| Summary: | 博士 === 國立陽明大學 === 藥理學研究所 === 99 === 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 were 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 to 20 μM respectively, whereas the human thioredoxin reductase 1 (hTrxR1) activity was inhibited with IC50 values in the range of 58 to 78 nM. Additionally, using X-ray crystallography and matrix-assisted laser desorption/ionization (MALDI) mass spectrometry, I elucidated that the TP-Pt(II) complexes inhibited hTrxR1 activity by blocking its C-terminal active-site selenocysteine. Besides, based on the similar active-site features of hTrxR1 and cysteine proteases, I investigated the interaction between TP-Pt(II) complexes and cysteine proteases. TP-Pt(II) complexes can selectively bind to the cysteine residue in the active site of pyroglutamyl peptidase I (PGP I) and other cysteine proteases and inhibit their functions, as demonstrated by X-ray crystallography, mass spectrometry and activity assays. At the cellular level, they possessed cytotoxicity with IC50 values between 7 and 19 μM against HeLa cells. My findings here can be useful in the design of new anti-cancer, anti-parasite or anti-virus platinum(II) compounds.
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