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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

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). Source

Li J.,National Center for Drug Screening | Zou Y.,CAS Shanghai Institute of Materia Medica | Xu L.,National Center for Drug Screening | Chen W.,CAS Shanghai Institute of Materia Medica | And 12 more authors.
European Journal of Medicinal Chemistry

We recently discovered and reported dual inhibitor 5 of AChE and BACE1 with N-benzylpiperidine ethyl as C-terminus. Compound 5 showed potent inhibitory activities for BACE1, and could reduce endogenous Aβ1-40 production in APP transgenic mice. In present work, we rapidly identified substituted triazole as the C-terminus of compound 5 by replacing the benzylpiperidine ethyl group with click chemistry and tested these synthesized compounds by in situ screening assay. As revealed by the crystal structures of BACE1 in complex with our triazole compound 12, we found that Pro70 and Thr72 located in the flap region were the critical components for binding with these inhibitors. With the aid of the crystal structure, a new series of five-membered heterocyclic compounds was prepared in order to explore the structure-activity relationship (SAR) of this class of molecules. From these efforts, pyrazole was discovered as a novel C-terminus of BACE1 inhibitors. After further modification of pyrazole with variable substituents, compound 37 exhibited good potency in enzyme inhibition assay (IC50 = 0.025 μM) and compound 33 showed moderate inhibition effects on Aβ production of APP transfected HEK293 cells. Moreover, these pyrazole derivatives demonstrated good selectivity versus cathepsin D. Our results indicated that the vicinity of Pro70 and Thr72 might be utilized as a subsite, and the discovered pyrazole derivatives might provide useful hints for developing novel BACE1 inhibitors as anti-AD drugs. © 2013 Elsevier Masson SAS. All rights reserved. Source

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

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. Source

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

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. Source

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

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. Source

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