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研究生:潘昶佑
研究生(外文):Chang Yu Pan
論文名稱:利用生物分子交互作用分析微量熱儀建立金屬離子螯合劑之活性評估方法
論文名稱(外文):Establishment of Bioactive Evaluation System For Metal Ion Chelating Agents Using Isothermal Titration Calorimetry
指導教授:謝珮文謝珮文引用關係
指導教授(外文):P. W. Hsieh
學位類別:碩士
校院名稱:長庚大學
系所名稱:中醫學系天然藥物
學門:醫藥衛生學門
學類:藥學學類
論文種類:學術論文
論文出版年:2016
畢業學年度:104
語文別:中文
論文頁數:226
中文關鍵詞:神經退化性疾病癌症金屬離子螯合劑生物分子交互作用分析微量熱儀
外文關鍵詞:neurodegenerative diseasescancerchelating agentsisothermal titration .calorimetry (ITC)
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近年來,神經退化性疾病 (neurodegenerative diseases) 與癌症的發生已被證實與人體內金屬離子 (metal ions) 的增加有關。因此金屬螯合劑 (chelating agents) 的開發被認為是治療或改善上述疾病的嶄新策略。為了探索新型金屬離子螯合劑,本研究擬利用生物分子交互作用分析微量熱儀 (isothermal titration calorimetry,ITC) 來建立一個可以應用於鋅離子螯合劑開發的活性評估平台,以利發現新的先導化合物 (lead compound) 或萃取物。首先,我們嘗試以目前醫療用之鋅離子螯合劑作為正對照藥物,再相同的實驗條件進行各種金屬離子之螯合試驗。結果顯示,由藥物濃度 1.5 mM 之氯化鋅 (ZnCl2) 分別滴定 0.2 mM DTPA (KD:1.46 ± 0.06 μM) 及 TPEN (KD:0.51 ± 0.03 μM) 等鋅離子螯合劑,以含 1% dimethyl sufoxide (DMSO) 之超純水水溶液做為緩衝液,可得到一個具有可信度的分析數據。此外,為了提升本平台篩選藥物之敏感度,藉由 ligand-displacement ITC (LDITC) 之競爭型模式來加強其敏感度,以藥物濃度 1.2 mM DTPA 及 TPEN 分別滴定 0.2 mM ZnCl2/0.2 mM etidronic acid (HEDP)、0.2 mM ZnCl2/0.2 mM suberoylailide hydroxamic acid (SAHA) 及 0.1 mM ZnCl2/0.2 mM oxytetracycline (OTC)、0.1 mM ZnCl2/0.1 mM clioquinol (CQ) 之混和液,可確定 HEDP、SAHA、OTC、CQ之 KD 值分別為 0.98 ± 0.04、0.74 ± 0.08 、1.19 ± 0.18 μM、與1.05 ± 0.20 μM。因此進一步利用 LDITC 分析方法,來篩選化學資料庫之化合物之螯合鋅離子之能力。研究結果顯示化合物 DSM-RX78、WHH30、DSM-RX116 及 WHH22 之 KD 值分別為0.29 ± 0.09, 0.33 ± 0.01, 0.35 ± 0.08, and 0.37 ± 0.00 μM,具有極佳的螯合鋅離子能力,期許未來可作為治療神經退化性疾病及癌症之治療藥物。

Recently, metal ions interferences in human body have been shown to highly correlate with neurodegenerative diseases and cancers, whereas development of effective metal ions chelating agents is considered as a therapeutic strategy for these diseases. The aim of this study is to set up a screening platform using isothermal titration .calorimetry (ITC) and to discover potent zinc ion chelating agents from pure compounds or extracts libraries. Firstly, chelating agents, DTPA and TPEN, were used as positive controls to determine their chelating effects on metal ions under the same experimental condition; DTPA or TPEN in 1% DMSO aqueous solution titrating to 1.5 mM ZnCl2 in 1% DMSO aqueous solution, respectively, and the results revealed that the affinity (KD) of TPEN and DTPA were 0.51 ± 0.03 and 1.46 ± 0.06 μM 0.2 M, respectively. Secondly, in order to improve the sensitivity of the results of bio-evaluation, a ligand-displacement ITC (LDITC) model, was used to evaluate the chelating effects of positive controls. The results demonstrates the affinity (KD) of HEDP, SHSA, oxytetracycline (OTC), and clioquinol (CQ) were 0.98 ± 0.04, 0.74 ± 0.08 and 1.19 ± 0.18, and 1.05 ± 0.20 μM, respectively. Finally, the LDITC competitive model was further to evaluate the chelating effects of compounds from the chemical library, and then demonstrated that compounds DSM-RX78, WHH30, DSM-RX116, and WHH22 showed potently chelating effects on Zn2+ ion with KD values at 0.29 ± 0.09, 0.33 ± 0.01, 0.35 ± 0.08, and 0.37 ± 0.00 μM, respectively. These compounds were able to approve as candidate compounds for treating neurodegenerative diseases and cancers.
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致謝 iii
摘要 iv
Abstract v
目錄 vi
表目錄 viii
圖目錄 x
第一章 緒論 1
第一節 前言 1
第二節 組蛋白去乙醯化酶抑制劑 (histone deacetylases inhibitor,HDACIs) 2
第三節 阿茲海默症 (Alzheimer’s disease,AD) 12
第四節 土黴素 (oxytetracycline,OTC) 16
第五節 氯碘羥 (clioquinol,CQ) 18
第六節 螯合劑 (chelating agents) 21
第七節 生物分子交互作用分析微量熱儀 (isothermal titration calorimetry, ITC) 29
第二章 研究動機 41
第三章 實驗材料與方法 43
第一節 實驗材料與儀器 43
第二節 實驗試劑 45
第三節 實驗方法 47
第四章 實驗結果 50
第一節 以 customary ITC 分析方法之建立 50
第二節 以 customary ITC 分析方法來評估臨床藥物之活性測試 68
第三節 以 ligand-displacement ITC (LDITC) 分析方法來評估臨床藥物之活性測試 76
第四節 以 ligand-displacement ITC (LDITC) 分析方法篩選具有螯合鋅離子之化合物109
第五章 綜合討論 143
參考文獻 173
表附錄 189
圖附錄 194

表目錄
表 1-1 與金屬離子濃度高低之相關疾病表 1
表 1-2 目前國外 HDACIs 研發狀況表 8
表 1-3 常見錯離子或配位化合物之結合軌域與幾何形狀表 24
表 1-4 八面體配位化合物之配穩場穩定化能能量表 26
表 1-5 有機團及官能基於螯合劑之應用表 27
表 3-1 緩衝溶液之 pH 值校正溶液表 47
表 3-2 實驗參數表 49
表 4-1 以 1.5 mM ZnCl2 滴定 0.2 mM TPEN 於 iTC200 之測試結果表...........51
表 4-2 以 1.2 mM Cl2O8Zn 滴定 0.16 mM TPEN 於 iTC200 之測試結果表.....51
表 4-3 以 3.0 mM ZnCl2 滴定 0.8 mM HEDP 於 iTC200 之測試結果表...........51
表 4-4 以 1.5 mM ZnCl2 滴定 0.2 mM DTPA 於 iTC200 之測試結果表 ...........52
表 4-5 鋅離子螯合劑螯合 Zn2+ 於 iTC200 之測試結果總表...............................52
表 4-6 以 1.2 mM DTPA 滴定 0.2 mM ZnCl2 於 iTC200 之測試結果表 ...........77
表 4-7 以 1.2 mM TPEN 滴定 0.1 mM ZnCl2 於 iTC200 之測試結果表...........77
表 4-8 以 1.2 mM DTPA 滴定 0.2 mM ZnCl2/0.2 mM HEDP 混和液於 iTC200之測試結果表 84
表 4-9 以 1.2 mM DTPA 滴定 0.2 mM ZnCl2/0.2 mM SAHA 混和液於 iTC200之測試結果表 84
表 4-10 以 1.2 mM TPEN 滴定 0.1 mM ZnCl2/0.2 mM SAHA 混和液於 iTC200之測試結果表 84
表 4-11 以 1.2 mM TPEN 滴定 0.1 mM ZnCl2/0.2 mM OTC 混和液於 iTC200之測試結果表 85
表 4-12 以 1.2 mM TPEN 滴定 0.1 mM ZnCl2/0.1 mM CQ 混和液於 iTC200之測試結果表 85
表 4-13 以 LDITC 測試鋅離子螯合性藥物於 iTC200 之親和力結果總表........85
表 4-14 以 TPEN 競爭型平台篩選出具有螯合鋅離子化合物於 iTC200 之親和力測試結果表 111
表 4-15 以 DTPA 競爭型平台篩選出具有螯合鋅離子化合物於 iTC200 之親和力測試結果表 111
表 5-1 以 1.5 mM Cl2O8Zn 滴定 0.2 mM TPEN 於 iTC200 之測試結果表......144
表 5-2 以 1.5 mM ZnCl2 滴定 0.2 mM HEDP 於 iTC200 之測試結果表 .........146

圖目錄
圖 1-1 染色質重組過程 3
圖 1-2 組蛋白乙醯化後染色質及基因的表達 3
圖 1-3 SAHA 之結構圖 9
圖 1-4 Zn2+ 與 HDACs8 結合位置 10
圖 1-5 SAHA 與 HDACs1 結合於 x-ray 晶體繞射研究結構............................10
圖 1-6 TSA 與 HDACs1 於 x-ray 晶體繞射研究結構........................................11
圖 1-7 阿茲海默症患部透視圖 13
圖 1-8 阿茲海默症三大假說示意圖 13
圖 1-9 雙功能螯合劑設計概念圖 15
圖 1-10 Oxytetracycline 之結構圖 16
圖 1-11 Chlortetracycline 之結構圖 17
圖 1-12 Demeclocycline 之結構圖 17
圖 1-13 Clioquinol 之結構圖 18
圖 1-14 Clioquinol 螯合 Zn2+ 於 x-ray 晶體繞射研究之分子結構 19
圖 1-15 Clioquinol 螯合 Cu2+ 於 x-ray 晶體繞射研究之分子結構 19
圖 1-16 5,7-diiodo-8-hydroxyquinoline 之結構 20
圖 1-17 PBT-2 之結構 1
圖 1-18 能級分裂後之 d 軌域空間分佈 25
圖 1-19 八面體晶體能級分裂圖 25
圖 1-20 八面體配位場穩定化能 26
圖 1-21 氨基羧酸鹽類之螯合劑 28
圖 1-22 磷酸鹽類之螯合劑 28
圖 1-23 羧酸類之螯合劑 29
圖 1-24 iTC200 儀器裝置圖 30
圖 1-25 iTC200 吸熱實驗圖 32
圖 1-26 iTC200 放熱實驗圖 32
圖 1-27 iTC200 偵測熱量概要圖 33
圖 1-28 C 值大小範圍曲線圖 34
圖 1-29 以 one sets of sites 分析模式之數據圖 35
圖 1-30 以 two sets of sites 分析模式之數據圖 36
圖 1-31 以 sequential binding sites 分析模式之數據圖 37
圖 1-32 以 competitive binding 分析模式之數據圖 38
圖 2-1 實驗架構圖 42
圖 3-1 Customary ITC 背景樣品製備示意圖 48
圖 3-2 LDITC 背景樣品製備示意圖 48
圖 3-3 iTC200 超純水校正實驗滴定圖 49
圖 4-1 以 1.5 mM ZnCl2 滴定 1% DMSO 超純水緩衝溶液之實驗結果...........53
圖 4-2 以 1% DMSO 超純水緩衝溶液滴定 0.2 mM TPEN 之實驗結果...........54
圖 4-3 1.5 mM ZnCl2 與 0.2 mM TPEN 於 iTC200 實驗結果.............................55
圖 4-4 TPEN 螯合 Zn2+ 之結構 57
圖 4-5 以 1.2 mM Cl2O8Zn 滴定 1% DMSO 超純水緩衝溶液之實驗結果.......58
圖 4-6 以 1% DMSO 超純水緩衝溶液滴定 0.16 mM TPEN 之實驗結果.........59
圖 4-7 1.2 mM Cl2O8Zn 與 0.16 mM TPEN 於 iTC200 實驗結果.......................59
圖 4-8 以 3.0 mM ZnCl2 滴定 1% DMSO 超純水緩衝溶液之實驗結果...........61
圖 4-9 以 1% DMSO 超純水緩衝溶液滴定 0.8 mM HEDP 之實驗結果 ..........61
圖 4-10 3.0 mM ZnCl2 與 0.8 mM HEDP 於 iTC200 實驗結果...........................62
圖 4-11 HEDP 螯合 Zn2+ 之結構 64
圖 4-12 以 1.5 mM ZnCl2 滴定 1 % DMSO 超純水緩衝溶液之實驗結果........65
圖 4-13 以 1% DMSO 超純水緩衝溶液滴定 0.2 mM DTPA 之實驗結果.........65
圖 4-14 1.5 mM Cl2O8Zn 與 0.2 mM DTPA 於 iTC200 實驗結果.......................66
圖 4-15 DTPA 螯合 Zn2+ 之結構 67
圖 4-16 以 1.5 mM ZnCl2 滴定 1 % DMSO 超純水緩衝溶液之實驗結果........69
圖 4-17 以 1% DMSO 超純水緩衝溶液滴定 0.2 mM SAHA 之實驗結果........69
圖 4-18 1.5 mM ZnCl2 與 0.2 mM SAHA 於 iTC200 實驗結果 ..........................70
圖 4-19 以 1.5 mM ZnCl2 滴定 1 % DMSO 超純水緩衝溶液之實驗結果........71
圖 4-20 以 1% DMSO 超純水緩衝溶液滴定 0.2 mM OTC 之實驗結果...........72
圖 4-21 1.5 mM ZnCl2 與 0.2 mM OTC 於 iTC200 實驗結果.............................73
圖 4-22 以 1.5 mM ZnCl2 滴定 1 % DMSO 超純水緩衝溶液之實驗結果........74
圖 4-23 以 1% DMSO 超純水緩衝溶液滴定 0.2 mM CQ 之實驗結果.............74
圖 4-24 1.5 mM ZnCl2 與 0.2 mM CQ 於 iTC200 實驗結果 ...............................75
圖 4-25 以 1.2 mM DTPA 滴定 1 % DMSO 超純水緩衝溶液之實驗結果........78
圖 4-26 以 1% DMSO 超純水緩衝溶液滴定 0.2 mM ZnCl2 之實驗結果.........78
圖 4-27 1.2 mM DTPA 與 0.2 mM ZnCl2 於 iTC200 實驗結果...........................79
圖 4-28 以 1.2 mM TPEN 滴定 1 % DMSO 超純水緩衝溶液之實驗結果........81
圖 4-29 以 1% DMSO 超純水緩衝溶液滴定 0.1 mM ZnCl2 之實驗結果.........81
圖 4-30 1.2 mM TPEN 與 0.1 mM ZnCl2 於 iTC200 實驗結果...........................82
圖 4-31 以 1.2 mM DTPA 滴定 0.2 mM HEDP 於 1% DMSO 超純水緩衝溶液之實驗結果 86
圖 4-32 以 1% DMSO 超純水緩衝溶液滴定 0.2 mM ZnCl2/0.2 mM HEDP 混和液之實驗結果 87
圖 4-33 1.2 mM DTPA 與 0.2 mM ZnCl2/0.2 mM HEDP 混和液於 iTC200 實驗結果 88
圖 4-34 以 DTPA 競爭型平台測試 0.2 mM HEDP 之熱焓變化圖 ....................89
圖 4-35 以 1.2 mM DTPA 滴定 0.2 mM SAHA 於 1% DMSO 超純水緩衝溶
圖 4-35 液之實驗結果 90
圖 4-36 以 1% DMSO 超純水緩衝溶液滴定 0.2 mM ZnCl2/0.2 mM SAHA 混和液之實驗結果 91
圖 4-37 1.2 mM DTPA 與 0.2 mM ZnCl2/0.2 mM SAHA 混和液於 iTC200 實驗結果 92
圖 4-38 以 DTPA 競爭型平台測試 0.2 mM SAHA 之熱焓變化圖....................93
圖 4-39 以 1.2 mM DTPA 滴定 0.2 mM OTC 於 1% DMSO 超純水緩衝溶之實驗結果 95
圖 4-40 以 1% DMSO 超純水緩衝溶液滴定 0.2 mM ZnCl2/0.2 mM OTC 混和液之實驗結果 95
圖 4-41 1.2 mM DTPA 與 0.2 mM ZnCl2/0.2 mM OTC 混和液於 iTC200 實驗結果 96
圖 4-42 以 1.2 mM TPEN 滴定 0.2 mM SAHA 於 1% DMSO 超純水緩衝溶液之實驗結果 97
圖 4-43 以 1% DMSO 超純水緩衝溶液滴定 0.1 mM ZnCl2/0.2 mM SAHA 混和液之實驗結果 97
圖 4-44 1.2 mM TPEN 與 0.1 mM ZnCl2/0.2 mM SAHA 混和液於 iTC200 實驗結果 98
圖 4-45 以 TPEN 競爭型平台測試 0.2 mM SAHA 之熱焓變化圖..................100
圖 4-46 以 1.2 mM TPEN 滴定 0.2 mM OTC 於 1% DMSO 超純水緩衝溶液之實驗結果 101
圖 4-47 以 1% DMSO 超純水緩衝溶液滴定 0.1 mM ZnCl2/0.2 mM OTC 混液之實驗結果 101
圖 4-48 1.2 mM TPEN 與 0.1 mM ZnCl2/0.2 mM OTC 混和液於 iTC200 實驗結果 102
圖 4-49 以 TPEN 競爭型平台測試 0.2 mM OTC 之熱焓變化圖.....................104
圖 4-50 以 1.2 mM TPEN 滴定 0.1 mM CQ 於 1% DSMO 超純水緩衝溶之實驗結果 105
圖 4-51 以 1% DMSO 超純水緩衝溶液滴定 0.1 mM ZnCl2/0.1 mM CQ 混和液之實驗結果 105
圖 4-52 1.2 mM TPEN 與 0.1 mM ZnCl2/0.1 mM CQ 混和液於 iTC200 實驗結果 106
圖 4-53 以 TPEN 競爭型平台測試 0.1 mM CQ 之熱焓變化圖.......................107
圖 4-54 本研究篩選之化合物 110
圖 4-55 以 1.2 mM TPEN 滴定 0.1 mM SMP3 於 1% DSMO 超純水緩衝溶液之實驗結果 112
圖 4-56 1.2 mM TPEN 與 0.1 mM ZnCl2/0.1 mM SMP3 混和液於 iTC200 實驗結果 113
圖 4-57 1.2 mM TPEN 與 0.1 mM ZnCl2/0.1 mM DSM-RX78 (左) 及 0.1 mMZnCl2/0.1 mM DSM-RX116 (右) 混和液於 iTC200 實驗結果................114
圖 4-58 以 TPEN 競爭型平台測試 0.1 mM DSM-RX78 之熱焓變化圖.........115
圖 4-59 以 TPEN 競爭型平台測試 0.1 mM DSM-RX116 之熱焓變化圖.......116
圖 4-60 1.2 mM DTPA 與 0.2 mM ZnCl2/0.1 mM DSM-RX78 (左)、0.2 mMZnCl2/0.1 mM DSM-RX116 (中) 及 0.2 mM ZnCl2/0.1 mM SMP3 (右)混和液於 iTC200 實驗結果 118
圖 4-61 以 DTPA 競爭型平台測試 0.1 mM DSM-RX78 之熱焓變化圖.........119
圖 4-62 以 DTPA 競爭型平台測試 0.1 mM DSM-RX116 之熱焓變化圖.......120
圖 4-63 以 DTPA 競爭型平台測試 0.1 mM SMP3 之熱焓變化圖 ..................120
圖 4-64 1.2 mM TPEN 與 0.1 mM ZnCl2/0.2 mM WHH22 (左)、0.1 mM ZnCl2/0.2 mM WHH30 (中) 及 0.1 mM ZnCl2/0.1 mM WHH46 (右) 混和液於 iTC200 實驗結果 122
圖 4-65 以 TPEN 競爭型平台測試 0.2 mM WHH22 之熱焓變化圖 ..............123
圖 4-66 以 TPEN 競爭型平台測試 0.2 mM WHH30 之熱焓變化圖 ..............124
圖 4-67 以 TPEN 競爭型平台測試 0.1 mM WHH46 之熱焓變化圖 ..............124
圖 4-68 以 1.2 mM TPEN 滴定 0.1 mM WWH31 於 1% DSMO 超純水緩衝溶液之實驗結果 127
圖 4-69 1.2 mM DTPA 與 0.2 mM ZnCl2/0.1 mM WWH31 混和液於 iTC200實驗結果 128
圖 4-70 以 DTPA 競爭型平台測試 0.1 mM WWH31 之熱焓變化圖..............129
圖 4-71 1.2 mM TPEN 與 0.1 mM ZnCl2/0.1 mM JYL-RX0 (左) 及 0.1 mMZnCl2/0.1 mM JYL-RX2 (右) 混和液於 iTC200 實驗結果.....................131
圖 4-72 以 TPEN 競爭型平台測試 0.1 mM JYL-RX0 之熱焓變化圖............132
圖 4-73 以 TPEN 競爭型平台測試 0.1 mM JYL-RX2 之熱焓變化圖............132
圖 4-74 1.2 mM TPEN 與 0.1 mM ZnCl2/0.1 mM HCH6-1 混和液於 iTC200實驗結果 134
圖 4-75 以 TPEN 競爭型平台測試 0.1 mM HCH6-1 之熱焓變化圖..............136
圖 4-76 1.2 mM TPEN 與 0.1 mM ZnCl2/0.2 mM ITA-02 混和液於 iTC200 實驗結果 137
圖 4-77 以 TPEN 競爭型平台測試 0.2 mM ITA-02 之熱焓變化圖 ................138
圖 4-78 以 1.2 mM TPEN 滴定 0.1 mM 3,5-DCQA 於 1% DSMO 超純水緩衝溶液之實驗結果 140
圖 4-79 1.2 mM DTPA 與 0.2 mM ZnCl2/0.2 mM 3,5-DCQA 混和液於 iTC200實驗結果 141
圖 4-80 以 DTPA 競爭型平台測試 0.2 mM 3,5-DCQA 之熱焓變化圖...........142
圖 5-1 以 1.5 mM Cl2O8Zn 滴定 0.2 mM TPEN 於 iTC200 之測試結果..........144
圖 5-2 以 1.5 mM ZnCl2 滴定 0.2 mM HEDP 於 iTC200 之測試結果 .............146
圖 5-3 以 4.0 mM ZnCl2 滴定 1% DMSO 超純水緩衝溶液之實驗結果.........147
圖 5-4 以 5.0 mM ZnCl2 滴定 1% DMSO 超純水緩衝溶液之實驗結果.........147
圖 5-5 HEDP 螯合 Zn2+ 之結構 147
圖 5-6 HEDP 螯合 Zn2+ 於 x-ray 晶體繞射研究之分子結構..........................148
圖 5-7 TPEN 螯合 Zn2+ 於 x-ray 晶體學研究之分子結構 ..............................148
圖 5-8 HEDP 螯合 Cu+ 於 x-ray 晶體學研究之分子結構 ...............................148
圖 5-9 DTPA 螯合 Cu+ 於 x-ray 晶體繞射研究之分子結構............................149
圖 5-10 DTPA 螯合 Zn2+ 於 x-ray 晶體繞射研究之分子結構.........................149
圖 5-11 鋅離子螯合劑螯合 Zn2+ 於 iTC200 之熱力學參數量化圖...................150
圖 5-12 以 1.2 mM TPEN 分別滴定 0.2 mM HEDP (左) 與 0.2 mM DTPA (右)混和液於 iTC200 實驗結果 153
圖 5-13 以 1.2 mM TPEN 分別滴定 0.1 mM ZnCl2/0.2 mM HEDP 混和液 (左)與 0.1 mM ZnCl2/0.2 mM DTPA 混和液 (右) 於 iTC200 實驗結果 ...153
圖 5-14 以 LDITC 測試鋅離子螯合性藥物於 iTC200 之親和力 (KD) 量化圖 154
圖 5-15 HPW-01 之結構 156
圖 5-16 Aurantiamide acetate 之結構 158
圖 5-17 以 1.2 mM TPEN 滴定 0.2 mM WHH46 於 1% DSMO 超純水緩衝溶液之實驗結果 159
圖 5-18 JYL-RXB 之結構 160
圖 5-19 1.5 mM ZnCl2 與 0.2 mM JYL-RXB 於 iTC200 實驗結果..................161
圖 5-20 以 LDITC 測試鋅離子螯合性藥物於 iTC200 之親和力 (KD) 量化圖(A) TPEN 競爭型平台 (B) DTPA 競爭型平台......................................161
圖 5-21 以 DS 電腦分子模擬軟體擬合 (fit) Zinc-TPEN (左)、Zinc-sirtinol (中)及 Zinc-CQ (右) 之配位化合物 63
圖 5-22 Sirtinol 螯合 Cu2+ 於 x-ray 晶體繞射研究之分子結構 ......................163
圖 5-23 以 DS 電腦分子模擬軟體擬合 (fit) Zinc-TPEN 之配位鍵鍵長 .........164
圖 5-24 以 DS 電腦分子模擬軟體擬合 (fit) Zinc-sirtinol 之配位鍵鍵長........164
圖 5-25 以 DS 電腦分子模擬軟體擬合 (fit) 擬合 Zinc-CQ 之配位鍵鍵長...164
圖 5-26 以 DS 電腦分子模擬軟體擬合 (fit) Zinc-DSM-RX78 (左)、Zinc-DSM-
圖 5-26 RX116 (中) 及 Zinc-SMP3 (右) 之配位化合物 165
圖 5-27 以 DS 電腦分子模擬軟體擬合 (fit) Zinc-DSM-RX78 之配位鍵鍵長 166
圖 5-28 以 DS 電腦分子模擬軟體擬合 (fit) Zinc-DSM-RX116 之配位鍵鍵長 166
圖 5-29 以 DS 電腦分子模擬軟體擬合 (fit) Zinc-SMP3 之配位鍵鍵長.........166
圖 5-30 以 DS 電腦分子模擬軟體擬合 (fit) Zinc-WHH22 (左)、Zinc-WHH30(中) 及 Zinc-WHH46 (右) 之配位化合物 167
圖 5-31 以 DS 電腦分子模擬軟體擬合 (fit) Zinc-WHH22 之配位鍵鍵長.....168
圖 5-32 以 DS 電腦分子模擬軟體擬合 (fit) Zinc-WHH30 之配位鍵鍵長.....168
圖 5-33 以 DS 電腦分子模擬軟體擬合 (fit) Zinc-WHH46 之配位鍵鍵長.....168
圖 5-34 以 DS 電腦分子模擬軟體擬合 (fit) Zinc-JYL-RX0 (左) 及 Zinc-JYL-RX2 之配位化合物 169
圖 5-35 以 DS 電腦分子模擬軟體擬合 (fit) Zinc-WWH31 之配位化合物....169
圖 5-36 以 DS 電腦分子模擬軟體擬合 (fit) Zinc-JYL-RX0 之配位鍵鍵長...170
圖 5-37 以 DS 電腦分子模擬軟體擬合 (fit) Zinc-JYL-RX2 之配位鍵鍵長...170
圖 5-38 以 DS 電腦分子模擬軟體擬合 (fit) Zinc-WWH31 之配位鍵鍵長....170
圖 5-39 以 DS 電腦分子模擬軟體擬合 (fit) Zn2+ 與化合物 HCH6-1 171
圖 5-40 以 DS 電腦分子模擬軟體擬合 (fit) Zn2+ 與化合物 ITA-02 ..............171
圖 5-41 以 DS 電腦分子模擬軟體擬合 (fit) Zn2+ 與化合物 3,5-DCQA ........171
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