蛋白質體學 (proteomics) 的發展，成功地應用於許多疾病的研究與藥物的開發。同時，親和型探針 (affinity-based probes, AfBPs) 的相關技術，為特定蛋白質的研究提供了一項新的方法。AfBPs 的作用機制主要在分子辨識的基礎下，利用光活化反應基團 (photoreactive groups, PGs) 達到對特定蛋白質形成共價標定。並藉由導入不同的受質 (substrate)，可以與相對應的受體蛋白 (receptor) 進行研究，幫助深入了解不同蛋白質與疾病之間的相互關係。
本論文的主軸主要分為三大部分：第一部分針對胚胎細胞遷移相關蛋白的研究，先前研究指出，孕烯醇酮 (pregnenolone, PREG) 具有穩定微管並促進胚胎發育的能力，但相對應的孕烯醇酮結合蛋白 (pregnenolone binding proteins, PBPs) 並不清楚。而在本實驗室近期的研究中發現，孕烯醇酮探針 (P5

The development of proteomics has opened up new horizons for the research of many diseases and drugs invention. Meanwhile, the related technology of affinity-based probes (AfBPs) provides more direct evidence about the mediation and regulation of protein in physiological condition. The actions of AfBPs are mainly based on molecular recognition, with the introducing of photoreactive groups (PGs) to achieve the specific covalent modification on protein. With the directing of different substrate, allowing scientists for the corresponding binding protein studies to understand the interaction between the protein and disease.
This thesis is mainly divided into three parts: The first part is to study the embryonic-cell-movement related proteins. Our previous research indicated pregnenolone (PREG) can preserve the abundance of microtubules and effectively promote the development of embryonic cell, but the corresponding pregnenolone binding proteins (PBPs) is not clear. However, our recent studies found that pregnenolone probe (P5-NBPN) can effectively promote microtubule assembly, increase cell migration rate and specifically target to cytoplasmic linker protein (CLIP1, or CLIP -170). To validate the structural interaction about the binding mode and mechanism between pregnenolone and CLIP-170, we introduced the reactive groups at different positions on pregnenolone. At this point, We designed and synthesized the photoreactive probes (P5C20-NBPN) composed of pregnenolone as recognition unit, benzophenone as the photo cross-linker and a biotin as the reporter. Hope to compare the efficiency among these regio-affinity probes of pregnenolone on photolabeling experiments, and to understand more details about the binding mode, as the basis for drug development in the future.
The second part is to study and discuss about G-quadruplex helicase. Many studies have demonstrated that the protein can maintain genomic stability, suppress inappropriate genetic recombination and inhibit of tumor progression, but still do not know about the mechanism of action. We designed and synthesized BMVC-DzN3, directing by the ligand of G-quadruplex. After reactive groups excited by irradiation, helicase is expected to be selectively labeling to obtain the direct binding evidence with G-quadruplex structures and explore its subsequent physiological functions.
Although DNA-alkylated agents display excellent ability to inhibit cancer cell growing, but due to low selectivity, resulting in extremely serious side effects on the clinical application. In the third part, we hope to take advantage on molecular recognition and the concept of prodrug. BMVC equipped with DNA-alkylated agents - nitrogen mustard sheltered by phenylboronic ester were synthesized, named BMVC-Ak, to achieve high cytotoxicity toward cancer cells with good selectivity.

目錄 I
圖目錄 IV
表目錄 VIII
中文摘要 IX
英文摘要 XI


緒論 1
第一章 孕烯醇酮結合蛋白質的鑑定 5
1-1 類固醇荷爾蒙 (steroid hormone) 5
1-2 孕烯醇酮簡介與其生理功能 7
1-2.1 孕烯醇酮下游代謝物之生理功能 9
1-2.2 孕烯醇酮衍生物及相關活性探討 11
1-3 孕烯醇酮與微管蛋白之作用 13
1-4 孕烯醇酮於斑馬魚胚胎外包作用的影響 17
1-5 AfBPs 技術應用於孕烯醇酮結合蛋白質的研究 19
1-5.1 分子設計 20
1-5.2 孕烯醇酮與 CLIP-170 的作用機制 21
1-5.2 CLIP-170 增強微管生長的機制 23
1-6 研究動機 25
1-7 P5-C20-NBPN 的合成策略與其合成方法 25
第二章 鳥嘌呤四股結構解旋酶的研究 32
2-1 鳥嘌呤四股結構 32
2-2 鳥嘌呤四股結構於生物體的重要性 36
2-2.1 端粒與端粒酶 36
2-2.2 DNA 啟動子與 RNA 40
2-3 鳥嘌呤四股結構結合劑 (穩定劑) 41
2-4 解旋酶的簡介及其生理作用 46
2-5 研究動機 48
2-5.1 分子設計 48
2-5.2 合成方法 50
第三章 BMVC-DzN3 後續測試之結果與討論 77
3-1 BMVC-DzN3 與不同 DNA 序列作用後的光物理性質 77
3-2 BMVC-DzN3 與端粒片段作用後之鳥嘌呤四股結構分析及解旋溫度的測量 80
3-3 BMVC-DzN3 與端粒序列的螢光滴定實驗 81
3-4 BMVC-DzN3 於光照下的反應活性 82
3-5 BMVC-DzN3 與端粒序列作用後之凝膠電泳分析 84
3-6 BMVC-DzN3 對端粒酶的活性與細胞毒性分析 84
3-7 BMVC-DzN3 之細胞顯影 87
3-8 總結 88
第四章 利用前導藥物概念合成端粒導向的去氧核醣核酸烷化劑 91
4-1 鳥嘌呤四股結構與癌症治療 91
4-2 DAN 烷化劑於癌症治療上的應用 93
4-2.1 順鉑類化合物 93
4-2.2 氮芥子氣類化合物 96
4-3 結合鳥嘌呤四股結構穩定劑的 DNA 烷化劑 98
4-4 研究動機與分子設計 99
4-5 合成策略及合成方法 102
實驗部分 113
一、 一般敘述………………………………………………………………………113
二、實驗步驟及光譜數據…………………………………………………………..115
三、生物實驗測試方法……………………………………………………………..140
參考文獻……………………………………………………………………………143
附錄…………………………………………………………………………………154

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