選擇性標記含胍基化合物的化學探針分子

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林俊甫(Jun-Fu Lin) 查詢紙本館藏

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化學學系

論文名稱

選擇性標記含胍基化合物的化學探針分子
(Selective Chemical Probes for Labelling of Guanidine-bearing Molecule傑)

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至系統瀏覽論文 (2029-7-31以後開放)

摘要(中)

胍基是一種強鹼性的含氮有機化合物官能基，通常在生理條件下帶有正電荷，能形成電荷-電荷作用力及多重氫鍵。精胺酸側鏈上的胍基是典型例子，精胺酸在蛋白質後修飾轉譯功能中發揮關鍵作用，如瓜胺酸化(citrullination)和甲基化(methylation)已被揭露與多種疾病生成有關，如類風濕性關節炎、狼瘡、朊病毒病和阿茲海默症等，近期科學家對於蛋白質上精胺酸後修飾對標靶蛋白的調節作用研究不遺餘力。在本篇論文中，我們合成一系列八環1,2-雙酮的衍生物，可以選擇性與胍基化合物或脲基化合物進行脫水重排反應，形成五七螺環的穩定產物；另一方面，我們設計製備具有偶氮官能基的八環1,2-雙酮化合物，透過照光預期可活化八環1,2-雙酮化合物與胍基的反應性，將使八環1,2-雙酮化合物成為更有應用性對含胍基化合物標定的化學探針工具。

摘要(英)

Guanidine is a strongly alkaline nitrogen-containing organic compound that typically has a positive charge under physiological conditions. It is capable of forming charge–charge interactions and multiple hydrogen bonds. The guanidino group on the side chain of arginine is a typical example. Arginine plays a crucial role in the post-translational modification of proteins, such as citrullination and methylation, which have been linked to various diseases, such as rheumatoid arthritis, lupus, prion diseases and Alzheimer′s disease. Recently, scientists have dedicated significant efforts to studying the regulatory effects of post-translational modifications (PTMs) of arginine on proteins. In this thesis, we synthesized a series of dibenzocyclooctendione derivatives capable of undergoing condensation and rearrangement reactions with guanidine- or urea-bearing compounds to form a stable product with 5,7-spiroring. On the other hand, we also designed and synthesized octahydro-1,2-quinoline compounds with azo functional groups as chemical probes. These probes are expected to regulate the reactivity of the probe with guanidino and urea groups by controlling the E/Z isomerization of the photoswtich. This design aims to make them more versatile chemical probe tools for selectively labeling guanidine- and urea-containing compounds.

關鍵字(中)

★ 胍
★ 精胺酸
★ 光開關
★ 1,2-雙酮
★ 轉譯後修飾
★ 標定

關鍵字(英)

★ guanidine
★ arginine
★ photoswitch
★ 1,2-diketone
★ post-translational modification
★ labelling

論文目次

摘要 ii
Abstract iii
誌謝 iv
目錄 v
圖目錄 viii
表目錄 x
縮寫表 xi
ㄧ、緒論 1
1-1 前言 1
1-2 抗體–藥物偶聯物(antibody-drug conjugate, ADC) 2
1-2-1 離胺酸醯胺(lysine amide)偶聯 3
1-2-2 半胱胺酸(cysteine)偶聯 3
1-3蛋白質轉譯後修飾(protein post-translational modification, PTM) 4
1-3-1 醣基化(glycoslation) 5
1-3-2 磷酸化(phosphorylation) 6
1-3-3 甲基化(methylation) 7
1-4 胺基酸的偶聯反應 8
1-4-1 離胺酸(lysine)的偶聯反應 9
1-4-2 半胱胺酸(cysteine)的偶聯反應 9
1-4-3 酪胺酸(tyrosine)的偶聯反應 10
1-5 胍(guanidine)及其衍生物的介紹 11
1-6 胍官能團(guanidine group)的偶聯反應 12
1-7 1,2-二氮環辛烷(1,2-diazocine)及應用的介紹 17
1-8 研究動機 18
二、實驗結果與討論 19
2-1 八環1,2-雙酮水溶性衍生物的合成 19
2-1-1 化合物6及7的合成 22
2-1-2 化合物12的合成 23
2-1-3 化合物17的合成 24
2-1-4 化合物23的合成 25
2-1-5 化合物29的合成 27
2-1-6 化合物35的合成 28
2-1-7 化合物40的合成 29
2-2 八環1,2-雙酮探針對精胺酸轉譯後修飾官能基的標定探討 31
2.3 反應機構的探討 33
2-4 光控制八環1,2雙酮的開發 34
三、結論 38
四、實驗部分 39
4.1 實驗儀器 39
4.1.1 核磁共振光譜儀(nuclear magnetic resonance spectroscopy, NMR) 39
4.1.2 高解析質譜儀 40
4.1.3 傅立葉轉換紅外光譜儀(Fourier transform infrared spectrometer, FT-IR) 40
4.2 實驗藥品 40
4.2.1 實驗藥品試劑 40
4.2.2 薄層色層分析(thin layer chromatography, TLC) 40
4.2.3 管柱色層分析(column chromatography) 41
4.3 合成步驟與光譜資料 41
參考文獻 72
附錄 79

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指導教授

謝俊結侯敦仁(Jiun-Jie Shie Duen-Ren Hou)

審核日期

2024-8-20

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