博碩士論文 100223042 詳細資訊




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姓名 呂柏葦(Po-wei Lu)  查詢紙本館藏   畢業系所 化學學系
論文名稱 含有香豆素的石膽酸類似物作為唾液酸轉移酶抑制劑的合成與初步活性測試
(A Series of Lithocholic Acid Analogs with Coumarin Moieties as Sialyltransferase Inhibitors: Synthesis and Preliminary Bioactivity Studies)
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摘要(中) 近年來,癌症的轉移往往伴隨唾液酸轉移酶的異常表現,因此發展唾液酸轉
移酶的抑制劑,並測試其抑制活性,了解化合物結構與抑制能力的關係,期望能
以抑制唾液酸轉移酶為分子標靶來達到抗癌症轉移的效果。
以Lith-O-Asp 為主結構,並透過DMMTM BF4 耦合試劑和SOCl2 醯氯化合
成醯胺鍵連接一系列的香豆素衍生物,分別透過細胞傷口癒合分析及唾液酸轉移
酶抑制實驗來探討香豆素衍生物上的取代基對於生物活性的影響。透過生物實驗
可以發現KE-49、KE-50、KE-89 及KE-126 有較明顯的抑制能力,代表香豆素
上的羥基有助於增進抑制活性,其中又以C7 號位的羥基取代最為明顯,另外在
C8 號位增加一個甲基取代也有助於活性的提升。
摘要(英) Recently, aberrant sialylation is found in cancer metastasis frequently.
Empolying the strategy of the relationships between structure and activity , we use
sialyltrasdferase as the molecular target to develop its inhibitors in order to attenuate
cancer metastasis.
Preparation of Lith-O-Asp-coumarin derivatives was successfully accomplished
through the coupling reaction between Lith-O-Asp and coumarin moieties using
DMMTM BF4 (4-(4,6-dimethoxy-(1,3,5)triazin-2-yl)-4-methyl-morpholinium tetrafluoroborate)
or SOCl2 as the reagents. Extensive SAR studies were performed using
different substituted-coumarin analogs under the wound healing and sialyltransferase
inhibitor assays. Among the Lith-O-Asp-coumarin derivatives, the
hydroxyl-substituent analogs at C-7 position were observed to have the hightest
biological activity. It is also noteworthy that the methyl-substituent analogs at C-8
position also display significantly increased biological activity toward both assays.
關鍵字(中) ★ 唾液酸
★ 唾液酸轉移酶
★ 香豆素
關鍵字(英) ★ sialic acid
★ Sialyltransferase
★ Coumarin
論文目次 中文摘要......... ......................................... I
Abstract ................................................ II
目錄.................................................... III
圖目錄.................................................... VI
表目錄................................................... VII
一、導論................................................... 1
1.1 唾液酸的結構與功能....................................... 1
1.2 生物上唾液酸轉移酶的功能.................................. 3
1.3 唾液酸轉移酶抑制劑....................................... 4
1.3.1 供體類似物抑制劑....................................... 4
1.3.2 過渡態類似物抑制劑..................................... 4
1.3.3 受體類似物抑制劑....................................... 5
1.4 石膽酸衍生物作為抑制劑.................................... 6
1.4.1 石膽酸的結構與功能..................................... 6
1.4.2 已知的石膽酸衍生物抑制劑................................ 7
1.5 香豆素(coumarin)的結構與應用 ............................ 8
二、結果與討論............................................. 10
2.1 實驗動機.............................................. 10
2.2 化學合成.............................................. 12
2.2.1 合成石膽酸-胺基酸衍生物 ............................... 12
2.2.2 合成香豆素衍生物...................................... 13
2.2.3 合成三嗪類(Triazines)的耦合試劑 ...................... 17
2.2.4 以耦合試劑合成含有香豆素的石膽酸-胺基酸衍生物 ............. 19
2.2.5 以SOCl2 合成含有香豆素的石膽酸-胺基酸衍生物 ............. 20
2.3 生物活性測試........................................... 22
2.3.1 細胞傷口癒合分析 (Wound healing assay) ............... 22
2.3.2 唾液酸轉移酶活性測試.................................. 27
2.4 結論................................................. 29
三、實驗步驟和數據.......................................... 30
3.1 實驗儀器.............................................. 30
3.2 實驗藥品.............................................. 32
3.3 一般實驗方法........................................... 35
3.3.1 化合物3 的合成:..................................... 35
3.3.2 化合物5 的合成:..................................... 36
3.3.3 化合物KE-46 的合成: ................................ 36
3.3.4 化合物KE-49 的合成: ................................ 38
3.3.5 化合物KE-50 的合成: ................................ 40
3.3.6 化合物KE-89 的合成: ................................ 42
3.3.7 化合物KE-90 的合成: ................................ 44
3.3.8 化合物KE-94 的合成: ................................ 46
3.3.9 化合物KE-106 的合成: ............................... 48
3.3.10 化合物KE-119 的合成: .............................. 50
3.3.11 化合物KE-123 的合成: .............................. 52
3.3.12 化合物KE-125 的合成: .............................. 53
3.3.13 化合物KE-126 的合成: .............................. 55
四、參考文獻............................................... 57
五、光譜附錄............................................... 60
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指導教授 李文山、侯敦仁
(Wen-shan Li、Duen-ren Hou)
審核日期 2013-8-26
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