臺灣博碩士論文加值系統

本論文的研究工作分為兩個部分：
第一部分的內容是根據親合型探針 (affinity-based probes, AfBP) 的設計概念，透過在孕烯醇酮於 C7 位置利用醚基衍伸出具有光活化基團 benzophenone 與標籤分子 biotin，用以研究在斑馬魚胚胎細胞發育中孕烯醇酮的結合蛋白。我們同時合成了不同連接長度與位向的孕烯醇酮光親合型探針，探討不同連接長度與位向對於其促進微管蛋白聚合活性的影響。由實驗結果得知，P5-NBPN (圖1) 保有與孕烯醇酮類似的生物活性，所以接著利用 P5-NBPN 在斑馬魚胚胎細胞液進行光標定實驗，並成功地共價性標定到孕烯醇酮結合蛋白。經由 LC-MS/MS 鑑定後，得知此孕烯醇酮結合蛋白為 cytoplasmic linker protein 170 (CLIP-170)。由缺失型突變體 (depletion mutant) 的實驗果得知孕烯醇酮與 CLIP-170的結合區間在胺基酸 920-970；競爭實驗也證明了 P5-NBPN 具有良好的標定選擇性與特異性。
第二部分的內容是探討一系列以 BMVC 骨架為辨識端，導入不同連結端長度的氮芥子氣衍伸物 (BMVC-CnM; n = 2, 3, 6) 或增加氮芥子氣攻擊端作用距離 (BMVC-SW)，對於不同DNA結構 (鳥嘌呤四股、雙股與單股) 烷化能力的影響 (圖2)。為了研究連接長度或作用距離對於三種鳥嘌呤四股結構 (混和型、逆平行與平行) 反應表現的影響，利用電噴灑離子化質譜 (electrospray ionization mass spectroscopy, ESI-MS)、液相層析-質譜分析 (liquid chromatography-mass spectrometry, LC-MS) 與化學/酵素足跡法 (footprinting) 進行共價產物的分析，以準確的決定作用產物的分布與共價位置的結合環境。由結果得知，連結端長度調控選擇性、特異性與反應性；而對細胞較具有傷害的鏈內交聯 (intrastrand cross-link) 的能力則是由反應端之間的作用距離決定。透過研究反應能力與分子結構的關係，希望能提供設計有效率的 DNA 交聯劑的準則，進而應用在選擇性癌細胞毒殺藥物。

The work presented here consists of two parts:
Section I describes that pregnenolone (P5) was equipped with benzophenone photoreactive group and biotin tag at C7 position in ether linkage to explore P5-binding proteins in the stage of embryonic development of the zebrafish. Various spacer lengths and orientations of P5-photoaffinity probes had been employed to investigate the influences on the activity of in vitro tubulin polymerization. With the preservation of the biological functions as P5, P5-NBPN was used to label P5-binding proteins from zebrafish embryo lysates and the P5 binding protein (Figure 1), cytoplasmic linker protein 170 (CLIP-170), had ultimately been found by LC-MS/MS identification. The photolabeling experiments of CLIP-170 and/or its various depletion mutants showed that the binding region of P5 on CLIP-170 located in the region between aa 920-970 with remarkable labeling selectivity and specificity.
Section II describes that a series of G-quadruplex (G-4)-directing alkylating agents, BMVC-CnM (n = 2, 3, and 6) and BMVC-SW, integrating BMVC with aniline mustard in spacers of various lengths or with longer bridge length to react with different G-4 structures (hybrid-2 type, antiparallel and parallel) (Figure 2). The intact alkylated adducts were elaborately characterized by electrospray ionization mass spectroscopy (ESI-MS), LC-MS, and chemical/enzymatic footprinting to determine precise alkylation sites and plausible binding profiles. These results indicated that alkylation selectivity, specificity, and reactivity are modulated by adjusting linker lengths, whereas intrastrand cross-link efficiency which showed higher cytotoxicity is determined by the distance between two reactive warheads. Our preliminary findings regarding the different distance effects on G-4-specific alkylation provide a structural foundation for the development of G-4-selective bifunctional alkylating agents.

TABLE OF CONTENTS
ABSTRACT i
TABLE OF CONTENTS v
LIST OF FIGURES ix
LIST OF TABLES xxiii
CHAPTER 1 Development of Pregnenolone (P5)-Conjugated Pho-toaffinity Probes for Identification of P5-Binding Proteins 1
1-1 Introduction 1
1-1-1 Steroid hormones and steroidogenic pathway 1
1-1-2 Functions of P5 and its derivatives 3
1-1-2-1 Roles in neurodevelopment 4
1-1-2-2 Roles in zebrafish embryogenesis 6
1-1-2-3 Roles in microtubule polymerization 11
1-1-2-4 Unclear mechanism underlying P5 action 16
1-1-3 Application of affinity-based protein profiling (AfBP) on the study of ster-oid-binding protein 17
1-1-3-1 Characteristics and mechanisms of photoaffinity probe 17
1-1-3-2 Steroid-photoaffinity probes 20
1-1-3-3 Molecular designs of P5-photoaffinity probes 22
1-2 Synthetic strategies and processes 25
1-3 Results and disscusion 34
1-3-1 Synthetic P5-photoaffinity probes functions as P5 34
1-3-2 Identification of Clip1 as the P5-binding candidate 36
1-3-3 Characterization of photoaffinity labeling efficiency 37
1-3-4 Exploration of P5-binding region in CLIP-170 39
1-4 Conclusion 40
CHAPTER 2 Delineation of G-Quadruplex Alkylation Sites Medi-ated by 3,6-Bis(1-methyl-4-vinylpyridinium io-dide)carbazole-Aniline Mustard Conjugates 41
2-1 Introduction 41
2-1-1 Platinum complexes 42
2-1-2 Naphthalene diimides and oxirane 43
2-1-3 Photo-induced cross-linking agents 45
2-1-4 Bifunctional G-4 alkylating agents 47
2-1-5 Molecular designs of BMVC-C3M 48
2-2 Results and disscusion 50
2-2-1 Probing structural changes and stability of G-4s in the pesence of BMVC-C3M based on circular dichroism and melting points measurements 51
2-2-2 Photophysical behavior and the intracellular localization 54
2-2-3 Alkylating reactivity, selectivity and specificity toward different types of DNA 57
2-2-4 ESI-MS analysis of alkylated adducts 62
2-2-5 Identification of nucleotides involved in the alkylation by LC-MS 68
2-2-6 Identification of Nucleotides Involved in the Alkylation by LC-MS 74
2-2-7 Delineation of the specific alkylation sites in combination with footprinting and LC-MS data 79
2-3 Conclusion 87
CHAPTER 3 Linker Effects on G-Quadruplex Alkyation Profiles Mediated by 3,6-Bis(1-methyl-4-vinylpyridinium io-dide)carbazole-Aniline Mustard Conjugates 88
3-1 Introduction 88
3-2 Results and disscusion 93
3-3 Conclusion 113
CHAPTER 4. Exploration of a New Tunable Alkylation Warhead- N1,N3-Bis(2-chloroethyl)-N1,N3-dimethylbenzene-1,3-diamine for Efficient Intrastranded Crosslinks toward G-Quadruplex DNA 114
4-1 Introduction 114
4-1-1 Hypoxia-activated prodrugs 115
4-1-2 H2O2-activated prodrugs 117
4-1-3 DNA-affinic-molecules conjugated nitrogen mustard 120
4-1-4 Effects of bridge lengths on ICL efficiency 123
4-2 Molecular designs of N1,N3-bis(2-chloroethyl) -N1,N3-dimethyl benzene-1,3-diamine-BMVC conjugate 127
4-2-1 Development of all-in-one new bifunctional warhead 127
4-2-2 Conjugation of all-in-one new bifunctional warhead on G-4-binder 128
4-3 Synthetic strategies and processes 132
4-4 Results and discussion 141
4-5 Conclusion 154
EXPERIMENTAL SECTION 155
Materials and Apparatus 155
Synthetic Procedures and Physical Data 157
Experimental Procedures 179
Reference 186
APPENDIX 192

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