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研究生:陳欣妤
研究生(外文):Chen,Hsing-Yu
論文名稱:合成具晚期糖化終產物阻斷劑及抗發炎潛能之噻唑衍生物
論文名稱(外文):Synthesis of Thiazolium Derivatives as Advanced Glycation End-Products(AGE)Breakers and Anti-inflammatory Agents
指導教授:黃文鑫黃文鑫引用關係
指導教授(外文):Wen-Hsin Huang
學位類別:碩士
校院名稱:國防醫學院
系所名稱:藥學研究所
學門:醫藥衛生學門
學類:藥學學類
論文種類:學術論文
論文出版年:2006
畢業學年度:94
語文別:中文
論文頁數:106
中文關鍵詞:晚期糖化終產物糖尿病ALT-711梅納反應噻唑
外文關鍵詞:Advanced Glycation End-ProductsDiabetesALT-711Maillard reactionthiazole
相關次數:
  • 被引用被引用:1
  • 點閱點閱:952
  • 評分評分:
  • 下載下載:333
  • 收藏至我的研究室書目清單書目收藏:2
摘要

梅納反應為還原糖和蛋白質之胺端形成之一系列複雜的化學反應,最後產生褐色、螢光的物質與蛋白質交聯。晚期糖化終產物於梅納反應後期產生,導致蓄積在長半衰期的蛋白質,且促進老化、糖尿病、類風濕性關節炎、動脈硬化症的產生。
目前發展的藥物分為AGE抑制劑、AGE阻斷劑、抗氧化劑。ALT-711為新型的thiazolium化合物,為可打斷AGE與蛋白質交聯的AGE阻斷劑。本實驗室以ALT-711作為先導化合物,進行結構合成與修飾,以篩選高效力、低毒性的化合物。本次論文研究旨在合成一系列benzothiazole化合物。並以離體和活體試驗評估所合成一系列ALT-711類似物其生物活性。
在活體實驗中以carrageenan誘導大白鼠足蹠浮腫來評估所合成之所有化合物抗炎活性效果顯示:化合物3、7a-7g、9、11、14、16不僅on set快且能達穩定延緩發炎浮腫效果,皆能維持和leflunomide有相近或更好的效果。尤其以化合物11具有更為顯著效果。挑選了15個化合物進行AGE抑制實驗活性篩選,結果待回報。
Maillard reaction is a complex series of reactions between reducing sugars and amino groups on proteins, which lead to browning, fluorescence, and cross-linking of protein. Advanced glycation end products(AGEs), formed during later stages of the Maillard reaction, accumulate in long lived tissue proteins, and may contribute to the development of complications in aging, diabetes, rheumatoid arthritis and atherosclerosis.
Current developed drugs for AGEs are AGE inhibitors、AGE breakers and antioxidants. ALT-711 is the first drug in a new class of thiazolium therapeutic agents that break established AGE cross-links between proteins. Regarding ALT-711 as the lead compound of AGE breakers in this laboratory, syntheses and modifications based on ALT-711 were performed. We aimed at synthesis of a series of benzothiazole chemicals to develop higher potency and lower toxicity. The selective target compounds were evaluated bioactivities in vitro and vivo.
The target compounds were evaluated to reduce inflammation of carrageenan-inducd paw edema in vivo. Among them, compounds 3、7a-7g、9、11、14、16 showed the better anti-inflammatory activity. Especially compound 11 had significant potent than that of leflunomide. Besides, the 15 compounds were subjected to the screening of AGE inhibition activity in vitro, the results are awaited reports.
目錄
頁次
正文目錄………………………………………………………………..Ⅰ
附圖目錄………………………………………………………………..Ⅲ
中文摘要………………………………………………………………..Ⅴ
英文摘要………………………………………………………………..Ⅵ

第一章、緒論……………………………………………………………1
第一節、前言……………….……………………………………….1
壹、AGEs之簡介……………………………………..………..2
第二節、研究目的…………..…………………….…………….....15
壹、藥物開發敘述........………………………..…………....15
貳、目前發展藥物......…………………………….………...18
第三節、研究方法………………………………………………....29
壹、藥物設計原理.…………………………………………...29
貳、合成反應概要……………………………………………32
第四節、生物活性試驗原理………………………………………38
壹、AGEs抑制試驗………………………….………………38
貳、鹿角菜( carrageenan )誘發足蹠浮腫…………………..39
第二章、材料與方法……………………………………………………41
第一節、試藥來源…………………………………………………41
第二節、重要儀器…………………………………………………43
第三節、合成實驗…………………………………………………44
第四節、生物活性試驗……………………………………………54
壹、AGEs抑制試驗…………………………………………54
貳、鹿角菜( carrageenan )誘發足蹠浮腫試驗….…………56 第三章、結果……………………………………………………………58
第一節、化學合成…………………………………………………58
第二節、生物活性…………………………………………………74
壹、AGEs生成抑制試驗…………………………………….74
貳、鹿角菜( carrageenan )誘發足蹠浮腫試驗……………..75
第四章、討論…………………………………………………………..78
第一節、化學合成…………………………………………………78
第二節、生物活性…………………………………………………83
第五章、結論……………………………………………………………85
第六章、參考文獻………………………………………………………86
表目錄
頁次
表一、AGEs蓄積所引起之疾病………………………………………14
表二、Antiinflammatory activity of 3-4c at dose 20 mg/kg i.p. for SD
rats……………………………...……………………………….76
表三、Antiinflammatory activity of 7b-16 at dose 20 mg/kg i.p. for
SD rats………..…………………………………………………77


圖目錄
頁次
圖一、AGEs之作用機轉…………………………………………………3
圖二、GOLD與MOLD的形成圖………………………………………4
圖三、麩甘胱胜肽( glutathione, GSH )的架構…………………….……5
圖四、二羧基化合物的來源、產生AGEs與去毒路徑圖…………….6
圖五、N-ε-(羧基烷基)離胺酸的形成…………………………….……...7
圖六、AGEs之架構分類…………………..……………………………9
圖七、AGEs之致病機轉…………...…………..………………………13
圖八、AGE inhibitors和AGE breakers之機轉…………………….…23
圖九、抗氧化劑之機轉………………..……………………………….25
圖十、維他命E之機轉………………………………..……………….27
圖十一、ALT-711打斷AGEs共價鍵之機轉…………….…………….30
圖十二、AGEs抑制試驗之實驗步驟…..………………………………55
圖十三、鹿角菜( carrageenan )誘發足蹠浮腫之實驗步驟……………57
圖十四、化合物3之1H-NMR及13C-NMR圖譜……………………92
圖十五、化合物7a之1H-NMR及13C-NMR圖譜……………………93
圖十六、化合物7b之1H-NMR及13C-NMR圖譜……………………94
圖十七、化合物7c之1H-NMR及13C-NMR圖譜……………………95
圖十八、化合物7d之1H-NMR及13C-NMR圖譜……………………96
圖十九、化合物7e之1H-NMR及13C-NMR圖譜……………………97
圖二十、化合物7f之1H-NMR及13C-NMR圖譜……………………98
圖二十一、化合物7g之1H-NMR及13C-NMR圖譜…………………99
圖二十二、化合物9之1H-NMR及13C-NMR圖譜……..………….100
圖二十三、化合物11之1H-NMR及13C-NMR圖譜………………101
圖二十四、化合物14之1H-NMR及13C-NMR圖譜………………102
圖二十五、化合物16之1H-NMR及13C-NMR圖譜……………….103
圖二十六、化合物4a之1H-NMR及13C-NMR圖譜………………104
圖二十七、化合物4b之1H-NMR及13C-NMR圖譜………………105
圖二十八、化合物4c之1H-NMR及13C-NMR圖譜………………106
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