Studies on the inhibitory mechanism of new terpyridine platinum(II) complexes toward mammalian topoisomerases, human thioredoxin reductase 1 and cysteine proteases
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) co...
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ndltd-TW-099YM0055500132015-10-13T20:37:08Z http://ndltd.ncl.edu.tw/handle/57002084508256200293 Studies on the inhibitory mechanism of new terpyridine platinum(II) complexes toward mammalian topoisomerases, human thioredoxin reductase 1 and cysteine proteases 新三聯吡啶類鉑錯合物對哺乳類拓樸異構酶、人類第一型硫氧還原蛋白還原酶和半胱氨酸蛋白酶抑制作用機制的研究 Yan-Chung Lo 羅彥中 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. Andrew H.-J. Wang 王惠鈞 2011 學位論文 ; thesis 86 en_US |
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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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author2 |
Andrew H.-J. Wang |
author_facet |
Andrew H.-J. Wang Yan-Chung Lo 羅彥中 |
author |
Yan-Chung Lo 羅彥中 |
spellingShingle |
Yan-Chung Lo 羅彥中 Studies on the inhibitory mechanism of new terpyridine platinum(II) complexes toward mammalian topoisomerases, human thioredoxin reductase 1 and cysteine proteases |
author_sort |
Yan-Chung Lo |
title |
Studies on the inhibitory mechanism of new terpyridine platinum(II) complexes toward mammalian topoisomerases, human thioredoxin reductase 1 and cysteine proteases |
title_short |
Studies on the inhibitory mechanism of new terpyridine platinum(II) complexes toward mammalian topoisomerases, human thioredoxin reductase 1 and cysteine proteases |
title_full |
Studies on the inhibitory mechanism of new terpyridine platinum(II) complexes toward mammalian topoisomerases, human thioredoxin reductase 1 and cysteine proteases |
title_fullStr |
Studies on the inhibitory mechanism of new terpyridine platinum(II) complexes toward mammalian topoisomerases, human thioredoxin reductase 1 and cysteine proteases |
title_full_unstemmed |
Studies on the inhibitory mechanism of new terpyridine platinum(II) complexes toward mammalian topoisomerases, human thioredoxin reductase 1 and cysteine proteases |
title_sort |
studies on the inhibitory mechanism of new terpyridine platinum(ii) complexes toward mammalian topoisomerases, human thioredoxin reductase 1 and cysteine proteases |
publishDate |
2011 |
url |
http://ndltd.ncl.edu.tw/handle/57002084508256200293 |
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