臺灣博碩士論文加值系統

氧化壓力造成的傷害可能引起生物提前老化及一些疾病，例如:癌症，動脈粥狀硬化以及神經退化等。Caffeic acid phenethyl ester (CAPE) 是由蜂膠萃取出來的多酚類天然物。過去的研究報告指出，CAPE具有抗腫瘤、抗病毒、免疫調節、抗發炎、抗氧化等活性。其抗生物活性與catechol環上的兩個氫氧基還有其溶解度及穩定度有關。氟化的CAPE (FCAPE) 的穩定度比CAPE好，在catechol環上加上氟原子，可能會改變CAPE在生物體內的代謝速率。合成新的CAPE衍生物，找出有更好的抗氧化活性的化合物有其重要性。在本研究中，以CAPE為基本骨架，合成九個CAPE等的衍生物： HST2a (CAPE)、HST2b、HST2c、HST2d、HST4、HST5a、HST6、HST8、和HST10。利用雙氧水誘使果蠅體內產生氧化壓力建立之果蠅動物篩選模式，測試我們所合成的藥物抗氧化活性。結果發現，CAPE處理的果蠅存活率比對照組高。而HST8會造成傷害，HST5a不具活性。與CAPE做比較，HST2b、HST2c、HST2d比CAPE的活性差，HST6、HST10跟CAPE的活性類似，但HST4比CAPE強。本實驗的結果證明在酚酸芳香B環上取代氟原子無法提高抗氧化活性。酚酸芳香A環上的3-hydroxyl group及5-flouro substitution 在酚酸酯類衍生物抗氧化壓力活性中扮演重要的角色。

Oxidative stress to organism over its lifespan can cause premature aging and disease including cancer, atherosclerosis and neurodegenerative disorders, etc. Caffeic acid phenethyl ester (CAPE) is a polyphenolic plant product of honeybee propolis. There is abundant evidence that CAPE has powerful properties include anti-tumor, anti-HIV, immunomodulatory, anti-inflammatory, antioxidant effect and apoptosis. It indicates that the antioxidative activity of CAPE depends not only on the number of hydroxyl groups or catechol moieties but also on its solubility and stability. In previous studies, fluorinated CAPE (FCAPE) was more stable than CAPE. FCAPE may display different protective ability from CAPE in vivo. Fluorine on the catechol ring may alter the rate of CAPE metabolism. Therefore, we intend to synthesize some new CAPE derivatives which might have better stability, antioxidative effect and low cytotoxicity. In this study, nine CAPE derivatives including three fluorinated derivatives have been synthesized. A model has been established using hydrogen peroxide-induced oxidative stress in Drosophila to evaluate their antioxidative activity. We found that the survival of flies feed by CAPE is better than ethanol (control) in this model. The survival rate of all tested compounds was not all better than control group. Comparing with CAPE, HST2b, HST2c and HST2d were less effective, HST4 was better and others were about the same. Comparing with control, HST8 was worse than control, but HST5a was equal to control. These results provide some insights that fluorination on ring B of CAPE derivatives did not improve the antioxidative activity and hydroxyl group para-substituted on ring A of CAPE and fluoride substitution played important role.

謝誌-------------------------------------------------------------------------------- I
中文摘要------------------------------------------------------------------------- II
英文摘要------------------------------------------------------------------------ III
縮寫表--------------------------------------------------------------------------- IV
圖目錄--------------------------------------------------------------------------- VI
目錄------------------------------------------------------------------------------VII
壹、背景介紹
一、 酚酸之介紹 ---------------------------------------------------------- 1
二、 C6-C3酚酸化合物的應用 --------------------------------------- 2
三、 酚酸類與其衍生物的生物活性 --------------------------------- 3
四、 酚酸酯類衍生物與抗氧化的關係 ------------------------------ 4
五、自由基與氧化性傷害的關係 ------------------------------------ 5
贰、文獻回顧與研究動機 --------------------------------------------------- 7
参、實驗儀器和材料 --------------------------------------------------------- 13
肆、化學藥品與試劑 --------------------------------------------------------- 15
伍、酚酸酯類衍生物化學合成之實驗流程、步驟與方法---------------- 17
陸、抗氧化活性分析
一、實驗模式-------------------------------------------------------------- 37
二、實驗條件-------------------------------------------------------------- 37
三、氧化壓力環境-------------------------------------------------------- 37
柒、實驗結果------------------------------------------------------------------- 38
捌、討論------------------------------------------------------------------------- 53
玖、結論------------------------------------------------------------------------- 56
拾、參考文獻------------------------------------------------------------------- 57
拾壹、圖表附錄---------------------------------------------------------------- 64
Fig. 1 (E)-3-[3-(Benzyloxy)phenyl]-2-propenoic acid 1H NMR 圖譜
------------------------------------------------------------------------------------- 65
Fig. 2 (E)-3-[3-(Benzyloxy)phenyl]-2-propenoic acid 13C NMR 圖譜------------------------------------------------------------------------------------- 66
Fig. 3 (E)-3-[3-(Benzyloxy)phenyl]-2-propenoic acid MS 圖譜------------------------------------------------------------------------------------- 67
Fig. 4 (E)-3-[4-(Benzyloxy)phenyl]-2-propenoic acid 1H NMR 圖譜------------------------------------------------------------------------------------- 68
Fig. 5 (E)-3-[4-(Benzyloxy)phenyl]-2-propenoic acid 13C NMR 圖譜------------------------------------------------------------------------------------- 69
Fig. 6 (E)-3-[4-(Benzyloxy)phenyl]-2-propenoic acid MS 圖譜------------------------------------------------------------------------------------- 70
Fig. 7 (E)-3-[3,4-(Dibenzyloxy)phenyl]-2-propenoic acid 1H NMR圖譜
------------------------------------------------------------------------------------- 71
Fig. 8 (E)-3-[3,4-(Dibenzyloxy)phenyl]-2-propenoic acid 13C NMR圖譜
------------------------------------------------------------------------------------ 72
Fig. 9 (E)-3-[3,4-(Dibenzyloxy)phenyl]-2-propenoic acid MS圖譜
------------------------------------------------------------------------------------ 73
Fig. 10 (E)-3-(3-Methoxyphenyl)-2-propenoic acid 1H NMR圖譜------------------------------------------------------------------------------------ 74
Fig. 11 (E)-3-(3-Methoxyphenyl)-2-propenoic acid 13C NMR圖譜------------------------------------------------------------------------------------ 75
Fig. 12 (E)-3-(3-Methoxyphenyl)-2-propenoic acid MS圖譜------------------------------------------------------------------------------------ 76
Fig. 13 Phenethyl (E)3-[3,4-(Dibenzyloxy)phenyl]-2-propenoate 1H NMR
圖譜------------------------------------------------------------------------------ 77
Fig. 14 Phenethyl (E)3-[3,4-(Dibenzyloxy)phenyl]-2-propenoate
13C NMR圖譜------------------------------------------------------------------ 78
Fig. 15 Phenethyl (E)3-[3,4-(Dibenzyloxy)phenyl]-2-propenoate MS圖譜
------------------------------------------------------------------------------------ 79
Fig. 16 Phenethyl (E)-3-[3-(benzyloxy)phenyl]-2-propenoate 1H NMR
圖譜------------------------------------------------------------------------------ 80
Fig. 17 Phenethyl (E)-3-[3-(benzyloxy)phenyl]-2-propenoate 13C NMR
圖譜------------------------------------------------------------------------------ 81
Fig. 18 Phenethyl (E)-3-[3-(benzyloxy)phenyl]-2-propenoate MS圖譜------------------------------------------------------------------------------------ 82
Fig. 19 Phenethyl (E)-3-[4-(benzyloxy)phenyl]-2-propenoate 1H NMR
圖譜------------------------------------------------------------------------------- 83
Fig. 20 Phenethyl (E)-3-[4-(benzyloxy)phenyl]-2-propenoate 13C NMR圖譜---------------------------------------------------------------------------------- 84
Fig. 21 Phenethyl (E)-3-[4-(benzyloxy)phenyl]-2-propenoate MS圖譜------------------------------------------------------------------------------------- 85
Fig. 22 Phenethyl (E)-3-(3-methoxyphenyl)-2-propenoate 1H NMR圖譜------------------------------------------------------------------------------------- 86
Fig. 23 Phenethyl (E)-3-(3-methoxyphenyl)-2-propenoate 13C NMR圖譜------------------------------------------------------------------------------------- 87
Fig. 24 Phenethyl (E)-3-(3-methoxyphenyl)-2-propenoate MS圖譜------------------------------------------------------------------------------------- 88
Fig. 25 4-(Benzyloxy)phenethyl (E)-3-(3-methoxyphenyl)-2-propenoate 1H NMR圖譜-------------------------------------------------------------------- 89
Fig. 26 4-(Benzyloxy)phenethyl (E)-3-(3-methoxyphenyl)-2-propenoate 13C NMR圖譜--------------------------------------------------------------------90
Fig. 27 4-(Benzyloxy)phenethyl (E)-3-(3-methoxyphenyl)-2-propenoate MS圖譜-------------------------------------------------------------------------- 91
Fig. 28 Phenethyl (E)-3-(3-hydroxyphenyl)-2-propenoate 1H NMR圖譜------------------------------------------------------------------------------------- 92
Fig. 29 Phenethyl (E)-3-(3-hydroxyphenyl)-2-propenoate 13C NMR圖譜------------------------------------------------------------------------------------- 93
Fig. 30 Phenethyl (E)-3-(3-hydroxyphenyl)-2-propenoate MS圖譜------------------------------------------------------------------------------------- 94
Fig. 31 Phenethyl (E)-3-(4-hydroxyphenyl)-2-propenoate 1H NMR圖譜------------------------------------------------------------------------------------- 95
Fig. 32 Phenethyl (E)-3-(4-hydroxyphenyl)-2-propenoate 13C NMR圖譜------------------------------------------------------------------------------------- 96
Fig. 33 Phenethyl (E)-3-(4-hydroxyphenyl)-2-propenoate MS圖譜------------------------------------------------------------------------------------- 97
Fig. 34 4-Hydroxyphenethyl (E)-3-(3-methoxyphenyl)-2-propenoate 1H NMR圖譜------------------------------------------------------------------------ 98
Fig. 35 4-Hydroxyphenethyl (E)-3-(3-methoxyphenyl)-2-propenoate 13C NMR圖譜------------------------------------------------------------------------ 99
Fig. 36 4-Hydroxyphenethyl (E)-3-(3-methoxyphenyl)-2-propenoate MS圖譜----------------------------------------------------------------------------- 100
Fig. 37 Phenethyl (E)-3-(3,4-dihydroxyphenyl)-2-propenoate 1H NMR
圖譜----------------------------------------------------------------------------- 101
Fig. 38 Phenethyl (E)-3-(3,4-dihydroxyphenyl)-2-propenoate 13C NMR圖譜-------------------------------------------------------------------------------- 102
Fig. 39 Phenethyl (E)-3-(3,4-dihydroxyphenyl)-2-propenoate 1H MS圖譜----------------------------------------------------------------------------------- 103
Fig. 40 4-Fluorophenethyl (E)-3-(3,4-dibenzyloxyphenyl)-2-propenoate 1H NMR 圖譜----------------------------------------------------------------- 104
Fig. 41 4-Fluorophenethyl (E)-3-(3,4-dibenzyloxyphenyl)-2-propenoate 13C NMR 圖譜---------------------------------------------------------------- 105
Fig. 42 4-Fluorophenethyl (E)-3-(3,4-dibenzyloxyphenyl)-2-propenoate
MS 圖譜---------------------------------------------------------------------- 106
Fig. 43 3-Fluorophenethyl (E)-3-(3,4-dibenzyloxyphenyl)-2-propenoate 1H NMR 圖譜---------------------------------------------------------------- 107
Fig. 44 3-Fluorophenethyl (E)-3-(3,4-dibenzyloxyphenyl)-2-propenoate MS圖譜----------------------------------------------------------------------- 108
Fig. 45 2-Fluorophenethyl (E)-3-(3,4-dibenzyloxyphenyl)-2-propenoate
1H NMR 圖譜---------------------------------------------------------------- 109
Fig. 46 2-Fluorophenethyl (E)-3-(3,4-dibenzyloxyphenyl)-2-propenoate
13C NMR 圖譜---------------------------------------------------------------- 110
Fig. 47 2-Fluorophenethyl(E)-3-(3,4-dibenzyloxyphenyl)-2-propenoate
MS圖譜------------------------------------------------------------------------ 111
Fig. 48 4-Fluorophenethyl (E)-3-(3,4-dihydroxyphenyl)-2-propenoate 1H NMR圖譜---------------------------------------------------------------------- 112
Fig. 49 4-Fluorophenethyl (E)-3-(3,4-dihydroxyphenyl)-2-propenoate 13C NMR圖譜---------------------------------------------------------------------- 113
Fig. 50 4-Fluorophenethyl (E)-3-(3,4-dihydroxyphenyl)-2-propenoate MS圖譜------------------------------------------------------------------------------ 114
Fig. 51 4-Fluorophenethyl (E)-3-(3,4-dihydroxyphenyl)-2-propenoate COSY圖譜 ------------------------------------------------------------------- 115
Fig. 52 4-Fluorophenethyl (E)-3-(3,4-dihydroxyphenyl)-2-propenoate HMQC圖譜-------------------------------------------------------------------- 116
Fig. 53 4-Fluorophenethyl (E)-3-(3,4-dihydroxyphenyl)-2-propenoat HMBC圖譜 ------------------------------------------------------------------ 117
Fig. 54 3-Fluorophenethyl (E)-3-(3,4-dihydroxyphenyl)-2-propenoate 1H NMR圖譜---------------------------------------------------------------------- 118
Fig. 55 3-Fluorophenethyl (E)-3-(3,4-dihydroxyphenyl)-2-propenoate 13C NMR圖譜---------------------------------------------------------------------- 119
Fig. 56 3-Fluorophenethyl (E)-3-(3,4-dihydroxyphenyl)-2-propenoat MS圖譜 ---------------------------------------------------------------------------- 120
Fig. 57 3-Fluorophenethyl (E)-3-(3,4-dihydroxyphenyl)-2-propenoat COSY圖譜 ------------------------------------------------------------------- 121
Fig. 58 3-Fluorophenethyl (E)-3-(3,4-dihydroxyphenyl)-2-propenoat HMQC圖譜 ------------------------------------------------------------------ 122
Fig. 59 3-Fluorophenethyl (E)-3-(3,4-dihydroxyphenyl)-2-propenoat HMBC圖譜 ------------------------------------------------------------------ 123
Fig. 60 2-Fluorophenethyl (E)-3-(3,4-dihydroxyphenyl)-2-propenoate 1H NMR圖譜---------------------------------------------------------------------- 124
Fig. 61 2-Fluorophenethyl (E)-3-(3,4-dihydroxyphenyl)-2-propenoate 13C NMR圖譜---------------------------------------------------------------------- 125
Fig. 62 2-Fluorophenethyl (E)-3-(3,4-dihydroxyphenyl)-2-propenoat MS圖譜------------------------------------------------------------------------------126
Fig. 63 2-Fluorophenethyl (E)-3-(3,4-dihydroxyphenyl)-2-propenoat COSY圖譜 -------------------------------------------------------------------- 127
Fig. 64 2-Fluorophenethyl (E)-3-(3,4-dihydroxyphenyl)-2-propenoat HMQC圖譜 ------------------------------------------------------------------- 128
Fig. 65 2-Fluorophenethyl (E)-3-(3,4-dihydroxyphenyl)-2-propenoat HMBC圖譜 ------------------------------------------------------------------- 129

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