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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 李水盛 | |
dc.contributor.author | Chin-Ting Lin | en |
dc.contributor.author | 林敬婷 | zh_TW |
dc.date.accessioned | 2021-06-15T13:09:20Z | - |
dc.date.available | 2021-08-26 | |
dc.date.copyright | 2016-08-26 | |
dc.date.issued | 2016 | |
dc.date.submitted | 2016-06-28 | |
dc.identifier.citation | (I)
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dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/50963 | - |
dc.description.abstract | 第一部分 TM-1-1磷酸酯衍生物之製備
缺血性心臟病為世界主要致死原因之一,過去本實驗室於阿朴芬生物鹼之氮原子上導入乙氧烯愈創木酚基團,製備出具保護缺血再灌流造成之心臟傷害作用之化合物TM-1與其活性代謝物TM-1-1。然TM-1與TM-1-1於動物急毒性實驗中因會造成震顫之中樞神經副作用而使後續研究停擺。 本研究以富含於台灣雅楠之laurolitsine,經:氮甲醯化、酚基苄基化、去甲醯基、還原性氮上烷基化、與催化性氫化反應,大量製備TM-1-1且總產率可達71%。 TM-1-1經酚基磷酸化與去苄基反應製備其雙磷酸酯衍生物TM-1-1 DP。N-Formyllaurolitsine經:選擇性酚基甲基化、去甲醯基、還原性氮上烷基化、磷酸化、與去苄基反應製備其單磷酸酯衍生物TM-1-1 MPa/b。 TM-1-1 DP較TM-1-1具較佳之水溶解度,經大鼠模式證明具較佳之心臟保護作用,且於60倍有效劑量下無觀察到震顫之副作用。TM-1-1 DP與TM-1-1 MPa/b於大鼠代謝研究中可知雙磷酸酯化合物無法穿過血腦障壁,於活體內可逐漸代謝為單磷酸酯代謝物與TM-1-1,而2號位置磷酸酯較9號位置易降解,且單磷酸酯化合物會增加腦內分佈。 第二部分 N-烷基苯-2-萘醯胺化合物之製備與其抗黃嘌呤氧化酶抑制之研究 黃嘌呤氧化酶近年來為高尿酸血症或心血管代謝相關疾病之重要研究標的,過去本實驗室發現植物頭花香苦草所含1,4-benzodioxane型neolignans類成份,具有良好之黃嘌呤氧化酶抑制活性。以活性化合物hyprohombin C進行電腦分子模擬分析其與黃嘌呤氧化酶之交互作用,並依此模擬結果計算出具N-arylalkyl-2-naphthamides架構之化合物與黃嘌呤氧化酶有良好之結合潛力。 本研究以此系列化合物為目標化合物以驗證其實際黃嘌呤氧化酶抑制活性。分別製備重要中間產物6,7-dimethoxy-2-naphtolic acid(IX)與3,4-dimethoxyphenyl-alkylamines化合物(Xa-e),再經由醯胺偶合反應與去甲基反應而得一系列之N-arylalkyl-2-naphthamides化合物(VIIa-e)。化合物VIIa-e和allopurinol (IC50 26.6 μM)相比皆具有中到高之體外抑制黃嘌呤氧化酶之活性且其趨勢可驗證電腦分子模擬之結果,其中以化合物VIIc(IC50 21.6 μM)與VIId(IC50 22.6 μM)具有最佳之抑制活性。以化合物VIIc進行高尿酸血症小鼠動物實驗,證實其具有降低血中尿酸濃度之作用。 第三部分 改良型鈀碳催化氫解反應於酚性生物鹼去酚基反應之研究 本研究將經由酚基轉換為1-phenyl-1H-tetrazol-5-yl ether衍生物後,以鈀碳催化氫解反應以移除酚性羥基之方法,藉由鎂粉或乙酸銨之添加進行方法改良。以五種常見之異喹:phenanthrene、aporphine、pavine、protoberberine、與1-benzyltetrahydroisoquinoline架構之生物鹼為反應物進行討論。結果顯示,與單純鈀碳催化氫解反應相比,鎂粉或乙酸銨之添加可提升其反應完全性、反應速率與產率、減少催化劑鈀碳之用量,因此有利於應用在量化去酚性羥基生物鹼之製備,有助於生物鹼結構與活性關係之探討時,修飾化合物之製備。 | zh_TW |
dc.description.abstract | Part 1. Preparation of TM-1-1 phosphate ester derivatives
Ischemic heart disease remains as the worldwide leading cause of death. Our lab has prepared the aporphine derivatives, TM-1 and its active metabolite TM-1-1, with incorporation of O-ethylene guaiacol moiety to the nitrogen atom. TM-1 exhibited good cardioprotective effect on ischemia/reperfusion animal models. However, the further study of TM-1 and TM-1-1 was pended due to CNS tremor side effect in the acute tocxicity animal study. In this study, a larger scale preparation of TM-1-1 was accomplished with a 71% total yield from laurolitsine, which presented abundantly in Phoebe formosana, via N-formylation, O-benzylation, de-formylation, reductiove N-alkylation, and catalytic hydrogenolysis reaction. TM-1-1 DP, a diphosphate ester of TM-1-1, was prepared from TM-1-1 via O-phosphorylation and de-benzylation. TM-1-1 MPa/b, monophosphate ester of TM-1-1, were prepared from N-formyllaurolitsine via selective O-methylation, de-formylation, reductive N-alkylation, O-phosphorylation, and de-benzylation. TM-1-1 DP has better water solubility than TM-1-1. It shows improved cardioprotective effect in vivo animal model and no tremor effect was observed at a dose 60 times as large as the effect dose. The result of rat metabolism study demonstrated that the diphosphate ester compound would not pass BBB and would metabolize to mono-dephosphorylated metabolites and TM-1-1. 9-phosphate ester would be more stable than 2-phosphate ester and the mono-phosphate ester compounds increase the distribution of brain. Part 2. Preparation and anti-xanthine oxidase activity evaluation of N-arylalkyl-2-naphthamides In the recent years, xanthine oxidase has been recognized as an important target for hyperuricemia or cardiovascular and metabolic disorders. Our lab has found that Hyptis rhomboides contains 1,4-benzodioxane type neolignans, which possess potent anti-xanthine oxidase activities. Computer assisted docking study was performed to analyze the interactions of potent inhibitor hyprohombin C with xanthine oxidase. Further virtual docking predicted a new series compounds with N-arylalkyl-2-naphthamides structure to have binding potential with xanthine oxidase. In this study, N-arylalkyl-2-naphthamides were prepared to verify their anti-xanthine oxidase activity. The key intermediates, 6,7-dimethoxy-2-naphtolic acid (IX) and 3,4-dimethoxyphenyl-alkylamines (Xa-e), were synthesized individually. The target compounds, N-arylalkyl-2-naphthamides (VIIa-e) were further prepared via amide coupling and demethylation reaction. VIIa-e exhibited medium to high inhibitiory potency compared with allopurinol (IC50 26.6 μM) in in vitro xanthine oxidase assay and the result was corroborated the results from molecular docking study. The VIIc (IC50 21.6 μM) and VIId (IC50 22.6 μM) showed the best inhibitory potency. The in vivo assay on hyperuricemia mice model demonstrated that VIIc possessed the effect in reducing blood uric acid level. Part 3. Removal of the phenolic groups in phenolic alkaloids by a modified Pd/C-catalyzed hydrogenolysis method A modified palladium on carbon (Pd/C) catalyzed hydrogenolysis method for removal of the phenolic-OH group in phenolic alkaloids as the 1-phenyl-1H-tetrazol-5-yl derivative by the addition of magnesium metal or ammonium acetate in acetic acid is described in this study. Five different types of isoquinoline alkaloids, ie., phenanthrene alkaloids, aporphine, pavine, protoberberine, and 1-benzyltetrahydroisoquinoline, were used as reactants. The results indicate that the addition of either magnesium metal or ammonium acetate has the advantage of decreasing the amount of Pd/C and the accelerating reaction rate over the simple Pd/C-catalyzed hydrogenolysis, thus it is practical for larger-scale preparation of de-phenolated alkaloids for pharmacological study. | en |
dc.description.provenance | Made available in DSpace on 2021-06-15T13:09:20Z (GMT). No. of bitstreams: 1 ntu-105-D99423004-1.pdf: 14397384 bytes, checksum: 646fe058b38a615fd7f01d1c122f6a38 (MD5) Previous issue date: 2016 | en |
dc.description.tableofcontents | 第一部分 TM-1-1磷酸酯衍生物之製備 1
1. 緒論 1 1.1 緣由與目的 1 1.2 TM-1-1磷酸酯衍生物之製備 4 2. 結果與討論 6 2.1 前驅藥概念預試驗 6 2.1.1 TM-1-1 DP之製備 6 2.1.2 TM-1-1 DP在活體中心臟保護作用及毒性預試驗 8 2.2 TM-1-1 Ps之製備 9 2.2.1 TM-1-1之製備條件優化與大量製備 9 2.2.2 TM-1-1 DP之大量製備 13 2.2.3 單磷酸基之TM-1-1 MPa/b之製備 14 2.2.3.1 Mono-O-methylated N-formyllaurolitsine之製備 14 2.2.3.2 TM-1-1 MPa/b之製備 16 2.3 動物實驗活性結果 19 2.3.1 TM-1-1 DP之心臟保護活性 19 2.3.1.1 TM-1-1 DP對大鼠心臟缺血後再灌流損傷之降低 19 2.3.1.2 TM-1-1 DP可改善大鼠心臟缺血後再灌流之功能 20 2.3.1.3 TM-1-1 DP可增加H2O2下之心肌細胞存活率 21 2.3.2 TM-1-1Ps於大鼠之體內代謝研究 22 2.3.2.1 TM-1-1 DP之藥品安定性 22 2.3.2.2 TM-1-1 Ps血中與腦內紋狀體濃度之變化與代謝情形 22 3. 結論 26 4. 實驗方法 27 4.1 儀器與材料 27 4.1.1 理化性質測定儀器 27 4.1.2 化合物合成、純化使用之材料、溶劑與試藥 27 4.2 N-[2-(2-Methoxyphenoxy)] ethyllaurolitsine(TM-1-1)之大量製備 29 4.2.1 N-Formyllaurolitsine(7)之製備 29 4.2.2 2,9-O,O-Dibenzyl-N-formyllaurolitsine(8)之製備 30 4.2.3 2,9-O,O-Dibenzyllaurolitsine(9)之製備 31 4.2.4 2-(2-Methoxyphenoxy)acetaldehyde(2)之製備 32 4.2.5 2,9-O,O-Dibenzyl-N-[2-(2-methoxyphenoxy)] ethyllaurolitsine(10)之製備 32 4.2.6 N-[2-(2-Methoxyphenoxy)] ethyllaurolitsine (TM-1-1)之製備 33 4.3 N-[2-(2-Methoxyphenoxy)] ethyllaurolitsine-2,9-diphosphate sodium salt (TM-1-1 DP)之製備 35 4.3.1 N-[2-(2-Methoxyphenoxy)] ethyllaurolitsine-2,9-diphosphoric acid dibenzyl ester(5)之製備 35 4.3.2 N-[2-(2-Methoxyphenoxy)] ethyllaurolitsine-2,9-diphosphate sodium salt(6, TM-1-1 DP)之製備 36 4.4 N-Formyllaurolitsine甲基化衍生物(11、12a及12b)之製備 37 4.5 TM-1-1 MPa/b(16a/b)之製備 39 4.5.1 Norpredicentrine(9-O-methyllaurolitsine, 13a)之製備 39 4.5.2 Laurotetanine(2-O-methyl-laurolitsine, 13b)之製備 40 4.5.3 N-(2-Methoxyphenoxy)ethylnorpredicentrine(14a)與N-(2-methoxyphenoxy)-ethyllaurotetanine(14b)之製備 40 4.5.4 N-(2-Methoxyphenoxy)ethylnorpredicentrine-2-phosphoric acid dibenzyl ester(15a)與 disodium N-(2-methoxyphenoxy)ethylnorpredicentrine-2-phosphate(16a, TM-1-1 MPa)之製備 43 4.5.5 N-(2-Methoxyphenoxy)ethyllaurotetanine-9-phosphoric acid dibenzyl ester(15b)與disodium N-(2-methoxyphenoxy)ethyl laurotetanine-9-phosphate(16b, TM-1-1 MPb)之製備 44 第二部分 N-烷基苯-2-萘醯胺化合物之製備與其抗黃嘌呤氧化酶抑制之研究 50 1. 緒論 50 1.1 黃嘌呤氧化酶 50 1.2 黃嘌呤氧化酶抑制劑 53 1.3 電腦分子模擬 55 1.4 研究目的 58 2. 實驗結果與討論 59 2.1 目標化合物之逆合成分析 59 2.2 6,7-Dimethoxy-2-naphthoic acid(IX)之製備 59 2.3 3,4-Dimethoxyphenyl-alkylamines Xa-e之製備 60 2.3.1 苯甲胺與苯丙胺化合物(Xa 與Xc)之製備 61 2.3.2 苯丁胺化合物Xd之製備 63 2.3.3 苯戊胺化合物Xe之製備 67 2.4 目標化合物之製備 69 2.5 藥物活性測試 72 2.5.1 體外黃嘌呤氧化酶抑制活性結果 72 2.5.2 高尿酸血症小鼠動物實驗結果 73 3. 結論 76 4. 實驗方法 77 4.1 儀器與材料 77 4.1.1 理化性質測定儀器 77 4.1.2 化合物合成、純化使用之材料、溶劑與試藥 77 4.1.3 黃嘌呤氧化酶抑制活性試驗所用試劑與儀器 80 4.1.4 高尿酸血症小鼠動物實驗所用試藥與儀器 80 4.2 化合物之製備 81 4.2.1 6,7-Dimethoxy-2-naphthoic acid(IX)之製備 81 4.2.1.1 2,3-Dimethoxynaphthalene(18)之製備 81 4.2.1.2 2-Acetyl-6,7-dimethoxynaphthalene(19)與1-(6,7-dimethoxynaphthalen-1-yl)ethanone(20)之製備 82 4.2.1.3 6,7-Dimethoxy-2-naphthoic acid(IX)之製備 83 4.2.2 3,4-Dimethoxyphenyl-alkylamines Xa-e之製備 84 4.2.2.1 化合物Xa之製備 84 4.2.2.1.1 Veratraldehyde oxime〔3,4-dimethoxybenzaldehyde oxime(22)〕之製備 84 4.2.2.1.2 (3,4-Dimethoxyphenyl)methanamine · HCl(Xa)之製備 85 4.2.2.2 化合物Xc之製備 85 4.2.2.2.1 O-Methylferulic acid ethyl ether(24)之製備 85 4.2.2.2.2 Ethyl 3-(3,4-dimethoxyphenyl)propanoate(25)之製備 86 4.2.2.2.3 3-(3,4-Dimethoxyphenyl)propan-1-ol(26)之製備 87 4.2.2.2.4 3-(3,4-Dimethoxy-phenyl)propanal(27)之製備 88 4.2.2.2.5 3-(3,4-Dimethoxy-phenyl)propanal-oxime(28)之製備 89 4.2.2.2.6 3-(3,4-Dimethoxyphenyl)propylamine · HCl(Xc)之製備 90 4.2.2.3 化合物Xd之製備 91 4.2.2.3.1 1-Nitro-4-(3,4-dimethoxyphenyl)butan-2-ol(29)之製備 91 4.2.2.3.2 1-Nitro-4-(3,4-dimethoxyphenyl)but-1-ene(30)之製備 92 4.2.2.3.3 1,2-Dimethoxy-4(4-nitrobutyl)benzene(31)之製備 92 4.2.2.3.4 (E)-5-(3,4-Dimethoxyphenyl)pent-3-enoic acid(32a)與(E)-5-(3,4-Dimethoxy-phenyl)pent-2-enoic acid(32b)混合物之製備 94 4.2.2.3.5 5-(3,4-Dimethoxyphenyl)pentanoic acid 〔δ-(3,4-dimethoxyphenyl)valeric acid〕(33)之製備 94 4.2.2.3.6 Sodium 2-(4-aminobutyl)-4,5-dimethoxybenzenesulfonate(34)之製備 95 4.2.2.3.7 4-(3,4-Dimethoxyphenyl)butylamine sulfate(Xd)之製備 96 4.2.2.4 化合物Xe之製備 97 4.2.2.4.1 Ethyl-(E)-5-(3,4-dimethoxyphenyl)pent-3-enoate(35a)與ethyl-(E)-5-(3,4-dimethoxyphenyl)pent-2-enoate(35b)混合物之製備 97 4.2.2.4.2 Ethyl 5-(3,4-dimethoxyphenyl)pentanoate(36)之製備 98 4.2.2.4.3 5-(3,4-Dimethoxyphenyl)pentan-1-ol(37)之製備 99 4.2.2.4.4 5-(3,4-Dimethoxyphenyl)pentanal(38)之製備 100 4.2.2.4.5 5-(3,4-Dimethoxyphenyl)pentanal-oxime(39)之製備 101 4.2.2.4.6 5-(3,4-Dimethoxyphenyl)pentylamine · HCl(Xe)之製備 102 4.2.3 N-Arylalkyl-2-naphthamides VIIa-e之製備 103 4.2.3.1 化合物VIIIa-e之製備 103 4.2.3.2 化合物VIIa-e之製備 108 4.2.3.3 化合物VIIc-Ac(40)之製備 112 4.3 黃嘌呤氧化酶抑制活性試驗 113 4.3.1 原理 113 4.3.2 實驗方法 114 4.3.2.1 試劑配製 114 4.3.2.2 實驗步驟 114 4.3.2.3 IC50之計算 115 4.4 高尿酸血症小鼠動物實驗 116 4.4.1 原理 116 4.4.2 實驗材料與方法 116 4.4.2.1 實驗動物 116 4.4.2.2 高尿酸血症小鼠動物實驗 116 4.4.2.3 實驗組別與給藥劑量 117 4.4.2.4 血液尿酸濃度之測定 117 4.4.2.4.1 分析方法與樣品萃取方法 117 4.4.2.4.2 尿酸濃度檢量線 118 4.4.2.4.3 血液中尿酸濃度之定量 119 4.4.2.5 統計分析 119 第三部分 改良型鈀碳催化氫解反應於酚性生物鹼去酚基反應之研究 126 1. 緒論 126 1.1 原由與目的 126 2. 結果與討論 129 3. 結論 136 4. 實驗方法 137 4.1.1 理化性質測定儀器 137 4.1.2 高壓反應器 137 4.1.3 化合物合成、純化使用之材料、溶劑與試藥 137 4.2 Triflyl ether之製備 139 4.3 1-Phenyl-1H-tetrazol-5-yl ether衍生物之製備 140 4.4 De-OTz衍生物之製備 144 附圖…………………………………………………………………………………………..154 | |
dc.language.iso | zh-TW | |
dc.title | 第一部份:TM-1-1磷酸酯衍生物之製備
第二部份:N-烷基苯-2-萘醯胺化合物之製備與其抗黃嘌呤氧化酶抑制之研究 第三部份:改良型鈀碳催化氫解反應於酚性生物鹼去酚基反應之研究 | zh_TW |
dc.title | Part 1 Preparation of TM-1-1 phosphate ester derivatives
Part 2 Preparation and anti-xanthine oxidase activity evaluation of N-arylalkyl-2-naphthamides Part 3 Removal of the phenolic groups in phenolic alkaloids by a modified Pd/C-catalyzed hydrogenolysis method | en |
dc.type | Thesis | |
dc.date.schoolyear | 104-2 | |
dc.description.degree | 博士 | |
dc.contributor.oralexamcommittee | 陳繼明,李安榮,忻凌偉,黃偉展,梁碧惠 | |
dc.subject.keyword | TM-1-1,磷酸酯衍生物,N-烷基苯-2-?醯胺,黃嘌呤氧化?抑制劑,催化氫解反應,酚性生物鹼,去酚基反應, | zh_TW |
dc.subject.keyword | TM-1-1,phosphate ester derivatives,N-arylalkyl-2-naphthamides,xanthine oxidase inhibitors,hydrogenolysis,Removal of the phenolic groups,phenolic alkaloids, | en |
dc.relation.page | 283 | |
dc.identifier.doi | 10.6342/NTU201600540 | |
dc.rights.note | 有償授權 | |
dc.date.accepted | 2016-06-29 | |
dc.contributor.author-college | 醫學院 | zh_TW |
dc.contributor.author-dept | 藥學研究所 | zh_TW |
顯示於系所單位: | 藥學系 |
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