Terpyridine–platinum(II) complexes are effective inhibitors of mammalian topoisomerases and human thioredoxin reductase 1

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 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.