請用此 Handle URI 來引用此文件:
http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/17136
標題: | Ⅰ 光反應型親和性探針的合成與應用:孕烯醇酮結合蛋白質的鑑定以及鳥嘌呤四股結構解旋酶的探討
Ⅱ 利用前導藥物概念合成端粒導向的去氧核醣核酸烷化劑 Ⅰ Synthesis and Application of Photoaffinity Probes : Identification of Pregnenolone Binding Proteins and Study of G-Quadruplex Helicase Ⅱ Synthesis of Telomere-Directed DNA Alkylating Agents Based on Prodrug Concept |
作者: | Shiao-Han Lin 林筱涵 |
指導教授: | 陳昭岑 |
關鍵字: | 蛋白質體學,親合型探針,光反應基團,受體蛋白,鳥嘌呤四股結構,解旋酶,分子辨識,前驅藥物, proteomics,affinity-based probes,photoreactive groups,receptor,G-quadruplex,helicase,molecular recognition,prodrug, |
出版年 : | 2013 |
學位: | 碩士 |
摘要: | 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. |
URI: | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/17136 |
全文授權: | 未授權 |
顯示於系所單位: | 化學系 |
文件中的檔案:
檔案 | 大小 | 格式 | |
---|---|---|---|
ntu-102-1.pdf 目前未授權公開取用 | 11.56 MB | Adobe PDF |
系統中的文件,除了特別指名其著作權條款之外,均受到著作權保護,並且保留所有的權利。