Showing papers by "Kaixian Chen published in 2016"

Bavachinin, as a novel natural pan-PPAR agonist, exhibits unique synergistic effects with synthetic PPAR-γ and PPAR-α agonists on carbohydrate and lipid metabolism in db/db and diet-induced obese mice.

Abstract: Pan-peroxisome proliferator-activated receptor (PPAR) agonists have long been sought as therapeutics against the metabolic syndrome, but current PPAR agonists show limited efficacy and adverse effects. Natural herbs provide a structurally untapped resource to prevent and treat complicated metabolic syndrome. Natural PPAR agonists were screened using reporter gene, competitive binding and 3T3-L1 pre-adipocyte differentiation assays in vitro. The effects on metabolic phenotypes were verified in db/db and diet-induced obese mice. In addition, potentially synergistic actions of bavachinin (BVC, a novel natural pan-PPAR agonist from the fruit of the traditional Chinese glucose-lowering herb malaytea scurfpea) and synthetic PPAR agonists were studied through nuclear magnetic resonance, molecular docking, reporter gene assays and mouse studies. BVC exhibited glucose-lowering properties without inducing weight gain and hepatotoxicity. Importantly, BVC synergised with thiazolidinediones, which are synthetic PPAR-γ agonists, and fibrates, which are PPAR-α agonists, to induce PPAR transcriptional activity, as well as to lower glucose and triacylglycerol levels in db/db mice. We further found that BVC occupies a novel alternative binding site in addition to the canonical site of synthetic agonists of PPAR, and that the synthetic PPAR-γ agonist rosiglitazone can block BVC binding to this canonical site but not to the alternative site. This is the first report of a synergistic glucose- and lipid-lowering effect of BVC and synthetic agonists induced by unique binding with PPAR-γ or -α. This combination may improve the efficacy and decrease the toxicity of marketed drugs for use as adjunctive therapy to treat the metabolic syndrome.

Trimer procyanidin oligomers contribute to the protective effects of cinnamon extracts on pancreatic β-cells in vitro.

Abstract: Cinnamon extracts rich in procyanidin oligomers have shown to improve pancreatic β-cell function in diabetic db/db mice. The aim of this study was to identify the active compounds in extracts from two species of cinnamon responsible for the pancreatic β-cell protection in vitro. Cinnamon extracts were prepared from Cinnamomum tamala (CT-E) and Cinnamomum cassia (CC-E). Six compounds procyanidin B2 (cpd1), (−)-epicatechin (cpd2), cinnamtannin B1 (cpd3), procyanidin C1 (cpd4), parameritannin A1 (cpd5) and cinnamtannin D1 (cpd6) were isolated from the extracts. INS-1 pancreatic β-cells were exposed to palmitic acid (PA) or H2O2 to induce lipotoxicity and oxidative stress. Cell viability and apoptosis as well as ROS levels were assessed. Glucose-stimulated insulin secretion was examined in PA-treated β-cells and murine islets. CT-E, CC-E as well as the compounds, except cpd5, did not cause cytotoxicity in the β-cells up to the maximum dosage using in this experiment. CT-E and CC-E (12.5–50 μg/mL) dose-dependently increased cell viability in both PA- and H2O2-treated β-cells, and decreased ROS accumulation in H2O2-treated β-cells. CT-E caused more prominent β-cell protection than CC-E. Furthermore, CT-E (25 and 50 μg/mL) dose-dependently increased glucose-stimulated insulin secretion in PA-treated β-cells and murine islets, but CC-E had little effect. Among the 6 compounds, trimer procyanidins cpd3, cpd4 and cpd6 (12.5–50 μmol/L) dose-dependently increased the cell viability and decreased ROS accumulation in H2O2-treated β-cells. The trimer procyanidins also increased glucose-stimulated insulin secretion in PA-treated β-cells. Trimer procyanidins in the cinnamon extracts contribute to the pancreatic β-cell protection, thus to the anti-diabetic activity.

Thermodynamics calculation of protein–ligand interactions by QM/MM polarizable charge parameters

Abstract: The calculation of protein–ligand binding free energy (ΔG) is of great importance for virtual screening and drug design. Molecular dynamics (MD) simulation has been an attractive tool to investigat...

Identification of Novel Disruptor of Telomeric Silencing 1-like (DOT1L) Inhibitors through Structure-Based Virtual Screening and Biological Assays.

Abstract: Histone methyltransferases are involved in many important biological processes, and abnormalities in these enzymes are associated with tumorigenesis and progression. Disruptor of telomeric silencing 1-like (DOT1L), a key hub in histone lysine methyltransferases, has been reported to play an important role in the processes of mixed-lineage leukemia (MLL)-rearranged leukemias and validated to be a potential therapeutic target. In this study, we identified a novel DOT1L inhibitor, DC_L115 (CAS no. 1163729-79-0), by combining structure-based virtual screening with biochemical analyses. This potent inhibitor DC_L115 shows high inhibitory activity toward DOT1L (IC50 = 1.5 μM). Through a process of surface plasmon resonance-based binding assays, DC_L115 was founded to bind to DOT1L with a binding affinity of 0.6 μM in vitro. Moreover, this compound selectively inhibits MLL-rearranged cell proliferation with an IC50 value of 37.1 μM. We further predicted the binding modes of DC_L115 through molecular docking anal...

Discovery of Novel Inhibitors Targeting the Menin-Mixed Lineage Leukemia Interface Using Pharmacophore- and Docking-Based Virtual Screening

Abstract: Disrupting the interaction between mixed lineage leukemia (MLL) fusion protein and menin provides a therapeutic approach for MLL-mediated leukemia. Here, we aim to discover novel inhibitors targeting the menin-MLL interface with virtual screening. Both structure-based molecular docking and ligand-based pharmacophore models were established, and the models used for compound screening show a remarkable ability to retrieve known active ligands from decoy molecules. Verified by a fluorescence polarization assay, five hits with novel scaffolds were identified. Among them, DCZ_M123 exhibited potent inhibitory activity with an IC50 of 4.71 ± 0.12 μM and a KD of 14.70 ± 2.13 μM, and it can effectively inhibit the human MLL-rearranged leukemia cells MV4;11 and KOPN8 with GI50 values of 0.84 μM and 0.54 μM, respectively.

Eutypenoids A–C: Novel Pimarane Diterpenoids from the Arctic Fungus Eutypella sp. D-1

Abstract: Eutypenoids A-C (1-3), pimarane diterpenoid alkaloid and two ring A rearranged pimarane diterpenoids, were isolated from the culture of Eutypella sp. D-1 obtained from high-latitude soil of the Arctic. Their structures, including absolute configurations, were authenticated on the basis of the mass spectroscopy (MS), nuclear magnetic resonance (NMR), X-ray crystallography, and electronic circular dichroism (ECD) analysis. The immunosuppressive effects of eutypenoids A-C (1-3) were studied using a ConA-induced splenocyte proliferation model, which suggested that 2 exhibited potent immunosuppressive activities.

Identification of novel small-molecule inhibitors targeting menin–MLL interaction, repurposing the antidiarrheal loperamide

Abstract: Leukemia with a mixed lineage leukemia (MLL) rearrangement, which harbors a variety of MLL fusion proteins, has a poor prognosis despite the latest improved treatment options. Menin has been reported to be a required cofactor for the leukemogenic activity of MLL fusion proteins. Thus, the disruption of the protein-protein interactions between menin and MLL represents a very promising strategy for curing MLL leukemia. Making use of menin-MLL inhibitors with a shape-based scaffold hopping approach, we have discovered that the antidiarrheal loperamide displays previously unreported mild inhibition for the menin-MLL interaction (IC50 = 69 ± 3 μM). In an effort to repurpose this drug, a series of chemical modification analyses was performed, and three of the loperamide-based analogues, DC_YM21, DC_YM25 and DC_YM26 displayed better activities with IC50 values of 0.83 ± 0.13 μM, 0.69 ± 0.07 μM and 0.66 ± 0.05 μM, respectively. Further treatment with DC_YM21 demonstrated potent and selective blockage of proliferation and induction of both cell cycle arrest and differentiation of leukemia cells harboring MLL translocations, which confirmed the specific mechanism of action. In conclusion, molecules of a novel scaffold targeting menin-MLL interactions were reported and they may serve as new potential therapeutic agents for MLL leukemia.

Outline Design of ITER Radial X-Ray Camera Diagnostic

Abstract: The radial X-ray camera (RXC) is designed to measure the poloidal profile of plasma X-ray emission with high spatial and temporal resolution. Its primary diagnostic role includes measuring low (m, ...

Preparation of Methylated Products of A‐type Procyanidin Trimers in Cinnamon Bark and Their Protective Effects on Pancreatic β‐Cell

Abstract: Polyphenols are partial metabolized to methylated conjugations in vivo, and then could modify bioavailability and bioactivity related to the uptake of parent compounds. Our previous studies have found that the antidiabetic effects of cinnamon barks are mainly related to polyphenol components, particularly A-type procyanidin trimer cinnamtannin-1 (CT1). It is necessary to understand the antidiabetic activity of methylations of CT1, nevertheless, sufficient amounts of methylated CT1 are difficult to obtain from metabolites in vivo. In this study, O-methyl derivatives of CT1 were prepared through one-pot methyl iodide reaction and isolation via column chromatography and RP-HPLC semipreparation. The structures of O-methyl substituents were determined through NMR (Nuclear Magnetic Resonance) and HPLC-ESI-MS (High-performance liquid chromatography-electrospray ionization-mass spectrometry). Five purified O-methyl substituents and 2 isomers of CT1 were obtained. Their protective effects on a palmitic acid-induced pancreatic β-cell apoptosis model were then evaluated. Results showed that the protective effects on pancreatic β-cell of O-methyl substituents were weaker than those of CT1. The results suggested that the methylation of catechol groups could be a relevant factor contributing to the decline of protective effects on pancreatic β-cell of CT1 via obstructing quinone intermediate formation and affecting antioxidant abilities. The antidiabetic effects of O-methyl derivatives of CT1 should be further determined by other antidiabetic models.

Facile Synthesis of 7‐epi‐Taxane and Its Derivatives and Preliminary Evaluation of Anticancer Activity

Abstract: 7-epi-Taxane has been achieved efficiently in gram scale from natural taxane via inversion of the 7-hydroxyl group simply using Ag2O as catalyst and DMF as solvent. The catalyst could be quantitatively recovered by filtration without loss of catalytic activity. This condition is also applicable to the direct epimerization of taxane derivatives (e.g., docetaxel and paclitaxel) to 7-epi-taxane derivatives (e.g., 7-epi-docetaxel and 7-epi-paclitaxel). Furthermore, 33 ester derivatives of 7-epi-taxane with different amino acid moieties at the position of C-13 were successfully synthesized via esterification without protecting C-7-OH. Bioassay results revealed that compounds 13 and 18 have good selectivity against prostatic cancer cell line DU145, with IC50 value as low as 15.9 nmol/L for 18.

Crystal form a of compound and preparation method thereof

Abstract: The present invention relates to the crystal form A of a compound. The present invention further discloses a preparation method and a pharmaceutical composition of the crystal form A of the compound. The crystal form A has a relative strong hypoglycemic activity in vivo, and is hoped to be a new pharmaceutically active ingredient for treating or preventing type II diabetes and/or the complications of type II diabetes.

1-(3-aminopropyl) substituted cyclic amine compounds, preparation method therefor, and pharmaceutical compositions and uses thereof

Abstract: Provided are 1-(3-aminopropyl) substituted cyclic amine compounds as represented by formula (I), pharmaceutically acceptable salts, enantiomers, diastereoisomers, racemates and mixtures thereof, and a method of synthesizing said 1-(3-aminopropyl) substituted cyclic amine compounds by using aromatic heterocyclic formaldehyde as raw material. Said compounds can be used as CCR 5 antagonist for the treatment of HIV infection.

Pharmaceutical use of hexahydro-dibenzo[a,g]quinolizine compounds

Abstract: Use of hexahydro-dibenzo[a,g]quinolizine compounds as shown in formula(I) in preparing a medicine for treating and/or preventing benign prostate hyperplasia diseases.

Hexahydrodibenzo[a,g]quinolizine compound, manufacturing method therefor, pharmaceutical composition and application thereof

Abstract: PROBLEM TO BE SOLVED: To provide a novel hexahydrodibenzo[a,g]quinolizine compound having strong effect for treating diseases such as neurological diseases related to a dopamine receptor and a serotonin receptor, especially Parkinson disease, schizophrenia, drug dependence and migraine.SOLUTION: There are provided a novel hexahydrodibenzo[a,g]quinolizine compound represented by the general formula (I) and a derivative thereof, enantiomers thereof, diastereomers, racemic bodies and a mixture thereof and a pharmaceutically acceptable salt thereof.SELECTED DRAWING: None