construct, the EC50 value manifested as a “right shift” of approximately two orders of magnitude with an increased Emax. Impressively, the molecular pharmacological phenotype was similar to the wild-type receptor for the introduction of Tyr at position 3086.51, though the EC50 value increased by approximately five-fold for the mutant. For F3096.52, the constitutive signalling for both F3096.52A and F3096.52L constructs were strongly impaired. In the F3096.52A construct, BRL-stimulated signalling showed a normal Emax but reduced potency. Leu substitution of F3096.52 reduced both the Emax and potency. When F3096.52 was mutated to Tyr, the constitutive activity was decreased approximately three-fold, and BRL-stimulated signalling was significantly impaired. Furthermore, the double mutant (F3086.51A_F3096.52A) caused the total loss of β3AR function. The predicted binding mode between β3AR and BRL revealed that both F3086.51 and F3096.52 were in the BRL binding pocket of β3AR, while F2135.47 and W3056.48 were distant from the binding site. These results revealed that aromatic residues, especially F3086.51 and F3096.52, play essential roles in the function of β3AR. Aromatic residues maintained the receptor in a partially activated state and significantly contributed to ligand binding. The results supported the common hypothesis that the aromatic cluster F[Y]5.47/F[Y]6.52/F[Y]6.51 conserved in class A G protein-coupled receptor (GPCR) plays an important role in the structural stability and activation of GPCRs.

Hexahydrodibenzo[a,g]quinolizine compound, preparation method therefor, pharmaceutical composition and use thereof

Abstract: The present invention relates to a novel hexahydrodibenzo[a,g]quinoline compound represented by general formula (I) and its derivatives, enantiomer, diastereoisomer, raceme and mixtures thereof, as well as pharmaceutically acceptable salts thereof. The present invention further relates to a method for preparing the compound, and the compound has good prevention and treatment effect on neurological diseases, especially diseases associated with dopamine receptor and 5-hydroxytryptamine receptor. The bioactivity experiment demonstrates that, the compound is expected to be developed into a novel and potent chemical entity for treating diseases associated with dopamine receptor and 5-hydroxytryptamine receptor, especially schizophrenia, Parkinson's disease, drug addiction, migraine and so on.

SOMEViz: a web service for site of metabolism estimating and visualizing.

Abstract: Phase I metabolism is an important consideration in drug discovery because it profoundly affects the toxicity and activity profile of a drug candidate. In these metabolic processes, CYP450 family is responsible for the majority of biotransformation events. However, it is still an important challenge to predict sites of metabolism (SOM) of a new chemical entity due to the complex reaction mechanism and variety in CYP450 enzymes. SOMEViz is an online service designed for predicting and visualizing human cytochromes P450 (CYP450)-mediated sites of metabolism (SOM) of a molecule, on the basis of a previously reported model. The service provides an access for predicting sites of metabolism of molecules with reasonable accuracy, and predicted results are shown in a user-friendly as well as interactive way, which may help chemists explore metabolism properties of chemicals in the early stage of drug discovery. The web-based GUI of SOMEViz offers user a straightforward way to manage and visualize the sites of metabolism (SOM) prediction results. The service and examples are available free of charge at http://www.dddc.ac.cn/some.

An Expedient Pd/DBU Mediated Cyanation of Aryl/Heteroaryl Bromides with K4[Fe(CN)6].

Abstract: A practical Pd(PPh3)4/DBU catalytic system for the synthesis of pharmaceutically relevant aminopyridine nitrile intermediates, as well as a variety of other aryl nitriles using non-toxic K4[Fe(CN)6] has been developed. The key features of our new protocol for cyanation lie in that the reaction can be carried out with readily available Pd(PPh3)4 under mild and green conditions, even without the assistance of other ligands.