研究生: |
湯欣儀 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 Characterization for Interaction of Antitumor-active Metal Complexes with Oligonucleotide by Electroespray Ionization Mass Spectrometry |
指導教授: |
林震煌
Lin, Cheng-Huang |
學位類別: |
碩士 Master |
系所名稱: |
化學系 Department of Chemistry |
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 |
英文關鍵詞: | Electrospray ionization mass spectrometry, Oligonucleotide, Ru-complexes, derivatives of azole-bridged dinuclear platinum (Ⅱ) complex, ionic/electrostatic force, Pt-N coordination bond |
論文種類: | 學術論文 |
相關次數: | 點閱:224 下載:0 |
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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.
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