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研究生:湯欣儀
研究生(外文):Hsin-I Tang
論文名稱:以電噴灑游離質譜技術研究具抗癌活性金屬錯合物與DNA鍵結之特性
論文名稱(外文):Characterization for Interaction of Antitumor-active Metal Complexes with Oligonucleotide by Electroespray Ionization Mass Spectrometry
指導教授:林震煌
指導教授(外文):Cheng-Huang Lin
學位類別:碩士
校院名稱:國立臺灣師範大學
系所名稱:化學研究所
學門:自然科學學門
學類:化學學類
論文種類:學術論文
論文出版年:2002
畢業學年度:90
語文別:中文
論文頁數:180
中文關鍵詞:電噴灑游離質譜法鉑族金屬化合物雙股螺旋DNA非共價鍵結共價鍵結
外文關鍵詞:Electrospray ionization mass spectrometryOligonucleotideRu-complexesderivatives of azole-bridged dinuclear platinum (Ⅱ) complexionic/electrostatic forcePt-N coordination bond
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本論文主要以軟性的「電噴灑游離質譜法(Electrospray ionization mass spectrometry)」,提供一個方便、快速的方法,研究具有抗癌活性的鉑族金屬化合物與DNA之間的鍵結關係,做為將來雙股螺旋DNA非共價鍵結及藥物設計的基礎研究。
  論文分成三大部分,其一,研究具有抗癌活性Ru金屬化合物對於單股DNA上鹼基G位置的選擇性,實驗結果認為: Ru金屬化合物對於單股DNA上「中間」位置的鹼基G,有較高的選擇性﹔其二,研究實驗的環境與DNA的雙股螺旋結構穩定度之間的關聯性,實驗結果認為:在負電的模式之下,使用isopropanol為揮發溶劑且與水的的比例達75%以上、毛細管溫度為120-140℃且加入的NH4OAc的量為DNA濃度的200-500倍時,可以得到最大量的雙股螺旋DNA﹔最後,研究具有抗癌活性雙核鉑金屬化合物與雙股螺旋DNA產生反應時,彼此之間的鍵結關係﹔實驗結果認為: 具有抗癌活性雙核鉑金屬化合物與雙股螺旋DNA產生反應時是先以ionic/electrostatic force形式相互吸引,最後形成Pt-N coordination bond。

The gentle nature of the ESI proess, however, means that ESI-MS is also finding application for the study of noncovalent and other fragile biomolecular complexes.
The thesis included three section:
First section: Determination of Binding Location Preference between Short Oligonucleotide and Ru-complexes Analyzed by Ion Trap Mass Spectrometry
The interaction of two ruthenium (II) complexes, [Ru(terpy)(bpy)Cl]Cl and cis-[Ru(bpy)]Cl2, with single-stranded DNA wereinvestigated by electrospry ionization mass spectrometry. The DNA binding sits preference of [Ru(terpy)(bpy)Cl]Cl and cis-[Ru(bpy)]Cl2 were located at central guanine, which was determined by tandem mass spectrometry technique. The Ru-complexes bounds to guanine also enhanced the loss of guanine-Ru, and gave a-B and w fragments.
Second section: Factors Influence on Gas-Phase Stability of Double Stranded Oligonucletoides Studied by Electrospray Mass Spectrometry
The topic studied in relativity between gas-phase stability of double stranded oligonucletides and experimental system. According to this experimental results: the experimental system was set up at capillary temperature at 120-140℃; adding concentration of NH4OAc is 200-500 times over concentration of oligonucletides; the volatile solvent- isopropanol have been used as and the compositions again water 75%.
Third stction: Kinetic of the DNA binding Azole-Bridged Dinuclear Platinum(II) compounds by Electrospray ionization Mass Spectrometry
The kinetics of the reaction between three new derivatives of azole-bridged dinuclear platinum (Ⅱ) complex , (1), [{cis-Pt(NH3)2}2(μ-OH)-(μ-pyrazolate)][NO3]2 (2), [{cis-Pt(NH3)2}2(μ-OH)-(μ-1,2,3-triazolate)][NO3]2 and (3), [{cis-Pt(NH3)2}2(μ-OH)-(μ-phenyltriazolate)][NO3]2 and complementary double-stranded DNA was investigated by electrospray ionization mass spectrometry. Products with different binding modes were observed and shows competition at different time intervals. Ionic/electrostatic binding products dominate at early stage of reaction and gradually transform into covalently modified adduct by removal of hydroxyl leaving group. We proposed that the binding of the dinuclear platinum complexes to the double-stranded nucleic acids may be considered as a three-step process: rapid initial electrostatic binding followed by covalent attachment of the drug by sequential displacement of the leaving group to the N7 position of guanosines, giving first monofunctional and subsequently bifunctional adducts. The binding affinity of three derivatives to complementary 12-mer oligonucleotides are in the order of 3>1»2, which are determined by the ratio of intensity of electrostatic adduct to that of unbound free DNA. On the hand, comparison of the relative intensities of mono- and difunctional platinum covalent adduct suggested that the reactivity for these Pt(Ⅱ) complexes are in the order 2 > 1 > 3, parallel to the trend of cytotoxicity.
Compared to other technique, the study shows that ESI is a sensitive and fast tool for confirmation of binding and determination of stoichometry for both covalent and noncovalent systems.

目錄
論文摘要
第一章 緒論
1-1 細胞內的遺傳物質 1
1-1.1 DNA的發現 1
1-1.2 DNA的化學組成 2
1-1.3 DNA的結構 5
1-2 DNA與惡性腫瘤之關聯性 6
1-3 癌症治療 7
1-4 抗癌藥物 8
1-4.1 鉑金屬化合物 9
1-4.2 鉑族金屬抗癌藥的抗癌作用機制 11
1-5 金屬抗癌藥物的未來展望 14
1-5.1 釕金屬化合物 15
1-5.2 多核鉑金屬化合物 16
1-6 藥物發展與質譜技術 17
第二章 質譜分析法
2-1 質譜儀的演進 19
2-2 電噴灑游離質譜法 (Electrospray ionization mass spectrometer, ESI/MS) 的演進 22
2-3 電噴灑游離質譜法 (Electrospray ionization mass spectrometer, ESI/MS) 的游離機制 23
2-4 質譜法 (mass spectrometry)的質量分析器 27
第三章 Determination of Binding Location Preference between Short Oligonucleotide and Ru-complexes Analyzed by Ion Trap Mass Spectrometry
3-1 研究背景 31
3-2 實驗藥品與方法 34
3-2.1 藥品來源 34
3-2.2 藥品配製 38
3-2.3 儀器設備 38
3-3 結果與討論 38
3-3.1 HPLC的純化 44
3-3.2 何為誘導碰撞解離(collisional-induced dissociation, CID) 53
3-3.3 MS/MS碎裂後之質量鑑定 54
3-3.4 MS/MS碎裂機制之探討 59
3-3.5 [s.s.DNA+Ru complex]的解離機制 65
3-3.6 利用串聯式質譜儀探討s.s.DNA與Ru化合物cis-[Ru(bpy)2]Cl2、[Ru(terpy)(bpy)Cl]Cl之反應性 78
3-3.7 79
3-3.8 結論 81
第四章 Factors Influence on Gas-Phase Stability of Double Stranded Oligonucletoides Studied by Electrospray Mass Spectrometry
4-1 研究背景 82
4-2 實驗藥品與方法 85
4-2.1 藥品來源 85
4-2.2 藥品配製 85
4-2.3 儀器設備 85
4-3 結果與討論 87
4-3.1 DNA濃度效應 89
4-3.2 溶劑效應 91
4-3.3 毛細管溫度(capillary temperture) 95
4-3.4 醋酸銨濃度效應 98
4-3.5 結論 101
第五章 Kinetic of the DNA binding Azole-Bridged Dinuclear Platinum(II) compounds by Electrospray ionization Mass Spectrometry
5-1 研究背景 102
5-2 實驗藥品與方法 106
5-2.1 藥品來源 106
5-2.2 藥品配製 106
5-2.3 儀器設備 107
5-3 結果與討論 111
5-3.1 DNA的質量鑑定 112
5-3.2 DNA與雙核鉑金屬鍵結化合物的質量鑑定 114
5-3.3 DNA與雙核鉑金屬鍵結化合物結構的安定度 134
5-3.4 DNA與雙核鉑金屬鍵結模式 140
5-3.5 DNA與雙核鉑金屬鍵結後雙股螺旋DNA的穩定性
144
5-3.6 三種雙核鉑金屬鍵結與DNA反應性的比較 145
5-3.7 在細胞體內和細胞體外雙核鉑金屬藥物與DNA鍵結反應性之比較 149
5-3.8 pH值與反應速率 152
第六章 結論及未來方向 153
參考文獻 155

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