臺灣博碩士論文加值系統

粗毛金星蕨(Thelypteris torresiana)為金星蕨科(Thelypteridaceae)金星蕨屬植物。本實驗以甲醇萃取全株植物，發現其萃取物對於人類乳癌細胞MDA-MB-231具有明顯的細胞毒殺活性。配合生物活性導引法，從具有細胞毒殺作用的fractions中，進行活性成分的分離純化的研究，在經過各式光譜解析與比對過去文獻後，共分離得到十六個化合物，包含十一個黃酮類化合物，其中五個為新化合物。所有的化合物皆為首次由本植物中分離得到，這些分離結果可做為植物化學分類學的研究基礎。
配合細胞毒殺活性篩選的結果發現，新奇的黃酮類化合物protoapigenone (TT-1)其B環上特殊對稱的para-quinol結構，與一般黃酮類化合物有很大不同。活性測試的結果顯示此一化合物對於人類肝癌細胞(HepG2及Hep3B)、乳癌細胞(MCF-7、MDA-MB-231及T47D)、肺癌細胞(A-549)、卵巢癌細胞(SKOV3及2774)、前列腺癌細胞(PC-3及DU145)皆具有明顯的細胞毒殺活性。特別的是，其對於正常人類乳腺細胞(MCF-10A)的細胞毒殺效果較低，僅為其他乳癌細胞(MCF-7及MDA-MB-231)的7.5至4.6倍，判斷protoapigenone可能對於抑制人類癌症細胞具有選擇性。
進一步以新藥開發的模式進行protoapigenone化學方法全合成的製備與活性衍生物研究。首先以Claisen-Schmidt縮和方式得到chalcone類化合物，再進行環化得到flavonoid；配合兩種不同保護基，依序保護5與7位置上的羥基，使欲反應的位置能夠單獨露出，並有效脫除，使得反應的產率可以提高。再利用高價碘氧化劑(TAIB)進行氧化反應，可得到B環上4''-hydroxy phenol氧化成為para-quinol結構。最後脫去剩下的保護基團，可以成功得到目標化合物protoapigenone (ANR-14)。
此外，以半合成方式製備各式衍生物，以固定protoapigenone化合物A、B、C環的骨架，透過改變化合物上C-5, C-7, C-1''位置的官能基，或增加一共軛的苯環在flavonoid 的A環上形成naphthoflavonoid，以研究是否能夠提高protoapigenone結構對於五種人類肝癌細胞(HepG2、Hep3B)、乳癌細胞(MCF-7、MDA-MB-231)、肺癌細胞(A-549)之體外細胞毒殺活性。在所有的衍生物之中，化合物ANR-23的毒殺效果甚佳，甚至可與臨床用藥doxorubicin相比擬。
本研究以活性天然物化學成分分離作為的起始點，確認其中主要活性成分，並以化學方式進行全合成研究與修飾結構，提高化合物的生物活性。目前的研究成果，已經提出兩個台灣專利與兩個個美國專利的申請，以保護研究成果。

In our continuing research of bioactive plants, a pteridophyte, Thelypteris torresiana (Gaud.) Alston (Thelypteridaceae), collected from the mountains in Taiwan was found that its methanol extract has cytotoxic effect toward human breast cancer cell line MDA-MB-231.
The results led us to aim at the isolation of bioactive compounds of Thelypteris torresiana (Gaud.) Alston (Thelypteridaceae). By bioactivity-guided fractionation, 6 novel flavonoids were found and characterized by UV, IR, 1D, 2D-NMR and comparing them with the previous literatures. A novel flavonoid, protoapigenone (TT-1), which has unique para-quinol B-ring showed obvious cytotoxic activities toward human liver cancer lines HepG2 and Hep3B, human breast cancer lines MCF-7 and MDA-MB-231, a human lung cancer cell line A-549, and human ovarian cancer cell lines SKOV3 and 2774, and human prostate cancer cell lines PC-3 and DU145. Comparing the data with the human normal cell line MCF-10A., it had less cytotoxic activity (only 1/7.5 to 1/4.6). This drawn our interests, and we decided to study more on this structure.
Further investigations focused on the total synthesis of this bioactive component, protoapigenone, and the partial synthesis of its analogs. A chalcone was synthesized by using Claisen-Schmidt condensation, and then it was cyclolized to afford a flavonoid structure. In order to specific the oxidation site, two different protective groups were used on this flavonoid. The key reaction was to oxidize the B-ring from phenol to para-quinol with hypervalent iodine oxidation reagent. The last step was to remove the protective group and then afforded the protoapigenone successfully.
Besides, we synthesized 10 analogs by partial synthesis from commercial available flavonoids. By modifying the C-5, C-7 and C-1'' positions of protoapigenone, or adding one more conjugated benzene group on the ring A, the cytotoxic activities toward five human cancer cell lines (HepG2, Hep3B, MCF-7, MDA-MB-231, and A-549) were obviously enhanced. Among all the analogs, the cytotoxic effects of compound ANR-23 was comparable to clinical use drug, doxorubicin.
Our research started from the extraction and isolation of a natural product. After characterized structure of its active components, we synthesized it and modified the structure to improve the cytotoxic activity. The results of our research have filed two Taiwan patents and two US patents.

目錄................................................................................................. I
圖表目錄.......................................................................................... III
中文摘要.......................................................................................... 1
英文摘要.......................................................................................... 3
第一章 緒論..................................................................................... 5
第一節 研究動機與背景.............................................................. 5
第二節 植物型態特性與分佈....................................................... 10
第三節 過去文獻整理.................................................................. 13
第二章 植物成分之抽取與分離................................................... 21
第三章 化合物之結構證明.......................................................... 27
第一節 Protoapigenone (TT-1)之結構證明之結構證明.............. 27
第二節 5'',6''-Dihydro-6''-methoxy-protoapigenone (TT-2)之結構證明................................................................................
32
第三節 Protoapigenin (TT-3)之結構證明.................................... 38
第四節 Protoapigenin 4-O-??-D-glucoside (TT-4)之結構證明...... 43
第五節 Flavotorresin (TT-8)之結構證明….................................. 48
第六節 Multiflorin C (TT-9)之結構證明....................................... 54
第七節 1??-Acetoxy-11,12-epoxy-7-drimen-11-ol (TT-10)之結構證明................................................................................
59
第四章Protoapigenone全合成探討. .............................................. 65
第一節 研究動機........................................................................ 65
第二節 相關研究概況.................................................................. 67
第三節 Protoapigenone之逆合成探討與合成策略..................... 75
第四節 Protoapigenone之合成探討（I）................................... 78
第五節 Protoapigenone之合成探討（II）.................................. 92
第五章 Protoapigenone衍生物之合成探討..................................... 113
第一節 C-1''位置甲氧基衍生物之合成......................................... 113
第二節 A環上取代基衍生物之合成............................................. 117
第六章 合成化合物純度測試............................................................ 143
第七章 生物活性試驗相關實驗方法................................................. 153
第一節 相關實驗方法.................................................................. 153
第二節 活性篩選結果.................................................................. 155
第八章 結 論.............................................................................. 165
第一節 天然物成分分離部分....................................................... 165
第二節 相關黃酮類化合物可能的生合成路徑.......................... 166
第三節 Protoapigenone之全合成與衍生物製備及生物活性部分 168
第九章 相關實驗部分...................................................................... 171
第一節 本實驗所使用之儀器與藥品........................................... 171
第二節 植物成分分離流程細節.................................................. 173
第三節 分離化合物物理與光譜數據........................................... 176
第四節 合成化合物物理與光譜數據........................................... 187
第十章 參考文獻.............................................................................. 199
第十一章 論文著作發表................................................................... 209


圖表目錄
圖目錄
圖1-2-1: 粗毛金星蕨之植物型態圖……………………….............. 10
圖1-2-2: 粗毛金星蕨Thelypteris torresiana (Gaud.) Alston…….. 11
圖1-2-3: 粗毛金星蕨分佈…………………………..…................... 12
圖2-1: 粗毛金星蕨全株植物成分分離流程………………………... 22
圖2-2: 粗毛金星蕨全株之化學成分結構分類與整理……………... 24
圖3-1-1: Protoapigenone (TT-1) 之MS斷片推測………………... 28
圖3-1-2: Protoapigenone (TT-1) 之1H-NMR光譜圖…………….. 29
圖3-1-3: Protoapigenone (TT-1) 之1C-NMR光譜圖…………….. 30
圖3-1-4: Protoapigenone (TT-1) 之EIMS圖譜…………………… 30
圖3-1-5: Protoapigenone (TT-1) 之FTIR光譜圖………………… 31
圖3-1-6: Protoapigenone (TT-1) 之UV光譜圖…………………… 31
圖3-2-1: 5'',6''-Dihydro-6''-methoxy-protoapigenone (TT-2) 之1H-NMR光譜圖…………………………………………….
34
圖3-2-2: 5'',6''-Dihydro-6''-methoxy-protoapigenone (TT-2) 之DEPT 光譜圖……………………………………………..
34
圖3-2-3: 5'',6''-Dihydro-6''-methoxy-protoapigenone (TT-2) 之HMBC光譜圖……………………………………………..
35
圖 3-2-4: 5'',6''-Dihydro-6''-methoxy-protoapigenone (TT-2) 之NOESY光譜圖……………………………………………
35
圖 3-2-5: 5'',6''-Dihydro-6''-methoxy-protoapigenone (TT-2) 之COSY光譜圖……………………………………………...
36
圖3-2-6: 5'',6''-Dihydro-6''-methoxy-protoapigenone (TT-2) 之HMQC光譜圖……………………………………………..
36
圖3-2-7: 5'',6''-Dihydro-6''-methoxy-protoapigenone (TT-2) 之EIMS圖譜…………………………………………………
37
圖3-2-8: 5'',6''-Dihydro-6''-methoxy-protoapigenone (TT-2) 之 IR光譜圖…………………………………………………..
37
圖3-3-1: Protoapigenin (TT-3) 之MS斷片推測………………… 39
圖3-3-2: Protoapigenin (TT-3) 之1H-NMR光譜圖……………….. 40
圖3-3-3: Protoapigenin (TT-3) 之13C-NMR光譜圖……………… 41
圖3-3-4: Protoapigenin (TT-3) 之COSY光譜圖…………………. 41
圖3-3-5: Protoapigenin (TT-3) 之EIMS圖譜…………………….. 42
圖3-3-6: Protoapigenin (TT-3) 之IR光譜圖………………………. 42
圖3-4-1: Protoapigenin 4-O-??-D-glucoside (TT-4) 之 1H-NMR光譜圖…………………………………………...
45
圖3-4-2: Protoapigenin 4-O-??-D-glucoside (TT-4) 之 13C-NMR光譜圖……………………………………………
45
圖3-4-3: Protoapigenin 4-O-??-D-glucoside (TT-4) 之 NOESY 光譜圖…………………………………………..
46
圖3-4-4: Protoapigenin 4-O-??-D-glucoside (TT-4) 之 FABMS圖譜………………………………………………
46
圖3-4-5: Protoapigenin 4-O-??-D-glucoside (TT-4) 之 EIMS圖譜…………………………………………………
47
圖3-4-6: Protoapigenin 4-O-??-D-glucoside (TT-4) 之UV光譜圖.. 47
圖3-5-1: Flavotorresin (TT-8) B環之1H-NMR訊號………………. 49
圖3-5-2: Flavotorresin (TT-8) 之1H-NMR光譜圖………………… 50
圖3-5-3: Flavotorresin (TT-8) 之13C-NMR光譜圖……………….. 50
圖3-5-4: Flavotorresin (TT-8) 之HMQC 光譜圖…………………. 51
圖3-5-5: Flavotorresin (TT-8) 之HMBC 光譜圖…………………. 51
圖3-5-6: Flavotorresin (TT-8) 之 EIMS圖譜……………………... 52
圖3-5-7: Flavotorresin (TT-8) 之 IR 圖譜... ……………………... 52
圖3-5-8: Flavotorresin (TT-8) 之 UV 圖譜……………………….. 53
圖3-6-1: Flavotorresin (TT-9) 之1H-NMR光譜圖………………… 56
圖3-6-2: Flavotorresin (TT-9) 之13C-NMR光譜圖……………….. 56
圖3-6-3: Flavotorresin (TT-9) 之HMBC 光譜圖…………………. 57
圖3-6-4: Flavotorresin (TT-9) 之UV圖譜………………………… 57
圖3-6-5: Flavotorresin (TT-9) 之ESIMS圖譜……………………. 58
圖3-7-1: Flavotorresin (TT-10) 之1H-NMR光譜圖………………. 60
圖3-7-2: Flavotorresin (TT-10) 之DEPT光譜圖…………………. 61
圖3-7-3: Flavotorresin (TT-10) 之COSY 光譜圖………………... 61
圖3-7-4: Flavotorresin (TT-10) 之HMQC 光譜圖……………….. 62
圖3-7-5: Flavotorresin (TT-10) 之HMBC 光譜圖………………... 62
圖3-7-6: Flavotorresin (TT-10) 之NOESY圖譜………………….. 63
圖3-7-7: Flavotorresin (TT-10) 之IR圖譜………………………… 63
圖4-2-1: Flavonoid 類化合物合成方式I…………………………… 67
圖4-2-2: Flavonoid 類化合物合成方式II………………………….. 68
圖4-2-3: 高價碘氧化劑 TAIB與DAIB…………………………….. 69
圖4-2-4: 利用高價碘氧化p-alkoxyphenols之反應………………. 70
圖4-2-5: 利用高價碘氧化p-cresol之反應………………………… 71
圖4-2-6: ortho與meta取代之phenol利用高價碘氧化phenols反應…………………………………………………………
71
圖4-2-7: Cyclohexadienones的製備與反應機構…………………. 72
圖4-2-8: 2-substituted benzothiazole利用高價碘氧化…………... 73
圖4-2-9: Quinols類化合物之結構與細胞毒殺活性關係（SAR）….. 73
圖4-2-10: 化合物AW 464………………………………………….. 74
圖4-2-11: Quinols類化合物與thioredoxin結合之關係…….….….. 74
圖4-3-1: Protoapigenone之逆合成推演…………………………… 75
圖4-3-2: 由apigenin直接進行氧化反應…………………………... 76
圖4-3-3: Protoapigenone製備流程………………………………… 77
圖4-4-1: Protoapigenone全合成路徑設計………………………… 78
圖4-4-2: 化合物ANR-3之製備流程簡圖………………………….. 79
圖4-4-3: 化合物ANR-3之1H-NMR光譜圖………………………. 80
圖4-4-4: 化合物ANR-3之13C-NMR光譜圖………………………. 81
圖4-4-5: 化合物ANR-3之ESIMS圖譜…………………………… 81
圖4-4-6: 化合物ANR-4之製備流程簡圖………………………….. 82
圖4-4-7: 化合物ANR-4之1H-NMR光譜圖………………………. 83
圖4-4-8: 化合物ANR-4之13C-NMR光譜圖………………………. 84
圖4-4-9: 化合物 ANR-4之EIMS圖譜…………………….………. 84
圖4-4-10: 化合物ANR-5之製備流程簡圖………………………… 85
圖4-4-11: 化合物ANR-5之1H-NMR光譜圖……………………… 86
圖4-4-12: 化合物ANR-5之13C-NMR光譜圖……………………. 87
圖4-4-13: 化合物ANR-5之EIMS圖譜…………………………… 78
圖4-4-14: 化合物ANR-6之製備流程簡圖………………………… 88
圖4-4-15: 化合物ANR-6之1H-NMR光譜圖……………………… 89
圖4-4-16: 化合物ANR-6之13C-NMR光譜圖……………………. 90
圖4-4-17: 化合物ANR-6之EIMS圖譜…………………………… 90
圖4-4-18: ANR-6甲基保護基無法脫除……………………………. 91
圖4-5-1: Protoapigenone全合成路徑設計………………………… 93
圖4-5-2: 化合物ANR-9之製備流程簡圖………………………….. 94
圖4-5-3: 化合物ANR-9之1H-NMR光譜圖………………………. 95
圖4-5-4: 化合物ANR-9之13C-NMR光譜圖……………………… 96
圖4-5-5: 化合物ANR-9之ESIMS光譜圖………………………… 96
圖4-5-6: 化合物ANR-9之製備流程簡圖………………………….. 97
圖4-5-7: 化合物ANR-10之1H-NMR光譜圖……………………… 98
圖4-5-8: 化合物ANR-10之13C-NMR光譜圖……………………. 99
圖4-5-9: 化合物ANR-10之ESIMS圖譜…………………………. 99
圖4-5-10: 化合物ANR-11之製備流程簡圖………………………. 100
圖4-5-11: 化合物ANR-11之1H-NMR光譜圖……………………. 102
圖4-5-12: 化合物ANR-11之13C-NMR光譜圖…………………… 102
圖4-5-13: 化合物 ANR-11之ESIMS圖譜……………………….. 103
圖4-5-14: 化合物ANR-12之製備流程簡圖……………………….. 104
圖4-5-15: 化合物ANR-12之1H-NMR光譜圖……………………. 105
圖4-5-16: 化合物ANR-12之13C-NMR光譜圖…………………… 106
圖4-5-17: 化合物ANR-12之ESIMS圖譜………………………… 106
圖4-5-18: 化合物ANR-13之製備流程簡圖………………………. 107
圖4-5-19: 化合物ANR-13之1H-NMR光譜圖……………………. 108
圖4-5-20: 化合物ANR-13之13C-NMR光譜圖…………………… 109
圖4-5-21: 化合物ANR-13之ESIMS圖譜………………………… 109
圖4-5-22: 化合物ANR-14之製備流程簡圖………………………. 110
圖4-5-23: 化合物ANR-14之1H-NMR光譜圖……………………. 111
圖4-5-24: 化合物ANR-14之13C-NMR光譜圖…………………… 111
圖4-5-25: 化合物ANR-14之EIMS圖譜………………………….. 112
圖5-1-1: Protoapigenone C-1''位置取代之的合成機轉………..….. 113
圖5-1-2: 化合物ANR-6之製備流程簡圖………………………….. 114
圖5-1-3: 化合物ANR-15之1H-NMR光譜圖……………………… 115
圖5-1-4: 化合物ANR-15之13C-NMR光譜圖……………………. 116
圖5-1-5: 化合物ANR-15之ESIMS圖譜…………………………. 116
圖5-2-1: 具有4''-OH結構的黃酮類化合物………………………… 117
圖5-2-2: Protoapigenone 衍生物ANR-17之合成……………….. 118
圖5-2-3: 化合物ANR-17之1H-NMR光譜圖……………………… 119
圖5-2-4: 化合物ANR-17之13C-NMR光譜圖……………………. 120
圖5-2-5: 化合物ANR-17之ESI-MS圖譜………………………… 120
圖5-2-6: Protoapigenone 衍生物ANR-17之合成……………….. 121
圖5-2-7: 化合物ANR-18之1H-NMR光譜圖……………………… 122
圖5-2-8: 化合物ANR-18之13C-NMR光譜圖……………………. 123
圖5-2-9: 化合物ANR-18之ESIMS圖譜………………………….. 123
圖5-2-10: Protoapigenone 衍生物ANR-20之合成…………..….. 124
圖5-2-11: 化合物ANR-20之1H-NMR光譜圖…………………….. 125
圖5-2-12: 化合物ANR-20之13C-NMR光譜圖………….……….. 126
圖5-2-13: 化合物ANR-20之ESIMS圖譜…………………….….. 126
圖5-2-14: Protoapigenone 衍生物ANR-21之合成…………..….. 127
圖5-2-15: 化合物ANR-21之1H-NMR光譜圖……………………. 128
圖5-2-16: 化合物ANR-21之13C-NMR光譜圖…………………… 129
圖5-2-17: 化合物ANR-21之ESIMS圖譜………………………… 129
圖5-2-18: Protoapigenone 衍生物ANR-23之合成…………..….. 130
圖5-2-19: 化合物ANR-23 之1H-NMR光譜圖……………….….. 131
圖5-2-20: 化合物ANR-23之13C-NMR光譜圖…………….…….. 132
圖5-2-21: 化合物ANR-23之ESIMS圖譜………………….…….. 132
圖5-2-22: Naphthoflavone…………….………………..……….….. 133
圖5-2-23: Protoapigenone 衍生物ANR-25之合成…………..….. 134
圖5-2-24: 化合物ANR-25 之1H-NMR光譜圖…………………… 135
圖5-2-25: 化合物ANR-25之13C-NMR光譜圖…………………… 136
圖5-2-26: 化合物ANR-25之ESIMS圖譜………………………… 136
圖5-2-27: Protoapigenone 衍生物ANR-26之合成……………… 137
圖5-2-28: 化合物ANR-26 之1H-NMR光譜圖…………………… 138
圖5-2-29: 化合物ANR-26之13C-NMR光譜圖…………………… 139
圖5-2-30: 化合物ANR-26之ESIMS圖譜………………………… 139
圖5-2-31: Protoapigenone 衍生物ANR-28之合成…………..….. 140
圖5-2-32: 化合物ANR-28 之1H-NMR光譜圖…………………… 141
圖5-2-33: 化合物ANR-28之13C-NMR光譜圖…………………… 142
圖5-2-34: 化合物ANR-28之EIMS圖譜………………………….. 142
圖6-1: ANR-6之純度測試結果……………………………………... 145
圖6-2: ANR-13之純度測試結果……………………………………. 145
圖6-3: ANR-14之純度測試結果……………………………………. 146
圖6-4: ANR-15之純度測試結果……………………………………. 146
圖6-5: ANR-17之純度測試結果……………………………………. 147
圖6-6: ANR-18之純度測試結果……………………………………. 147
圖6-7: ANR-20之純度測試結果……………………………………. 148
圖6-8: ANR-21之純度測試結果……………………………………. 148
圖6-9: ANR-23之純度測試結果……………………………………. 149
圖6-10: ANR-25之純度測試結果…………………………………... 149
圖6-11: ANR-26之純度測試結果…………………………………... 150
圖6-12: ANR-28之純度測試結果…………………………...……… 150
圖7-3-1: Protoapigenone類化合物結構活性關係………………… 161
圖7-3-2: 17??-Estradiol、genistein、daidzein與控制組之 螢光表現....………………………………………………..
163
圖8-2-1: 粗毛金星蕨中黃酮類化合物之可能的生合成路徑……… 166
圖8-2-2: 4-Dimethoxycyclohexane可能產生之路徑……………... 167


表目錄
表1-1-1: 台灣產金星蕨科植物................................................. 8
表1-3-1: 金星蕨科植物相關植物化學成分研究結果...... 13
表2-1：粗毛金星蕨 (T. torresiana) 成分分離之成果…………. 23
表6-1: 合成化合物純度測試結果……………………………….. 151
表6-2: 高解析質譜測試結果…………………………………….. 152
表7-2-1: 粗毛金星蕨分離化合物細胞毒殺活性測試結果……... 155
表7-2-2: Protoapigenone (TT-1) 細胞毒殺活性測試結果……. 157
表7-2-3: 合成化合物細胞毒殺活性測試結果…………………... 158
表7-2-4: Protoapigenone與其他化合物之雌激素活性……… 164

1.李時珍, 本草綱目. 1596.
2.賴榮祥, 1998 年12月16日在臺東區農業改良場所舉行：「蕨類植物種原蒐集及應用」之演講稿. 1998.
3.Editoral Committee of Flora of Taiwan. Flora of Taiwan Vol. I; Lungwei Printing Co. Ltd.: Taipei, 1994, pp 411-412.
4.Newman, D. J.; Cragg, G. M., Natural Products as Sources of New Drugs over the Last 25 Years. J. Nat. Prod. 2007, 70, (3), 461-477.
5.Southwell, I. A., 25 Years of natural product R&D with New South Wales agriculture. Molecules 2005, 10, (10), 1232-1241.
6.郭城孟, 蕨類圖鑑. 遠流出版社 2001.
7.Wada, H.; Fujita, H.; Murakami, T.; Saiki, Y.; Chen, C. M., Chemical and chemotaxonomical studies of ferns. LXXIII. New flavonoids with modified B-ring from the genus Pseudophegopteris (Thelypteridaceae). Chem. Pharm. Bull. 1987, 35, (12), 4757-4762.
8.Adam, K.-P., Phenolic constituents of the fern Phegopteris connectilis. Phytochemistry 1999, 52, (5), 929-934.
9.Fang, W.; Ruan, J.; Wang, Z.; Zhao, Z.; Zou, J.; Zhou, D.; Cai, Y., Acetylated Flavanone Glycosides from the Rhizomes of Cyclosorus acuminatus. J. Nat. Prod. 2006, 69, (11), 1641-1644.
10.Tanaka, N.; Murakami, T.; Wada, H.; Gutierrez, A. B.; Saiki, Y.; Chen, C.-M., Chemical and Chemotaxonomical Studies of Filices. LXI. Chemical Studies on the Constituents of Pronephrium triphyllum HOLLT. . Chem. Pharm. Bull. 1985, 33, 5231-5238.
11.Quadri-Spinelli, T.; Heilmann, J.; Rali, T.; Sticher, O., Bioactive coumarin derivatives from the fern Cyclosorus interruptus. Planta Med. 2000, 66, (8), 728-733.
12.Socolsky, C.; Muruaga, N.; Bardon, A., Drimanes and other terpenoids from the fern Thelypteris hispidula (Decne.) Reed. Chem. Biodiver. 2005, 2, (8), 1105-1108.
13.Anderson, O. M.; Markham, K. R., Flavonoids: Chemistry, Biochemistry and applications. 2006, Talor & Francis Group, (Florida).
14.Pauli, G. F., Higher Order and Substituent Chemical Shift Effects in the Proton NMR of Glycosides. J. Nat. Prod. 2000, 63, (6), 834-838.
15.Harborne, J. B.; Mabry, T. J.; Mabry, H., The Flavonoids. Academic Press Inc. 1975, New York.
16.Lin, Y.-L.; Kuo, Y.-H.; Shiao, M.-S.; Chen, C.-C.; Ou, J.-C., Flavonoid glycosides from Terminalia catappa L. J. Chin. Chem. Soc. 2000, 47, (1), 253-256.
17.Lin, Y.-L.; Wang, C.-N.; Shiao, Y.-J.; Liu, T.-Y.; Wang, W.-Y., Benzolignanoid and polyphenols from Origanum vulgare. J. Chin. Chem. Soc. 2003, 50, (5), 1079-1083.
18.Deng, Y.-R.; Song, A.-X.; Wang, H.-Q., Chemical components of Seriphidium santolium Poljak. J. Chin. Chem. Soc. 2004, 51, (3), 629-636.
19.Hauteville, M.; Chopin, J.; Geiger, H.; Schuler, L., Protogenkwanin, a new flavonoid from Equisetum arvense L. Tetrahedron 1981, 37, (2), 377-381.
20.Tanaka, N.; Murakami, T.; Saiki, Y.; Chen, C. M.; Gomez P, L. D., Chemical and chemotaxonomical studies of ferns. XXXVII. Chemical studies on the constituents of Costa Rican ferns. 2. Chem. Pharm. Bull. 1981, 29, (12), 3455-3463.
21.Veit, M.; Beckert, C.; Hoehne, C.; Bauer, K.; Geiger, H., Interspecific and intraspecific variation of phenolics in the genus Equisetum subgenus Equisetum. Phytochemistry 1995, 38, (4), 881-891.
22.Bilia, A. R.; Palme, E.; Marsili, A.; Pistelli, L.; Morelli, I., A flavonol glycoside from Agrimonia eupatoria. Phytochemistry 1993, 32, (4), 1078-1079.
23.Budzianowski, J., Kaempferol glycosides from Hosta ventricosa. Phytochemistry 1990, 29, (11), 3643-3647.
24.Chiale, C. A.; Cabrera, J. L.; Juliani, H. R., Kaempferol 3-(6"-cis-cinnamoylglucoside) from Solanum elaeagnifolium. Phytochemistry 1991, 30, (3), 1042-1043.
25.Pandey, V. B.; Dwivedi, S. P. D.; Rao, Y. V.; Goel, R. K., Flavonoids of Rhamnus procumbens and pharmacological actions of kaempferol-4''-O-methyl ether. Fitoterapia 1990, 61, (3), 243-244.
26.Wang, J.; Kasai, R.; Sakimori, M.; Miyakoshi, M.; Tanaka, O.; Jia, M.; Ling, Y., Flavonol glycosides from the fruits of Rhamnus leptophylla. Phytochemistry 1988, 27, (12), 3995-3996.
27.Ebata, N.; Nakajima, K.; Hayashi, K.; Okada, M.; Maruno, M., Saponins from the root of Bupleurum falcatum. Phytochemistry 1996, 41, (3), 895-901.
28.Teng, R.; Xie, H.; Li, H. Z.; Liu, X.; Wang, D.; Yang, C., Two new acylated flavonoid glycosides from Morina nepalensis var. alba Hand.-Mazz. Magn. Reson. Chem. 2002, 40, (6), 415-420.
29.Siems, K.; Weigt, F.; Wollenweber, E., Drimanes from the epicuticular wax of the fern Nephrolepis biserrata. Phytochemistry 1996, 41, (4), 1119-1121.
30.Socolsky, C.; Muruaga, N.; Bardon, A., Drimanes and other terpenoids from the fern Thelypteris hispidula (Decne.) Reed. Chem. Biodiver. 2005, 2, (8), 1105-1108.
31.Kiyota, H.; Shi, Q.-W.; Oritani, T., A new drimane from the heartwood of the Japanese yew, Taxus cuspidata. Nat. Prod. Lett. 2002, 16, (1), 21-24.
32.Lin, A.-S.; Chang, F.-R.; Wu, C.-C.; Liaw, C.-C.; Wu, Y.-C., New cytotoxic flavonoids from Thelypteris torresiana. Planta Med. 2005, 71, (9), 867-870.
33.Huang, Y.-L.; Yeh, P.-Y.; Shen, C.-C.; Chen, C.-C., Antioxidant flavonoids from the rhizomes of Helminthostachys zeylanica. Phytochemistry 2003, 64, (7), 1277-1283.
34.Lu, B.; Wu, X.; Shi, J.; Dong, Y.; Zhang, Y., Toxicology and safety of antioxidant of bamboo leaves. Part 2: Developmental toxicity test in rats with antioxidant of bamboo leaves. Food Chem. Toxicol. 2006, 44, (10), 1739-1743.
35.McPhail, D. B.; Hartley, R. C.; Gardner, P. T.; Duthie, G. G., Kinetic and Stoichiometric Assessment of the Antioxidant Activity of Flavonoids by Electron Spin Resonance Spectroscopy. J. Agric. Food Chem. 2003, 51, (6), 1684-1690.
36.Nichita, C.; Bazdoaca, C.; Parvu, L.; Giurginca, M.; Meghea, A., Antioxidant capacity of some plant extracts reach in flavons for therapeutical applications. Scientific Bulletin 2005, 67, (3), 39-42.
37.Op de Beck, P.; Cartier, G.; David, B.; Dijoux-Franca, M.-G.; Mariotte, A.-M., Antioxidant flavonoids and phenolic acids from leaves of Leea guineense G. Don (Leeaceae). Phytother. Res. 2003, 17, (4), 345-347.
38.Susanti, D.; Sirat, H. M.; Ahmad, F.; Ali, R. M.; Aimi, N.; Kitajima, M., Antioxidant and cytotoxic flavonoids from the flowers of Melastoma malabathricum L. Food Chem. 2007, 103, (3), 710-716.
39.Yu, J.; Wang, L.; Walzem, R. L.; Miller, E. G.; Pike, L. M.; Patil, B. S., Antioxidant Activity of Citrus Limonoids, Flavonoids, and Coumarins. J. Agric. Food Chem. 2005, 53, (6), 2009-2014.
40.Panthong, A.; Tassaneeyakul, W.; Kanjanapothi, D.; Tantiwachwuttikul, P.; Reutrakul, V., Anti-inflammatory activity of 5,7-dimethoxyflavone. Planta Med. 1989, 55, (2), 133-136.
41.Sarma, S. P.; Aithal, K. S.; Srinivasan, K. K.; Udupa, A. L.; Kumar, V.; Kulkarni, D. R.; Rajagopal, P. K., Anti-inflammatory and wound healing activities of the crude alcoholic extract and flavonoids of Vitex leucoxylon. Fitoterapia 1990, 61, (3), 263-265.
42.Onwukaeme, N. D., Anti-inflammatory activities of flavonoids of Baphia nitida Lodd. (Leguminosae) on mice and rats. J. Ethnopharmacol. 1995, 46, (2), 121-124.
43.Kao, E.-S.; Wang, C.-J.; Lin, W.-L.; Yin, Y.-F.; Wang, C.-P.; Tseng, T.-H., Anti-inflammatory Potential of Flavonoid Contents from Dried Fruit of Crataegus pinnatifida in Vitro and in Vivo. J. Agric. Food Chem. 2005, 53, (2), 430-436.
44.Ismaili, H.; Tortora, S.; Sosa, S.; Fkih-Tetouani, S.; Ilidrissi, A.; Della Loggia, R.; Tubaro, A.; Aquino, R., Topical anti-inflammatory activity of Thymus willdenowii. J. Pharm. Pharmacol. 2001, 53, (12), 1645-1652.
45.Elangovan, V.; Sekar, N.; Govindasamy, S., Chemopreventive potential of dietary bioflavonoids against 20-methylcholanthrene-induced tumorigenesis. Cancer Lett. 1995, 88, (1), 119-120.
46.Havsteen, B. H., The biochemistry and medical significance of the flavonoids. Pharmacol. Ther. 2002, 96, (2-3), 67-202.
47.Middleton, E., Jr.; Kandaswami, C.; Theoharides, T. C., The effects of plant flavonoids on mammalian cells: Implications for inflammation, heart disease, and cancer. Pharmacolo. Rev. 2000, 52, (4), 673-751.
48.Sonnenbichler, J.; Pohl, A., Mechanism of silybin action, IV. Structure-action relationship (author''s transl). Hoppe Seylers Z. Physiol. Chem. 1980, 361, (11), 1757-1761.
49.Sonnenbichler, J.; Mattersberger, J.; Hanser, G., Mechanism of silybin action, III. Resorption of the flavonolignane derivative silybin into rat liver cells (author''s transl). Hoppe Seylers Z. Physiol. Chem. 1980, 361, (11), 1751-1756.
50.Baker, M. E., Flavonoids as hormones. A perspective from an analysis of molecular fossils. Adv. Exp. Med. Biol. 1998, 439, 249-267.
51.Treeck, O.; Haldar, C.; Ortmann, O., Antiestrogens module MT1 melatonin receptor expression in breast and ovarian cancer cell lines. Oncol. Rep. 2006, 15, (1), 231-235.
52.Honma, N.; Takubo, K.; Sawabe, M.; Arai, T.; Akiyama, F.; Sakamoto, G.; Utsumi, T.; Yoshimura, N.; Harada, N., Estrogen-metabolizing enzymes in breast cancers from women over the age of 80 years. J. Clin. Endocrinol. Metab. 2006, 91, (2), 607-613.
53.Ganmaa, D.; Sato, A., The possible role of female sex hormones in milk from pregnant cows in the development of breast, ovarian and corpus uteri cancers. Med. Hypotheses 2005, 65, (6), 1028-1037.
54.林煌雄, 類黃酮的合成及藥理活性研究. 嘉南藥理科技大學 2003, pp 4-13.
55.Horie, T.; Tominaga, H.; Kawamura, Y.; Hada, T.; Ueda, N.; Amano, Y.; Yamamoto, S., Syntheses of 5,7,8- and 5,6,7-trioxygenated 3-alkyl-3'',4''-dihydroxyflavones and their inhibitory activities against arachidonate 5-lipoxygenase. J. Med. Chem. 1991, 34, (7), 2169-2176.
56.Huang, W.-H.; Chien, P.-Y.; Yang, C.-H.; Lee, A.-R., Novel synthesis of flavonoids of Scutellaria baicalensis Georgi. Chem. Pharm. Bull. 2003, 51, (3), 339-340.
57.Tamura, Y.; Yakura, T.; Haruta, J.; Kita, Y., Hypervalent iodine oxidation of p-alkoxyphenols and related compounds: a general route to p-benzoquinone monoacetals and spiro lactones. J. Org. Chem. 1987, 52, (17), 3927-3930.
58.Pelter, A.; Elgendy, S., Phenolic oxidation with (diacetoxyiodo)benzene. Tetrahedron Lett. 1988, 29, (6), 677-680.
59.Pelter, A.; Elgendy, S. M. A., Phenolic oxidations with phenyliodonium diacetate. J. Chem. Soc. Perkin Trans 1 1993, (16), 1891-1896.
60.Pelter, A.; Satchwell, P.; Ward, R. S.; Blake, K., Effective, direct biomimetic synthesis of dibenzocyclooctene lignans by hypervalent iodine oxidation of phenolic dibenzylbutylrolactones. J. Chem. Soc. Perkin Trans 1 1995, (18), 2201-2202.
61.Wipf, P.; Kim, Y., Studies on the synthesis of Stemona alkaloids; stereoselective preparation of the hydroindole ring system by oxidative cyclization of tyrosine. Tetrahedron Lett. 1992, 33, (38), 5477-5480.
62.Wipf, P.; Kim, Y., p-Facial Selectivity in Nucleophilic Additions to 4,4-Disubstituted Dienones: Experimental Support for Electrostatic Control. J. Am. Chem. Soc. 1994, 116, (26), 11678-11688.
63.McKillop, A.; McLaren, L.; Taylor, R. J. K., A simple and efficient procedure for the preparation of p-quinols by hypervalent iodine oxidation of phenols and phenol tripropylsilyl ethers. J. Chem. Soc. Perkin Transa 1 1994, (15), 2047-2048.
64.McKillop, A.; McLaren, L.; Taylor, R. J. K.; Watson, R. J.; Lewis, N. J., The total synthesis of the diepoxycyclohexanone antibiotic aranorosin and novel synthetic analogs. J. Chem. Soc. Perkin Trans 1 1996, (12), 1385-1393.
65.Ward, R. S.; Pelter, A.; Abd-El-Ghani, A., Preparation of tetrahydrodibenzocyclooctene lignans and spirodienones by hypervalent iodine oxidation of phenolic dibenzylbutyrolactones. Tetrahedron 1996, 52, (4), 1303-1336.
66.Wells, G.; Bradshaw, T. D.; Diana, P.; Seaton, A.; Shi, D.-F.; Westwell, A. D.; Stevens, M. F. G., Antitumour benzothiazoles. Part 10. The synthesis and antitumour activity of benzothiazole-substituted quinol derivatives. Bioorg. Med. Chem. Lett. 2000, 10, (5), 513-515.
67.Wells, G.; Berry, J. M.; Bradshaw, T. D.; Burger, A. M.; Seaton, A.; Wang, B.; Westwell, A. D.; Stevens, M. F. G., 4-Substituted 4-Hydroxycyclohexa-2,5-dien-1-ones with Selective Activities against Colon and Renal Cancer Cell Lines. J. Med. Chem. 2003, 46, (4), 532-541.
68.Pallis, M.; Bradshaw, T. D.; Westwell, A. D.; Grundy, M.; Stevens, M. F. G.; Russell, N., Induction of apoptosis without redox catastrophe by thioredoxin-inhibitory compounds. Biochem. Pharmacol. 2003, 66, (9), 1695-1705.
69.Dao Tran, T.; Chi Yeon, S.; Kim, J.; Kim Hyun, P.; Kim, S.; Park, H., Synthesis and inhibitory activity against COX-2 catalyzed prostaglandin production of chrysin derivatives. Bioorg. Med. Chem. Lett. 2004, 14, (5), 1165-1167.
70.Lin, Y.-M.; Zhou, Y.; Flavin, M. T.; Zhou, L.-M.; Nie, W.; Chen, F.-C., Chalcones and flavonoids as anti-Tuberculosis agents. Bioorg. Med. Chem. 2002, 10, (8), 2795-2802.
71.Kosmeder, J. W., II; Moriarty, R. M.; Pezzuto, J. M.; Song, L. L.; Moon, R. C. Use of 4''-bromoflavone in a cancer chemopreventative composition and method. US Patent 6046231, 2000.
72.Kim, S.; Sohn, D. W.; Kim, Y. C.; Kim, S. A.; Lee, S. K.; Kim, H. S., Fine tuning of a reported synthetic route for biologically active flavonoid, baicalein. Arch. Pharm. Res. 2007, 30, (1), 18-21.
73.Peng, W.; Li, Y.; Zhu, C.; Han, X.; Yu, B., Synthesis of tamarixetin and isorhamnetin 3-O-neohesperidoside. Carbohydr. Res. 2005, 340, (10), 1682-1688.
74.Wu, X.; Cheng, L.; Xiang, D.; Wei, Y., Syntheses of carbamate derivatives of quercetin by reaction with amino acid ester isocyanates. Lett. Org. Chem. 2005, 2, (6), 535-538.
75.Alluis, B.; Dangles, O., Quercetin (=2-(3,4-dihydroxyphenyl)-3,5,7- trihydroxy-4H-1-benzopyran-4-one) glycosides and sulfates: chemical synthesis, complexation, and antioxidant properties. Helv. Chim. Acta 2001, 84, (5), 1133-1156.
76.Parker, K. A.; Petraitis, J. J., Synthesis of ansamycins: an approach to the naphthoquinone portion of the rifamycins and streptovaricins. Tetrahedron Lett. 1981, 22, (5), 397-400.
77.Anson, C. E.; Creaser, C. S.; Malkov, A. V.; Mojovic, L.; Stephenson, G. R., Flavonoid derivatives as organometallic bioprobes. J. Organomet. Chem. 2003, 668, (1-2), 101-122.
78.Kumazawa, T.; Minatogawa, T.; Matsuba, S.; Sato, S.; Onodera, J. i., An effective synthesis of isoorientin: the regioselective synthesis of a 6-C-glucosylflavone. Carbohydr. Res. 2000, 329, (3), 507-513.
79.Wang, Y.; Tan, W.; Li, W. Z.; Li, Y., A Facile Synthetic Approach to Prenylated Flavanones: First Total Syntheses of (±)-Bonannione A and (±)-Sophoraflavanone A. J. Nat. Prod. 2001, 64, (2), 196-199.
80.Huang, W.-J.; Singh, O. V.; Chen, C.-H.; Lee, S.-S., Synthesis of (±)-glaucine and (±)-neospirodienone via an one-pot Bischler- Napieralski reaction and oxidative coupling by a hypervalent iodine reagent. Helv. Chim. Acta 2004, 87, (1), 167-174.
81.Gelardi, A.; Morini, F.; Dusatti, F.; Penco, S.; Ferro, M., Induction by xenobiotics of phase I and phase II enzyme activities in the human keratinocyte cell line NCTC 2544. Toxicol. In Vitro 2001, 15, (6), 701-711.
82.Seubert, J. M.; Darmon, A. J.; El-Kadi, A. O. S.; D''Souza, S. J. A.; Bend, J. R., Apoptosis in murine hepatoma hepa 1c1c7 wild-type, C12, and C4 cells mediated by bilirubin. Mol. Pharmacol. 2002, 62, (2), 257-264.
83.Cardenas, M.; Marder, M.; Blank Viviana, C.; Roguin Leonor, P., Antitumor activity of some natural flavonoids and synthetic derivatives on various human and murine cancer cell lines. Bioorg. Med. Chem. 2006, 14, (9), 2966-2971.
84.Elliott, W. M.; Auersperg, N., Comparison of the neutral red and methylene blue assays to study cell growth in culture. Biotech. Histochem. 1993, 68, (1), 29-35.
85.Chang, F.-R.; Hayashi, K.-i.; Chua, N.-H.; Kamio, S.; Huang, Z.-Y.; Nozaki, H.; Wu, Y.-C., The transgenic Arabidopsis plant system, pER8-GFP, as a powerful tool in searching for natural product estrogen-agonists/antagonists. J. Nat. Prod. 2005, 68, (7), 971-973.
86.戴佳惠, I. 跨界活性篩選系統及II. 黃豆、葛根異黃酮與萃取物活性最適化之研究. 高雄醫學大學天然藥物研究所 碩士論文 2007.
87.Endo, K.; Seya, K.; Hikino, H., Biogenesis-like transformation of salidroside to rengyol and its related cyclohexylethanoids of Forsythia suspensa. Tetrahedron 1989, 45, (12), 3673-3682.
88.Srivastava, N.; Dasgupta, S. K.; Banik, B. K., A remarkable bismuth nitrate-catalyzed protection of carbonyl compounds. Tetrahedron Lett. 2003, 44, (6), 1191-1193.