阿玆海默症(Alzheimer’s disease, AD)為不可逆且漸進性的神經退化疾病，病理特徵發現有β-類澱粉胜肽(beta-amyloid, Aβ)的沉積和神經纖維糾結(neurofibrillary tangles, NFTs)的形成，而Aβ的過度產生和累積是最主要的致病因素。Aβ由類澱粉前驅蛋白(amyloid precursor protein, APP)依序由β及γ分泌酶切割而成的片段，而細胞內的NFTs為過度磷酸化的tau蛋白所聚合。因此對於阿玆海默症的藥物開發，γ分泌酶的抑制仍然是一個活躍的領域，且具有發展的潛力。
一些含芳烴基磺醯胺的抑制劑具有選擇性且效果不錯，例如GSI-953 (begacestat)，視其為先導化合物作結構修飾得到一系列的N-取代的芳烴基磺醯胺(N-substituted arylsulfonamide)衍生物。
將合成的化合物進行γ分泌酶抑制的活性試驗，其分析方法透過Gal4-tagged APP和Gal4-promotor luciferase reporter gene的表現而確立。活性結果在10 μM濃度下，化合物C6-7可以抑制59%的γ-分泌酶活性；而C5-5g可抑制42%的γ-分泌酶活性。由劑量反應曲線得到C6-7的IC50為8.7 μM；C5-5g為11.7 μM。

Alzheimer’s disease (AD) is an irreversible, progressive neurodegenerative disease characterized by beta-amyloid (Aβ) deposition and neurofibrillary tangles (NFTs) formation. The overproduction and accumulation of Aβ are key pathogenic events in AD progression. Aβ is generated from proteolytic cleavage of amyloid precursor protein (APP) sequentially by β- and γ-secretases, whereas NFTs observed intracellularly are a result of the aggregation of hyperphosphorylated tau. Therefore, γ-secretase inhibition has been and remains an active field of drug discovery for AD.
Some arylsulfones have been reported to be selective, potent γ-secretase inhibitors. One of them is GSI-953 (begacestat), which is actually a hexafluorovalinol derivative. Aiming at developing new molecules for AD therapies, we took it as a lead compound and manipulated its structure to provide a series of N-substituted arylsulfonamide derivatives.
These synthetic arylsulfonamides were screened by using a Gal4-tagged APP and a Gal4-promotor luciferase reporter gene assays to moniter the inhibitory potencies against γ-secretase activity. Among them, only compounds C6-7 (IC50 = 8.7 μM) and C5-5g (IC50 = 11.7 μM) showed moderate potencies with 59% and 42% inhibitions of γ-secretase activity, respectively, at 10 μM levels.

第一章、 緒論…………………………………………..……………………….1
第一節、 前言…………………………………..……………………….....1
壹、 阿玆海默症簡介.………………………………………………1
貳、 診斷方法……...…………………….…………………….…....3
參、 病理……………………………..…..……………..…….……..6
肆、 類澱粉胜肽(Amyloid-β peptide, Aβ)的產生……….…….…...9
伍、 類澱粉蛋白假說(Amyloid hypothesis)………………………11
陸、 γ分泌酶和Notch訊息傳遞途徑………………………...….15
柒、 AD治療機制與臨床用藥……………………………………18
第二節、 研究目的……………………………………………………….23
第三節、 研究方法…………………………………………………….…25
壹、 γ分泌酶抑制劑(γ-secretase inhibitors, GSIs)分類…………..25
貳、 藥物設計……………………………………………………...33
參、 合成反應概要……...…………………………………………36
第二章、實驗部份…………………………………………………………….48
第一節、儀器與材料………………………………………………….…48
壹、 實驗儀器………………………………………………….…..48
貳、 分析方法………………………………………………….…..49
參、 試藥來源……………………………………………….……..49
第二節、合成步驟及結構鑑定………………………………….………54
第三節、生物活性試驗…………………………………………………130
壹、 APP蛋白的γ分泌酶活性試驗………………………….…130
貳、 Notch蛋白的γ分泌酶活性試驗………………...…………132
參、 MTS細胞存活試驗…………………………………………133
肆、 活化ERK-related pathway試驗………………………….…134
第三章、實驗結果……………………………………………………………136
第一節、化學合成結果…………………………………………………136
第二節、生物活性試驗結果…………………………...……….………140
第四章、討論…………………………………………………………………155
第一節、化學合成部份…………………………………………………155
第二節、活性部分……………………………………...……….………159
第五章、結論……………………………………………..………………..…163
第六章、參考文獻……………………………………………………………165

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