在此論文研究中，本人致力於DNA鍵結試劑的設計與合成。具有DNA鍵結能力的天然物Distamycin及Belomycin是我作為設計DNA鍵結試劑的主要模板。幾個系列的小分子化合物作為DNA鍵結試劑被成功的合成後並完成了其生物物性測試。疊氮聚醯胺化合物雖表現較弱的鍵結能力，但其具有光誘導切割DNA以及辨識鹼基對混合序列的能力。具thiophene環的化合物系列中對於雙股螺旋表現極強的鍵結能力。2,2-bithiophene針對DNA小凹槽有極佳的鍵結能力，對於某些特定序列可比擬天然物netropsin 以及 distamycin的鍵結強度。吡啶化合物系列對於雙股螺旋DNA列並未表現好的鍵結能力但藉由分子內氫形成的平面架構對於四重鳥糞嘌呤有較佳的穩定能力。以Belomycin上DNA鍵結區域作為設計模板的2,2-bithiophene雙嘧啶化合物對於5’-AAGCTT-3’有極佳的選擇性並具有穩定四重鳥糞嘌呤的特性。喹啉化合物系列結合了喹啉以及吡咯聚醯胺化合物探討穩定四重鳥糞嘌呤的因素，所得研究結果對穩定四重鳥糞嘌呤的鍵結試劑提供了新的策略。在此論文研究當中，我順利合成了王志偉老師實驗室發展的幾個系列的小分子DNA鍵結試劑並經由生化實驗測試發現基於小分子個別不同的特性對於DNA二級結構有不同的交互作用

I am interested in the design of DNA binding ligands which are including DNA minor groove binders and G-quadruplex stabilizing agents. Certain natural products, distamycin and belomycin are considered as models for designing new DNA binding agents. A variety of DNA binding ligands were synthesized and accordingly characterized by different bioassays. In the series of azo-pyrrole-polyamide, it showed slight DNA binding affinity but has the properties of DNA photo-cleavage and recognition of mixed sequence. The thiophene series showed strong binding ability for duplex DNA. Bithiophene series showed a remarkable binding affinity to duplex DNA which is compatible to natural products netropsin and distamycin. The pyridodicarboxamide series remain intramolecular hydrogen bonding with poor preferences for duplexes DNA even though they stabilized quadruplex DNA. The bithiophene-bipyrimidine compound binds to specific hexanucleotide sequence 5’-AAGCTT-3’ and acts as an unfused quadruplex stabilization ligand. In the quinoline series, the combination of quinoline and methylpyrrole polyamide proves the attenuation effect for quadruplexes stabilization which provides a novel strategy for development of quadruplex binding logands. In this study, several series of small molecules for DNA binding have been successfully synthesized and proved to interact with DNA secondary structures according to the particular properties of themselves.

Chapter 1
Small Molecules Bound to DNA Minor Grooves and DNA G-quadruplex – Their Similarity and Differences
1-1. Introduction 1
1-2. Introduction of Quadruplex Structure Differences 9
1-2-1. Conformational Study of Human Telomer Sequence 10
1-2-2. Conformational Study of c-myc Promoter Gene 12
1-2-3. Conformational Study of c-kit Promoter Gene 14
1-3. Stabilization Ligands of Quadruplex Sequences 17
1-4. Similarity and Differences for Designing DNA Minor Grooves and G-quadruplex Ligands 18
1-5 Conclusions 20
1-6. Overall Experiments Used In My studies 22
1-6-1. General 22
1-6-2. UV DNA melting temperature (△Tm) measurement 23
1-6-3. Ethidium bromide displacement assay 23
1-6-4. Fluorescence melting studies 24
1-6-5. DNase I Footpring Studies 25
1-7. References 26

Chapter 2
Synthesis of Directly Linked Diazine Isosteres of Pyrrole-Polyamide That Photochemically Cleave DNA.

2-1. Introduction 34
2-2. Results and Discussion 37
2-2-1. Synthesis of diazene compounds 37
2-2-2. Photoinduced DNA Cleavage and Mechanistic Characterization 40
2-2-3. Binding Studies and DNase I Footprinting for Ib 45
2-3. Conclusion 51
2-4. Experimental 51
2-4-1. Synthesis 51
2-5. References 64

Chapter 3
Introduction of Thiophene and Bithiophene Ring into Distamycin A Analogues as Strong Minor Groove Binders.
3-1. Introduction 58
3-1-1. Properties of Heterocyclic Aromatic Rings Replacement of Polyamindes 58
3-1-2. Thiophene Ring Enhance The AT Binding Ability of The Diamidine Minor Groove Reagent 62
3-1-3. Bithiazole Moiety of Belomycin as Designing Model for DNA Minor Groove Binders 65
3-3. Results and Discussion 71
3-3-1. Site of Inserting Thiophene ring intoPyrrole Polyamide as Novel DNA Minor Groove Binder 71
3-2-1. Synthesis of Thiophene Polyamide Analogues as Minor Groove Binders. 71
3-2-2. DNA Binding Studies of Thiophene Compounds for Duplex DNA. 73
3-2-3. DNA Binding Studies for Quadruplex DNA. 85
3-2-4. Synthesis of Bithiophene Polyamide Analogues as Minor Groove Binders. 101
3-2-5. DNA Binding Studies of Bithiophene Compounds for Duplex DNA. 103

3-2-6. DNA Binding Studies of Bithiophene Compounds for Quadruplex DNA. 115
3-3. Conclusion - Comparison of Thiophene and Bithiophene Compounds. 130
3-4. Experimental 135
3-4-1. Synthesis. 135
3-5. References. 139

Chapter 4
Designing Flat Small Moiety Through Intramolecular Hydrogen Bonding with Pyrrole Polyamide to Stabilized G-quadruplex DNA.
4-1. Introduction 147
4-2. Results and discussion 153
4-2-1. Synthesis of novel pyridodicarboxamide compounds as G-quadruplex binding ligands 153
4-2-2. DNA Binding Studies of pyridocarboxamide 6 154
4-2-3. DNA Binding Studies of pyridodicarboaxmide 10 and 11 168
4-3. Conclusion 187
4-4. Experimental 188
4-4-1. Synthesis 188
4-5. References 189

Chapter 5
Synthesis of Poly-Unfused Bithiophene-Bipirimidine as A Strong DNA Duplex and Quadruplex Stabilization Ligands.
5-1. Introduction 196
5-2. Results and discussion 196
5-2-1. Synthesis of bithiophene-bipirimidine compound 4 197
5-2-2. DNA Binding Studies for Duplex DNA 198
5-2-3. DNA Binding Studies for Quadruplex DNA 201
5-3. Conclusion 210
5-4. Experimental 211
5-4-1. Synthesis 211
5-5. References 212

Chapter 6
Factors Controlling Binding to G-quadruplex DNA Through Bisquinoline and Minor Groove Binding Agents.
6-1. Introduction 214
6-2. Results and discussion 216
6-3. Conclusion 224
6-4. Experimental 224
6-4-1. Synthesis 224
6-5. References 229

Chapter 7
Conclusion.
7-1. Introduction 234
7-1. References 237

Chapter 1
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Chapter 2
Synthesis of Directly Linked Diazine Isosteres of Pyrrole-Polyamide That Photochemically Cleave DNA.
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Chapter 3
Introduction of Thiophene and Bithiophene Ring into Distamycin A Analogues as Strong Minor Groove Binders.
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Chapter 4
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Chapter 6
Factors Controlling Binding to G-quadruplex DNA Through Bisquinoline and Minor Groove Binding Agents.
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Chapter 7
Conclusions
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