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Designing anticancer copper(II) complexes by optimizing 2-pyridine-thiosemicarbazone ligands
Deng, J. Yu, P. Zhang, Z. Wang, J. Cai, J. Sun, H. Liang, H. Yang, F.
Deng, J.
Yu, P.
Zhang, Z.
Wang, J.
Cai, J.
Sun, H.
Liang, H.
Yang, F.
Publication Date
2018-10
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© 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.
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openAccess
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08/09/2018
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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.
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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.
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Article