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研究生:蘇崇仁
研究生(外文):Chung-Ren Su
論文名稱:黃藤莖部之成分研究與具有生理活性之天然化合物的合成研究
論文名稱(外文):Constituents from the stem of Fibraurea tinctoria and synthesis of biologically active natural products
指導教授:吳天賞吳天賞引用關係
指導教授(外文):Tian-Shung Wu
學位類別:博士
校院名稱:國立成功大學
系所名稱:化學系碩博士班
學門:自然科學學門
學類:化學學類
論文種類:學術論文
畢業學年度:96
語文別:中文
論文頁數:242
中文關鍵詞:黃藤deoxypergularinine吡喃香豆素antofineviscolin
外文關鍵詞:antofineviscolindeoxypergularininepyranocoumarinFibraurea tinctoria
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從黃藤莖部分離得到45個化合物,經光譜分析與化學方法鑑定確認其結構,其中有11個為天然界首次分離得到之化合物,分別為fibrauretin A–F、epi-8- hydroxycolumbin、epi-12-palmatoside G、fibrauretinoside A、epi-fibrauretinoside A與fibrauecdyside A,而除了fibrauretin D曾有合成的報導外,其餘均為首次發現之新化合物。由於本研究分離得到多個不同取代型式的呋喃二萜類,因此可歸納其光譜特徵,提供做為此類clerodane骨架呋喃二萜類化合物結構解析之依據,且由所分離得到之成分,推論呋喃二萜類之可能生合成路徑。此外,所分離的成分fibraurin及floribundic ester在劑量100 mg/kg下,具有抑制由carrageenan所誘發大白鼠足蹠浮腫的活性,而fibrauretin A在濃度2 μg/mL抑制NO產生的活性最強,palmatine及jatrorrhizine則對人類細胞色素CYP3A4具有顯著的抑制活性,其半數抑制濃度IC50分別為 0.9及2.1 μM。
Viscolin是由槲寄生(Viscum coloratum)所分離出的一個具有抗發炎活性的成分,本研究利用Wittig反應成功的合成出具有1,3-二苯基丙烷(1,3-diphenylpropane)骨架的viscolin,且針對合成出的viscolin、前驅物223及衍生物224進一步做抗發炎活性的評估,包含對人類白血球中的活性氧屬自由基(ROS)及一氧化氮(NO)產生之抑制活性、前發炎細胞激素生成的抑制活性等,發現viscolin能明顯的抑制白血球氧屬自由基(ROS)及一氧化氮(NO)的產生,所以viscolin有潛力開發成治療氧化壓力所誘發疾病的藥物。
菲并吲哚啶生物鹼,由於具有許多的生理活性,特別是對於多種癌細胞之生長有顯著抑制活性,一直以來都受到大家的注意,並有潛力將其發展為先導藥物。為了確定其結構上的特異性與細胞毒殺活性關係,我們著手進行合成antofine(226)與 deoxypergularinine(227)及其脫氫衍生物。由細胞毒殺活性篩選結果顯示化合物226與227對於數種癌細胞及多重抗藥性癌細胞,具有很強的細胞毒殺活性,其半數有效濃度EC50值範圍介於0.16–16 ng/mL。
吡喃香豆素clausenidin(255)、nordentatin(256)、clausarin(257)及xanthoxyletin(258)是由藥用植物過山香(Clausena excavata)所分離得到,而最近我們發現化合物255及256有抑制HepA2細胞株上的B型肝炎表面抗原活性,以及化合物255–257對於四種癌細胞株也有很強的細胞毒殺活性(A549、MCF7、KB及KB-VIN)。為了探討其活性與結構的關連性,我們以化合物255–258為前驅物,利用半合成的方法合成得到衍生物259–275。在這些化合物中,以259及264顯示出具有極佳的抑制B型肝炎病毒的活性,其半有效濃度EC50值分別為1.14與1.34 μM。此外,化合物255、259及260對於多重抗藥性鼻咽癌細胞(KB-VIN)的細胞毒殺活性強,而對於鼻咽癌細胞(KB)則無明顯的細胞毒殺活性,此對於目前發展多重抗藥性的癌細胞株之治療藥物可能有相當大的幫助。
Forty-five compounds were isolated from the stems of Fibraurea tinctoira and were characterized by comprehensive analyses of their 1D, 2D-NMR and mass spectral data, and also by chemical transformation studies. A phytochemical investigation of this plant has led to the isolation of ten new compounds, fibrauretin A–F, epi-8-hydroxycolumbin, epi-12-palmatoside G, fibrauretinoside A, epi-fibrauretinoside A, and fibrauecdyside A, as well as fibraurein D isolated from the natural sources for the first time. The thorough studies on the spectral characteristics of the different types of furanoditerpenoids provided a clear reference to distinguish at an early stage for the scientists interested in this field. Besides, the proposed biosynthetic pathway of furanoditerpenoids was also deduced. Among the isolates, fibraurin and floribundic ester showed a significant anti-inflammatory action administered at a dose of 100 mg/kg of reducing carrageenan mice paw edema, fibrauretin A at a concentration of 2 μg/mL was more potent to inhibit NO production, and palmatine and jatrorrhizine showed inhibitory effects against CYP3A4 with IC50 values of 0.9 and 2.1 μM, respectively.
Total synthesis of viscolin, an anti-inflammatory 1,3-diphenylpropane isolated from Viscum coloratum, employing the Wittig reaction is reported. Anti-inflammatory potency of the synthetic viscolin, its precursor product 223, and its analogue 224, through their effect on reactive oxygen species (ROS), nitric oxide (NO), and pro-inflammatory cytokine production in leukocytes and microglial cells were evaluated. Excellent inhibition of ROS and NO production in inflammatory cells could confer the synthetic viscolin to be a potent anti-inflammatory agent for the treatment of oxidative stress-induced diseases.
Phenanthroindolizidine alkaloids have received attention as potential therapeutic leads due to their profound cytotoxic activities and interesting biochemical effects. To define the structural features of the molecules that are essential for cytotoxicity, the alkaloids antofine (226), deoxypergularinine (227), and their dehydro congeners were synthesized. Compounds 226 and 227 showed significant potency against various human tumor cell lines, including a drug-resistant variant, with EC50 values ranging from 0.16–16 ng/mL.
Pyranocoumarin natural products clausenidin (255), nordentatin (256), clausarin (257), and xanthoxyletin (258), were isolated from the medicinal plant Clausena excavata. Recently, compounds 255 and 256 were found to suppress hepatitis B virus surface antigen in HepA2 cells, and in addition, 255–257 showed cytotoxic activity against four human cancer cell lines (A549, MCF7, KB, and KB-VIN). To explore the structure-activity relationships of this type of pyranocoumarin, seventeen analogs (259–275) were designed and synthesized. Among these analogs, 259 and 264 were the most potent against hepatitis B virus with EC50 values of 1.14 and 1.34 μM, respectively. The most interesting results in the cytotoxicity assay were the significant activities of 255, 259, and 260 against the multi-drug resistant cell line, KB-VIN, without activity against the KB cell line. This data suggested that these three compounds could be useful hits for developing MDR-inverse drugs.
英文摘要…………………………………………………………………I
中文摘要………………………………………………………………III
誌謝………………………………………………………………………V
第一章 緒論…………………………………………………………1
第二章 天仙藤屬植物研究之回顧…………………………………3
第一節 黃藤之植物形態……………………………………………3
第二節 天仙藤屬(Fibraurea)植物之藥理研究回顧……………4
第三節 天仙藤屬(Fibraurea)植物之成分研究回顧……………6
第四節 黃藤莖部之成分抽取與分離………………………………20
第三章 黃藤莖部成分之化學構造研究及藥理試驗………………27
第一節 Fibraurin(1)之構造研究………………………………27
第二節 Fibleucin(5)之構造研究………………………………33
第三節 Fibrauretin A(166)之構造研究………………………39
第四節 epi-8-Hydroxycolumbin(167)之構造研究……………46
第五節 Fibrauretin B(168)之構造研究………………………52
第六節 Fibrauretin C(169)之構造研究………………………58
第七節 Fibrauretin D(171)之構造研究………………………64
第八節 Fibrauretin E(172)之構造研究………………………70
第九節 Fibrauretin F(173)之構造研究………………………76
第十節 epi-12-Palmatoside G(174)之構造研究……………82
第十一節 Fibrauretinoside A(175)之構造研究………………88
第十二節 epi-Fibrauretinoside A(176)之構造研究…………94
第十三節 Makisterone A(195)之構造研究……………………100
第十四節 Fibraurecydyside A(196)之構造研究………………103
第十五節 其它化合物之構造決定…………………………………108
第十六節 呋喃二萜類之光譜特徵整理……………………………109
第十七節 呋喃二萜類之生合成路徑推論…………………………115
第十八節 黃藤莖部成分之抑制人類細胞色素CYP3A4之活性試驗.120
第十九節 黃藤莖部成分對於carrageenan所誘發大白鼠足蹠浮腫活性試驗…………………………………………………………………121
第二十節 黃藤莖部成分抑制以LPS刺激巨噬細胞(RAW264.7)產生NO的活性試驗…………………………………………………………126
第四章 Viscolin之全合成研究及藥效評估……………………127
第一節 Viscolin之相關生理活性概況及研究動機……………127
第二節 合成策略…………………………………………………127
第三節 結果與討論………………………………………………128
第四節 抗發炎作用機制與生理活性探討………………………130
第五章 Antofine和deoxypergularine及其脫氫衍生物之全合成研究及藥效評估…………………………………………………………135
第一節 Phenanthroindolizidine之相關生理活性概況及研究動機………………………………………………………………………135
第二節 合成策略……………………………………………………136
第三節 結果與討論…………………………………………………137
第四節 細胞毒殺活性及抗愛滋病毒活性試驗之研究……………141
第六章 吡喃香豆素之半合成研究及藥效評估…………………144
第一節 香豆素之相關生理活性概況及研究動機…………………144
第二節 合成策略……………………………………………………145
第三節 結果與討論…………………………………………………145
第四節 抑制B型肝炎表面抗原及細胞毒殺活性試驗之研究……149
第七章 結論………………………………………………………153
第八章 實驗部分…………………………………………………155
第一節 本實驗所使用之儀器與藥品……………………………155
第二節 黃藤的採集及鑑定………………………………………156
第三節 黃藤莖部成分之萃取與分離……………………………156
第四節 Viscolin全合成研究之實驗步驟………………………161
第五節 Antofine和deoxypergularine及其脫氫衍生物全合成研究之實驗步驟……………………………………………………………166
第六節 吡喃香豆素半合成研究之實驗步驟……………………171
第七節 抑制人類細胞色素CYP3A4之活性試驗…………………174
第八節 Carrageenan所誘發大白鼠足蹠浮腫活性試驗…………176
第九節 抑制以LPS刺激巨噬細胞(RAW264.7)產生NO的活性試驗………………………………………………………………………176
第十節 發炎指標性反應之相關細胞活性試驗…………………177
第十一節 細胞毒殺活性試驗………………………………………180
第十二節 抗愛滋病毒活性試驗……………………………………181
第十三節 抑制B型肝炎表面抗原(HBsAg)之活性試驗…………181
第九章 光譜數據…………………………………………………183
第一節 黃藤莖部所分離得到成分之光譜數據…………………183
第二節 Viscolin全合成研究之光譜數據………………………207
第三節 Antofine和deoxypergularine及其脫氫衍生物全合成研究之光譜數據……………………………………………………………212
第四節 吡喃香豆素半合成研究之光譜數據……………………221
參考文獻………………………………………………………………228
附錄:反應機制圖……………………………………………………238
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