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研究生:侯明宏
研究生(外文):Ming-Hon Hou
論文名稱:專一性GpC之核酸結合藥物與DNA雙螺旋結合機制及其在相關疾病治療之應用探討
論文名稱(外文):The mechanistic study of GpC specific DNA-binding drugs bound to DNA duplexes and their potential application in disease therapy
指導教授:王惠鈞
指導教授(外文):Andrew H.-J. Wang
學位類別:博士
校院名稱:國立臺灣大學
系所名稱:生化科學研究所
學門:生命科學學門
學類:生物科技學類
論文種類:學術論文
論文出版年:2003
畢業學年度:91
語文別:英文
論文頁數:128
中文關鍵詞:核酸結合藥物鳥嘌呤-胸腺嘧啶-胞嘧啶三重複基因神經遺傳疾病治療癌症去氧核醣核酸雙螺旋結晶學結構雙體複合物
外文關鍵詞:GpC specific DNA-binding drugsdisease therapyX-ray diffractionactinomycin Dchromomycin A3 (mithramycin) dimerDNA duplexneurological disease (CTG triplet repeat)cancer chemotherapy
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許多的藥物和抗生素是作用在細胞的去氧核醣核酸鏈上才能顯示其治療疾病的功能,我們稱之為核酸結合藥物。 為了了解核酸結合藥物和去氧核醣核酸鏈的分子的作用機制,一般會利用X 光繞射和其他的物理方法來決定他們的三級結構。 這樣的實驗結果確實讓我們更進一步的去設計新穎的藥物來對抗疾病。 核酸結合藥物作用在去氧核醣核酸鏈的方法主要可分為四類;第一類為崁入法(intercalation),第二類為凹槽結合法(groove-binding)。 前兩類皆屬於非共價鍵結合法。 而第三類為共價鍵結合法 (covalent linkages),另外最後一類為切斷核酸鏈骨幹法 (DNA backbone cleavages)。 而本篇論文主要是針對利用非共價鍵結合法的核酸結合藥物(包括;Actinomycin D和Chromomycin A3 (或Mithramycin)) 與去氧核醣核酸雙螺旋結合機制及其在相關疾病治療之應用作一些詳盡探討。
Actinomycin D和Chromomycin A3 (或Mithramycin))皆屬於專一性GpC之核酸結合藥物。這些藥物已經被研究有一段時間了。 它們主要是從細菌萃取出來的,並且具有治療癌症的活性,其抗癌活性主要是抑制細胞核酸的複製或是轉錄。 本論文大概可以分為三大主題;第一我們針對Actinomycin D對於抑制鳥嘌呤-胸腺嘧啶-胞嘧啶三重複基因延長的機制作一系列的討論。 鳥嘌呤-胸腺嘧啶-胞嘧啶三重複基因(CTG triplet repeat)延長常發生在神經遺傳疾病,而本論文從生化和生物物理結果,具體提出了Actinomycin D應用在治療神經遺傳疾病上的潛力。 第二,我們決定了Chromomycin A3雙體和去氧核醣核酸雙螺旋的結晶學結構,並且增加了之前從核磁共振光譜所獲得的資訊,並更真實顯示出其專一性GpC之核酸結合機制。 最後我們利用得到的Chromomycin A3雙體的結晶學結構來設計出會和特定鐵金屬離子形成穩定螯合鐵新型雙體複合物,並且探討其應用在治療癌症的可行性。

Many drugs and antibiotics are known to interact with DNA in order to exert their biological activities. The three-dimensional structures of several DNA-antitumor drug complexes have been determined by high resolution X-ray diffraction and other biophysical methods. These results have provided significant insights into DNA conformations and drug-DNA interactions to design useful novel drugs. There are several different interaction modes between drugs and DNA, namely, intercalation (such as daunorubicin and doxorubicin), groove-binding (such as distamycin A), covalent linkages (cisplatin, mitomycin C, and ecteinascidins) and DNA backbone cleavages (duocarmycin/CC-1065, bleomycin/ pepleomycin, and enediyne antibiotics). Here, we mainly focus on the mechanism study of the two DNA-binding drugs, actinomycin D and chromomycin A3, which noncovalently bind to DNA via the modes of intercalation and groove-binding respectively, and their potential disease therapeutic applications.
Actinomycin D (ActD) and chromomycin A3 (Chro) (or mithramycin (Mith) belong to the GpC specific DNA-binding drugs and isolated from bacteria. Their antitumor properties are believed to associate with the inhibitory effects of these drugs on replication and transcription. The binding mechanisms and biophysical properties of these two drugs to DNA have been studied for many years. There are three major subjects in my research. First, I focused on the interference mechanism of ActD on the expansion of CTG triplet repeats linked to neurological disease. In this section, our biochemical and biophysical results offer new possible biological consequences of ActD bound to the CTG triplet repeats found in neurological diseases. In the second section, we solved the crystal structure of Chro bound to DNA duplex, and this structural information provides real and clear action modes of the Chro dimer on the DNA structure, which has greatly expanded the information obtained from previous studies. In the last section, based on Chro dimer structure, we have successfully formed the novel dimers of aureolic family antibiotics, Chro and Mith, in the presence of Fe2+, which may warrant further investigations involving those agents as potential candidates in cancer chemotherapy.

Table of Contents
Chinese abstract …………………………………………………………I
Abstract ………………………………………………………………….…III
Chapter 1. Introduction
1.1 Background …………………………………………………..1
Chapter 2. The interference mechanism of actinomycin D on the expansion of CTG triplet repeats linked to neurological disease
2.1 Abstract ………………………………………………………...5
2.2 Introduction …………………………………………………….6
2.3 Materials and methods ……………………………………….9
2.4 Results and discussion ……………………………………...14
2.5 Conclusion ……………………………………………………24
Chapter 3. Crystal structure of chromomycin A3 bound to DNA duplex reveals GpC specificity binding mechanism
3.1 Abstract ………………………………………………………26
3.2 Introduction …………………………………………………..27
3.3 Materials and methods ……………………………………...30
3.4 Results and discussions ………………………………….…33
3.5 Conclusion ……………………………………………………45
Chapter 4. Structure-based design of potent anticancer drugs using the novel stable dimeric complex of chromomycin A3 and mithramycin chelated with Fe2+ ion
4.1 Abstract ………………………………………………………48
4.2 Introduction …………………………………………………..49
4.3 Materials and methods ……………………………………...52
4.4 Results ………………………………………………………..59
4.5 Discussions ……………………………………………….….70
Supplementary data ………………………………………………….75
Reference ……………………………………………………………….. 76

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