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Zhang X.,East China Normal University | Kong Y.,East China Normal University | Zhang J.,CAS Shanghai Institute of Materia Medica | Su M.,National Center for Drug Screening | And 6 more authors.
European Journal of Medicinal Chemistry | Year: 2015

A new class of colchicine derivatives were designed and synthesized as tubulin-HDAC dual inhibitors. Biological evaluations of these hybrids included the inhibitory activity of HDAC, tubulin polymerization analysis, in vitro cell cycle analysis in HCT-116 cells and cytotoxicity against different cancer cell lines. Hybrid 6d behaved as potent HDAC-tubulin dual inhibitor and showed comparable cytotoxicity with colchicine. Compound 11a exhibited powerful tubulin inhibitory activity, moderate anti-HDAC activity and the most potent cytotoxicity (IC50 Combining double low line 2-105 nM). © 2015 Elsevier Masson SAS.


Liu Q.,CAS Shanghai Institute of Materia Medica | Liu Q.,National Center for Drug Screening | Liu Q.,Fudan University | Wang M.-W.,CAS Shanghai Institute of Materia Medica | And 2 more authors.
Acta Pharmacologica Sinica | Year: 2016

Post-translational epigenetic modification of histones is controlled by a number of histone-modifying enzymes. Such modification regulates the accessibility of DNA and the subsequent expression or silencing of a gene. Human histone methyltransferases (HMTs)constitute a large family that includes histone lysine methyltransferases (HKMTs) and histone/protein arginine methyltransferases (PRMTs). There is increasing evidence showing a correlation between HKMTs and cancer pathogenesis. Here, we present an overview of representative HKMTs, including their biological and biochemical properties as well as the profiles of small molecule inhibitors for a comprehensive understanding of HKMTs in drug discovery. © 2016 CPS and SIMM.


Xu Y.,Tongji University | Xu Y.,CAS Shanghai Institute of Materia Medica | Wei X.,Tongji University | Wei X.,CAS Shanghai Institute of Materia Medica | And 10 more authors.
Journal of Biological Chemistry | Year: 2013

The discovery of induced pluripotent stem (iPS) cells provides not only new approaches for cell replacement therapy, but also new ways for drug screening. However, the undefined mechanism and relatively low efficiency of reprogramming have limited the application of iPS cells. In an attempt to further optimize the reprogramming condition, we unexpectedly observed that removing c-Myc from the Oct-4, Sox-2, Klf-4, and c-Myc (OSKM) combination greatly enhanced the generation of iPS cells. The iPS cells generated without c-Myc attained salient pluripotent characteristics and were capable of producing fullterm mice through tetraploid complementation. We observed that forced expression of c-Myc induced the expression of many genes involved in cell cycle control and a hyperproliferation state of the mouse embryonic fibroblasts during the early stage of reprogramming. This enhanced proliferation of mouse embryonic fibroblasts correlated negatively to the overall reprogramming efficiency. By applying small molecule inhibitors of cell proliferation at the early stage of reprogramming, we were able to improve the efficiency of iPS cell generation mediated by OSKM. Our data demonstrated that the proliferation rate of the somatic cell plays critical roles in reprogramming. Slowing down the proliferation of the original cells might be beneficial to the induction of iPS cells. © 2013 by The American Society for Biochemistry and Molecular Biology, Inc.


Hu H.-N.,State Key Laboratory of Drug Research | Hu H.-N.,National Center for Drug Screening | Zhou P.-Z.,CAS Shanghai Institute of Materia Medica | Chen F.,State Key Laboratory of Drug Research | And 5 more authors.
Acta Pharmacologica Sinica | Year: 2013

Aim: Retigabine, an activator of KCNQ2-5 channels, is currently used to treat partial-onset seizures. The aim of this study was to explore the possibility that structure modification of retigabine could lead to novel inhibitors of KCNQ2 channels, which were valuable tools for KCNQ channel studies. Methods: A series of retigabine derivatives was designed and synthesized. KCNQ2 channels were expressed in CHO cells. KCNQ2 currents were recorded using whole-cell voltage clamp technique. Test compound in extracellular solution was delivered to the recorded cell using an ALA 8 Channel Solution Exchange System. Results: A total of 23 retigabine derivatives (HN31-HN410) were synthesized and tested electrophysiologically. Among the compounds, HN38 was the most potent inhibitor of KCNQ2 channels (its IC 50 value=0.10±0.05 μmol/L), and was 7-fold more potent than the classical KCNQ inhibitor XE991. Further analysis revealed that HN38 (3 μmol/L) had no detectable effect on channel activation, but accelerated deactivation at hyperpolarizing voltages. In contrast, XE991 (3 μmol/L) did not affect the kinetics of channel activation and deactivation. Conclusion: The retigabine derivative HN38 is a potent KCNQ2 inhibitor, which differs from XE991 in its influence on the channel kinetics. Our study provides a new strategy for the design and development of potent KCNQ2 channel inhibitors. © 2013 CPS and SIMM.


Gao X.,Fudan University | Zhao X.-L.,Fudan University | Zhu Y.-H.,CAS Shanghai Institute of Materia Medica | Li X.-M.,Fudan University | And 4 more authors.
Life Sciences | Year: 2011

Aims: Tetramethylpyrazine (TMP), one of the active ingredients isolated from a Chinese herbal prescription, possesses protective effects against oxidative stress caused by high glucose in endothelial cells. In this study, the role of TMP in preventing muscle cells from palmitate-induced oxidative damage was investigated and the possible mechanisms of action elucidated. Main methods: Mitochondrial reactive oxygen species (ROS) were measured in C2C12 myotubes, a palmitate-induced oxidative stress cell model, with or without TMP. Both mitochondrial membrane potential (MMP) and oxygen consumption were assessed in conjunction with quantification of mitochondrial DNA and mitochondrial biogenesis-related factors, such as peroxisome proliferator-activated receptor-γ coactivator 1 α (PGC1α), nuclear respiratory factor 1 (NRF1) and mitochondrial transcription factor A (Tfam), by real-time polymerase chain reaction. Expression of mitochondrial respiratory chain complex III as an index of mitochondrial function was evaluated by immunoblotting, and glucose transport into the C2C12 myotube examined by analyzing 2-deoxy-[ 3H]glucose uptake. Key findings: TMP significantly alleviated palmitate-induced mitochondrial ROS production, mitigated mitochondrial dysfunction and increased D-loop mRNA expression as compared with the control. This was accompanied by a marked reversal of palmitate-induced down-regulation in the expression of mitochondrial biogenesis-related factors (PGC1α, NRF1 and Tfam) and decreased glucose uptake in C2C12 myotubes. As a result, cell respiration, as reflected by the elevated expression of mitochondrial respiratory chain complex III and oxygen consumption, was enhanced. Significance: TMP is capable of protecting C2C12 myotubes against palmitate-induced oxidative damage and mitochondrial dysfunction, and improving glucose uptake in muscle cells partially through the up-regulation of mitochondrial biogenesis. © 2011 Elsevier Inc.


Wantha S.,Ludwig Maximilians University of Munich | Wantha S.,RWTH Aachen | Alard J.-E.,Ludwig Maximilians University of Munich | Megens R.T.A.,Ludwig Maximilians University of Munich | And 13 more authors.
Circulation Research | Year: 2013

RATIONALE:: The leukocyte response in acute inflammation is characterized by an initial recruitment of neutrophils preceding a second wave of monocytes. Neutrophil-derived granule proteins were suggested to hold an important role in this cellular switch. The exact mechanisms by which neutrophils mediate these processes are only partially understood. OBJECTIVE:: To investigate the role of neutrophils and their granule contents in the adhesion of monocyte subpopulations in acute inflammation. METHODS AND RESULTS:: Here, we show that neutrophil-derived cathelicidins (human: LL37, mouse: CRAMP) induce adhesion of classical monocytes but not of nonclassical monocytes in the mouse cremaster muscle and in in vitro flow chamber assays. CRAMP is released from emigrated neutrophils and then transported across the endothelium, where it is presented to rolling leukocytes. Endothelial-bound cathelicidin activates formyl-peptide receptor 2 on classical monocytes, resulting in monocytic β1- and β2-integrin conformational change toward an extended, active conformation that allows for adhesion to their respective ligands, vascular cell adhesion molecule 1 and intercellular adhesion molecule 1. CONCLUSIONS:: These data elucidate a novel mechanism of neutrophil-mediated monocyte recruitment, which could be targeted in conditions where recruitment of classical monocytes plays an unfavorable role. © 2013 American Heart Association, Inc.


Ye Q.,Zhejiang University | Ye Q.,Zhejiang University of Technology | Shen Y.,Anyang Institute of Technology | Zhou Y.,National Center for Drug Screening | And 4 more authors.
European Journal of Medicinal Chemistry | Year: 2013

A series of 7-azaindazolyl-indolyl-maleimides were designed, synthesized and evaluated for their GSK-3β inhibitory activity. Most compounds exhibited potent activity against GSK-3β. Among them, compounds 17a, 17b, 17g, 17i, 29a and 30 significantly reduced Aβ-induced Tau hyperphosphorylation, showin;g the inhibition of GSK-3β at the cell level. Preliminary structure-activity relationships were discussed based on the experimental data obtained. © 2013 Elsevier Masson SAS. All rights reserved.


Huang W.,Zhejiang University | Lv D.,Zhejiang University | Yu H.,National Center for Drug Screening | Sheng R.,Zhejiang University | And 5 more authors.
Bioorganic and Medicinal Chemistry | Year: 2010

Dual-target-directed 1,3-diphenylurea derivatives were designed by hybridizing BACE 1 inhibitor 1 with metal chelator LR-90. A database consisted of 1,3-diphenylurea derivatives was built and screened by the pharmacophore model (Hypo 1) of BACE 1 inhibitor. Based on the predicted results, 11 compounds (6a-d, 9a-g) with favorable Fitvalues were selected, synthesized and evaluated for their BACE 1 inhibitory activities, which showed that the predicted results were in good agreement with the experimental values. Besides, the synthesized compounds also displayed the ability to chelate metal ions. The most effective BACE 1 inhibitor 9f (27.85 ± 2.46 μmol/L) was selected for further receptor-binding studies, the result of which indicated that an essential hydrogen bonds was formed between the urea group of 9f and the catalytic aspartate Asp228. © 2010 Elsevier Ltd.


Zhang H.-Q.,East China Normal University | Zhang Q.-Y.,East China Normal University | Li J.,National Center for Drug Screening | Liu D.,East China Normal University | And 2 more authors.
Gaodeng Xuexiao Huaxue Xuebao/Chemical Journal of Chinese Universities | Year: 2012

Two vanadium-amino acid-hydroxylamido complexes, [VO(NH 2O) 2 (C 5H 10O 2N)](1) and K[VO(NH 2O) 2 (C 6H 12NO 2)] 2Cl · H 2O(2) were synthesized. Their structures and components were characterized by elemental analysis, IR spectrometry, UV-Vis spectrometry, thermal analysis and X-ray single crystal diffraction and their PTP1B inhibitory activities were also explored. Complexes 1 and 2 both crystallize in triclinic system with space group P1[TX-*8]. The central vanadium and seven coordinated atoms form a distorted pentagonal bipyramidal. Two O atoms and three N atoms from hydroxylamine and amino-acids define an equatorial plane approximately perpendicular to V[CDS1]O. The N of hydroxylamine is cis to N of amino-acids and the O of amino-acids is trans to V[CDS1]O. Complex 2 displays a good inhibitory activity against PTP1B(inhibition rate is 90.51% at 20 μg/mL).


Huang W.,Zhejiang University | Huang W.,Chinese Institute of Materia Medica | Tang L.,Zhejiang University | Shi Y.,Zhejiang University | And 7 more authors.
Bioorganic and Medicinal Chemistry | Year: 2011

A novel series of quinoxaline derivatives, as Multi-Target-Directed Ligands (MTDLs) for AD treatment, were designed by lending the core structural elements required for H 3R antagonists and hybridizing BACE 1 inhibitor 1 with AChE inhibitor BYYT-25. A virtual database consisting of quinoxaline derivatives was first screened on a pharmacophore model of BACE 1 inhibitors, and then filtered by a molecular docking model of AChE. Seventeen quinoxaline derivatives with high score values were picked out, synthesized and evaluated for their biological activities. Compound 11a, the most effective MTDL, showed the potent activity to H 3R/AChE/BACE 1 (H 3R antagonism, IC 50 = 280.0 ± 98.0 nM; H 3R inverse agonism, IC 50 = 189.3 ± 95.7 nM; AChE, IC 50 = 483 ± 5 nM; BACE 1, 46.64 ± 2.55% inhibitory rate at 20 μM) and high selectivity over H 1R/H 2R/H 4R. Furthermore, the protein binding patterns between 11a and AChE/BACE 1 showed that it makes several essential interactions with the enzymes. © 2011 Elsevier Ltd. All rights reserved.

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