Terpyridine-platinum(II) complexes are effective inhibitors of mammalian topoisomerases and human thioredoxin reductase 1 |
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Authors: | Yan-Chung Lo Tzu-Ping Ko Wen-Chi Su Andrew H-J Wang |
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Institution: | a Department and Institute of Pharmacology, National Yang-Ming University, Taipei 112, Taiwan b Institute of Biological Chemistry, Academia Sinica, Taipei 115, Taiwan c Institute of Molecular Biology, Academia Sinica, Taipei 115, Taiwan d Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan e Core Facility for Protein Crystallography, Academia Sinica, Taipei 115, Taiwan |
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Abstract: | Terpyridine-platinum(II) (TP-Pt(II)) complexes are known to possess DNA-intercalating activity and have been regarded as potential antitumor agents. However, their cytotoxic mechanism remains unclear. To investigate the possible mechanism, a series of TP-Pt(II) compounds were prepared and their biological activities assessed. The DNA binding activities of the aromatic thiolatoTP-Pt(II)] complexes were stronger than the aliphatic 2-hydroxylethanethiolato(2,2′:6′,2′′-terpyridine)platinum(II) TP(HET)]. TP-Pt(II) complexes inhibited topoisomerase IIα or topoisomerase I activity at IC50 values of about 5 μM and 10-20 μM, respectively, whereas the human thioredoxin reductase 1 (hTrxR1) activity was inhibited with IC50 values in the range of 58-78 nM. At the cellular level, they possessed cytotoxicity with IC50 values between 7 and 19 μM against HeLa cells. Additionally, using X-ray crystallography and matrix-assisted laser desorption/ionization (MALDI) mass spectrometry, we elucidated that the TP-Pt(II) complexes inhibited hTrxR1 activity by blocking its C-terminal active-site selenocysteine. Therefore, TP-Pt(II) complexes possess inhibitory activities against multiple biological targets, and they may be further studied as anticancer agents. |
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Keywords: | Anticancer drug Synthesis DNA intercalators Cytotoxicity Crystal structure |
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