臺灣博碩士論文加值系統

神經退化性疾病包括 Alzheimer''s Disease、Parkinson''s Disease，另外，物理性造成之神經傷害，例如缺血性神經傷害(Ischemia/Stroke) 或頭部劇烈撞擊都是常見之神經傷害疾病。而研究指出，這些傷害會因為神經細胞中之膠質細胞如星狀細胞的維持而具有被保護之作用，相反的疾病造成之星狀細胞受損或凋亡，皆會進一步造成神經細胞之保護喪失而造成神經細胞之傷害甚至凋亡反應之發生，並可能為神經退化性疾病之重要機轉之一。因此保護星狀細胞可能具有保護神經細胞之作用。
在眾多研究中發現，上述之傷害皆與 Ceramide 具有關連性，因此本實驗利用易於穿透細胞膜之 C2-ceramide 作為模擬星狀細胞(C6 glioma)因疾病或外力傷害而凋亡之過程，並以此作為藥物篩選之工具，評估合成化合物對於細胞保護之作用。
1,3-Benzothiazinone 衍生物在細胞毒性評估時發現具有細胞數量增加之現象，並且於正常細胞中不具有明顯毒性之特性，再加上關於抑制凋亡活性作用之報導，因此將這類衍生物作為評估細胞保護作用之化合物。
其中發現，compound 5 在 5 及 10 μM下具有微弱的dose-dependent 的保護作用趨勢，但當濃度提高至 20μM以上即產生毒性作用，由結果推測compound 5 確實具有細胞保護之作用。
如果藉由compound 5 作為 lead compound 並設法去除其毒性作用，可能有機會發展成為具有細胞保護功能之藥物。

Neurodegenerative diseases such as Alzheimer’s Disease, Parkinson’s Disease, and Stroke are common diseases of neuronal damage. It has been reported that these kind of damage might be protected by the maintance of astrocytes. On the contrary, diseases caused astrocyte damage or apoptosis would result in it’s loss in neuro- protective activities, even cause neuron damage and cell apoptosis. Which could be one of the mechanisms of neurodegenerative diseases. As a result, astrocytes protection might be a route for neuroprotection.
Many researches have been reported that such damage is related to ceramide. As a result, we use C2-ceramide to induce apoptotic effect in C6-glioma, the astrocyte like cell line, to mimic the apoptotic condition in neurodegenerative disease and use it as a drug screening model to evaluate the cell protective activities of our compounds.
During the cytotoxic evaluation of 1,3-benzothiazinone derivatives, we found that there is a increased cell number phenomena, their nearly no toxic character in the normal cell line, and reported antiapoptotic effect, which prompt us to evaluate if these compounds have cell protective activities
We found that compound 5 in 5 and 10μM seems to have minor dose-dependent trend of cell protective activities, but the toxicity become profound when the concentration doubled. The results showed that compound 5 actually have cell protective activity
Use compound 5 as a lead compound to reduce it’s toxicity might be a route for the development of cell protective agents.

目錄
目錄 3
圖表目錄 6
光譜目錄 7
縮寫索引 9
摘要 10
Abstract 11
一、研究背景 12
Glial cell and Astrocyte 12
提供抗氧化物質 12
清除glutamate 12
1,3-Benzothiazinone 衍生物 14
Antiapoptotic effect of 2-Substituted 4H-1,3-Benzothiazin-4-one 衍生物 16
Ceramide 17
Ceramide 引發細胞凋亡之機轉： 19
1. 作為二級傳遞訊號 19
2. Ceramide本身具有的signaling lipid 的功能 20
Ceramide 與神經退化性疾病及缺血性腦傷害的關係： 20
Alzheimer’s disease 21
Parkinson’s disease 21
Ischemic brain injury / Stroke 22
二、研究方法及目的 24
化學部份 24
活性部份 25
以C2-Ceramide 對C6-glioma引發之凋亡反應作為神經傷害及神退化性疾病藥物治療以達到細胞保護作用之藥物篩選模型： 25
MTT Assay (評估細胞存活率) 25
C2-Ceramide Assay 26
三、結果與討論 27
化學合成 27
圖譜解析 29
合成討論 31
細胞保護作用評估 32
C2-Ceramide Assay 反應條件確認實驗 32
C2-Ceramide Assay 藥物篩選實驗 32
四、實驗部份 36
儀器與試藥 37
化合物合成流程及光譜資料 39
化合物(1) 40
2-mercapto-4H-benzo[e][1 ,3]thiazin-4-one 40
化合物(2) 41
2-(methylthio)-4H-benzo[e][1 ,3]thiazin-4-one 41
化合物(3) 42
2-hydroxy-4H-benzo[e][1 ,3]thiazin-4-one 42
化合物(4) 43
2-amino-4H-benzo[e][1 ,3]thiazin-4-one 43
化合物(5) 44
2-hydrazinyl-4H-benzo[e][1 ,3]thiazin-4-one 44
化合物(6) 45
2-(methylamino)-4H-benzo[e][1 ,3]thiazin-4-one 45
化合物(7) 46
2-(ethylamino)-4H-benzo[e][1 ,3]thiazin-4-one 46
化合物(8) 47
2-(butylamino)-4H-benzo[e][1 ,3]thiazin-4-one 47
化合物(9) 48
2-(octylamino)-4H-benzo[e][1 ,3]thiazin-4-one 48
化合物(10) 49
2-(3-hydroxypropylamino)-4H-benzo[e][1 ,3]thiazin-4-one 49
化合物(11) 50
2-(benzylamino)-4H-benzo[e][1 ,3]thiazin-4-one 50
化合物(12) 51
2-(phenylamino)-4H-benzo[e][1 ,3]thiazin-4-one 51
化合物(13) 52
2-(naphthalen-1-ylmethylamino)-4H-benzo[e][1 ,3]thiazin-4-one 52
化合物(14) 53
2-(naphthalen-2-ylamino)-4H-benzo[e][1 ,3]thiazin-4-one 53
化合物(15) 54
2-(furan-2-ylmethylamino)-4H-benzo[e][1 ,3]thiazin-4-one 54
化合物(16) 55
2-(pyridin-2-ylmethylamino)-4H-benzo[e][1 ,3]thiazin-4-one 55
化合物(17) 56
2-(pyrrolidin-1-yl)-4H-benzo[e][1 ,3]thiazin-4-one 56
化合物(19) 58
2-(azepan-1-yl)-4H-benzo[e][1 ,3]thiazin-4-one 58
化合物(20) 59
2-(cyclohexylamino)-4H-benzo[e][1 ,3]thiazin-4-one 59
化合物(21) 60
2-((1r ,4r)-4-hydroxycyclohexylamino)-4H-benzo[e][1 ,3]thiazin-4-one 60
化合物(22) 61
3-(chloromethyl)-5H-benzo[e][1 ,2 ,4]triazolo[3 ,4-b][1 ,3]thiazin-5-one 61
化合物(23) 62
2-(chloromethyl)-9H-benzo[e][1 ,2 ,4]triazolo[5 ,1-b][1 ,3]thiazin-9-one 62
化合物(24) 63
2-(azidomethyl)-9H-benzo[e][1 ,2 ,4]triazolo[5 ,1-b][1 ,3]thiazin-9-one 63
化合物(25) 64
2-((9-oxo-9H-benzo[e][1 ,2 ,4]triazolo[5 ,1-b][1 ,3]thiazin-2-yl)methyl)isoindoline-1 ,3-dione 64
化合物(26) 65
(9-oxo-9H-benzo[e][1 ,2 ,4]triazolo[5 ,1-b][1 ,3]thiazin-2-yl)methyl carbamimidothioate 65
化合物(27) 66
2-((9-oxo-9H-benzo[e][1 ,2 ,4]triazolo[5 ,1-b][1 ,3]thiazin-2-yl)methylthio)benzoic acid 66
活性測試實驗 67
細胞培養 68
試藥處理 68
MTT Assay實驗步驟： 68
C2-Ceramide確認試驗之實驗步驟： 69
C2-Ceramide 試藥篩選之實驗步驟： 69
C2-Ceramide 測試試藥dose-dependent之實驗步驟： 70
數據統計： 70
五、圖譜 71
六、參考文獻 125

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