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    Designing anticancer copper(II) complexes by optimizing 2-pyridine-thiosemicarbazone ligands

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    Publication date
    2018-10
    Author
    Deng, J.
    Yu, P.
    Zhang, Z.
    Wang, J.
    Cai, J.
    Wu, Na (Anna)
    Sun, H.
    Liang, H.
    Yang, F.
    Keyword
    Cu(II) complexes
    Thiosemicarbazone
    Anticancer
    p53
    Telomerase
    Rights
    © 2018 Elsevier Masson SAS. All rights reserved. Reproduced in accordance with the publisher's self-archiving policy. This manuscript version is made available under the CC-BY-NC-ND 4.0 license.
    Peer-Reviewed
    Yes
    
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    Abstract
    To develop potential next-generation metal anticancer agents, we designed and synthesised five Cu(II) 2-pyridine-thiosemicarbazone complexes by modifying the hydrogen atom at the N-4 position of ligands, and then investigated their structure-activity relationships and anticancer mechanisms. Modification of the N-4 position with different groups caused significant differences in cellular uptake and produced superior antitumor activity. Cu complexes arrested the cell cycle at S phase, leading to down-regulation of levels of cyclin and cyclin-dependent kinases and up-regulation of expression of cyclin-dependent kinase inhibitors. Cu complexes exerted chemotherapeutic effects via activating p53 and inducing production of reactive oxygen species to regulate expression of the B-cell lymphoma-2 family of proteins, causing a change in the mitochondrial membrane potential and release of cytochrome c to form a dimer with apoptosis protease activating factor-1, resulting in activation of caspase-9/3 to induce apoptosis. In addition, Cu complexes inhibited telomerase by down-regulating the c-myc regulator gene and expression of the human telomerase reverse transcriptase.
    URI
    http://hdl.handle.net/10454/17847
    Version
    Accepted Manuscript
    Citation
    Deng J, Yu P, Zhang Z et al (2018) Designing anticancer copper(II) complexes by optimizing 2-pyridine-thiosemicarbazone ligands. European Journal of Medicinal Chemistry. 158: 442-452.
    Link to publisher’s version
    https://doi.org/10.1016/j.ejmech.2018.09.020
    Type
    Article
    Collections
    Life Sciences Publications

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