title: Terpyridine-platinum(II) complexes are effective inhibitors of mammalian topoisomerases and human thioredoxin reductase 1.
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 thiolato[TP-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 IIalpha or topoisomerase I activity at IC(50) values of about 5 microM and 10-20 microM, respectively, whereas the human thioredoxin reductase 1 (hTrxR1) activity was inhibited with IC(50) values in the range of 58-78 nM. At the cellular level, they possessed cytotoxicity with IC(50) values between 7 and 19 microM 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.
authors.affiliation: Department and Institute of Pharmacology, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Yan-Chung
authors.initials: YC
authors.lastname: Lo
authors.forename: Tzu-Ping
authors.initials: TP
authors.lastname: Ko
authors.forename: Wen-Chi
authors.initials: WC
authors.lastname: Su
authors.forename: Tsann-Long
authors.initials: TL
authors.lastname: Su
authors.forename: Andrew H-J
authors.initials: AH
authors.lastname: Wang
mesh_terms: D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D004247:DNA / Q000378:metabolism; D004250:DNA Topoisomerases, Type II; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006367:HeLa Cells; D006801:Humans; D007364:Intercalating Agents / Q000737:chemistry / Q000494:pharmacology*; D009944:Organoplatinum Compounds / Q000737:chemistry / Q000494:pharmacology*; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology*; D054481:Thioredoxin Reductase 1 / Q000037:antagonists & inhibitors*; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors
chemical_list: D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D007364:Intercalating Agents; D009944:Organoplatinum Compounds; D011725:Pyridines; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors; D004247:DNA; D054481:Thioredoxin Reductase 1; D004250:DNA Topoisomerases, Type II