臺灣博碩士論文加值系統

目錄
目錄………………………………………………..………..……I
附表目錄………………………….………….........………..……II
附圖目錄………………………………………….………..……..III
附路徑目錄... .……………………………………....……………VI
中文摘要………………………………………………..……......VII
Abstract………………………………………………..……........VIII
壹、緒論…………………………………………..………..……1
貳、實驗目的與設計……………………………..………..……45
參、化學合成……………………………………..………..……48
肆、實驗部分……………………………………..……….……..63
伍、參考文獻……………………………………..………..……66
附表目錄
表一 國內民國111年十大死因…………………………………………………………......3
表二 HDAC抑制劑聯合療法……………………………………………………………….44
表三 化合物17實驗條件……………………………………………………………………51
表四 化合物18實驗條件……………………………………………………………………54
表五 化合物19實驗條件……………………………………………………………………55
表六 化合物20b-c實驗條件………………………………………………………………...56
表七 化合物29實驗條件……………………………………………………………………59
表八 化合物30實驗條件……………………………………………………………………61
表九 化合物20 UPLC 純度及滯留時間總表………………………………………………91
附圖目錄
圖一 2000年癌症標記…………………………………………………………………2
圖二 2011年新增癌症標記……………………………………………………………2
圖三 臨床試驗組蛋白去乙醯化酶抑制劑……………………………………………4
圖四 Nucleosome結構…………………………………………………………………5
圖五 Chromatin結構…………………………………………………………………..5
圖六 表觀遺傳調控……………………………………………………………………6
圖七 HDAC基因遺傳調控……………………………………………………………7
圖八 藥物表觀遺傳調控………………………………………………………………7
圖九 (HAT) 和 (HDAC)調節…………………………………………………………8
圖十 各種組蛋白去乙醯酶結構域特徵………………………………………………10
圖十一 Class I、II、III、IV HDACs位置………………………………………………11
圖十二 Class III HDACs SIRTs家族在細胞中的分佈…………………………11
圖十三 HDAC亞型的位置、胺基酸含量………………………………………………12
圖十四 HDAC1內腔…………………………………………………………………….13
圖十五 HDAC2內腔……………………………………………………………………14
圖十六 HDAC3 : [Ins(1,4,5,6)P 4]複合物的結構………………………………15
圖十七 HDAC3:SMRT-DAD 複合物的結構…………………………………………..15
圖十八 HDAC3 在疾病中的應用………………………………………………………16
圖十九 HDAC4 四聚體的整體結構……………………………………………………17
圖二十 HDAC4 富含麩醯胺酸結構域的結構和化學特性……………………………17
圖二十一 HDAC4 表達和活性的調節模式總結…………………………………………18
圖二十二 HDAC5的調節………………………………………………………………….19
圖二十三 HDAC6 CD2結構結合位置處……………………………………………20
圖二十四 TSA 結合HDAC 7的整體結構………………………………………………21
圖二十五 TSA結合HDAC 7結構活性位置………………………………………………21
圖二十六 HDAC7 控制內皮完整性………………………………………………………22
圖二十七 HDAC8不對稱單體帶狀圖…………………………………………………….23
圖二十八 HDAC8單體帶狀圖……………………………………………………………23
圖二十九 HDAC8 活性位置的分子表面特性與結構……………………………………24
圖三十 HDAC8 的配體和SAHA晶體結構……………………………………………25
圖三十一 HDAC8 在不同疾病中的意義…………………………………………………26
圖三十二 HDAC9 癌症的潛在標靶和作用蛋白…………………………………………27
圖三十三 HDAC9 慢性疾病發展的影響…………………………………………………27
圖三十四 HDAC10結構域及催化位置……………………………………………………28
圖三十五 HDAC10疾病及相關途徑………………………………………………………29
圖三十六 Gly-[Lys-decanoyl]-Phe三肽對接至HDAC 11的同源模型……30
圖三十七 HDAC抑制劑用於不同癌症…………………………………………………….31
圖三十八 HDAC 抑制劑抗癌作用機轉……………………………………………………32
圖三十九 HDAC 活化多種致癌途徑………………………………………………………33
圖四十 HDAC抑制劑典型特徵………………………………………………………….34
圖四十一 HDAC抑制劑選擇性關係………………………………………………………35
圖四十二 HDAC Hydroxamic acid抑制劑…………………………………………………38
圖四十三 HDAC Cyclic peptide抑制劑……………………………………………………39
圖四十四 HDAC Benzamides抑制劑………………………………………………………41
圖四十五 HDAC Short-chain fatty acids抑制劑……………………………………42
圖四十六 組合藥物協同抗腫瘤生物效應………………………………………………….43
圖四十七 Capecitabine作用機轉…………………………………………………………...46
圖四十八 化合物合理化設計 ……………………………………………………………...47
圖四十九 化合物20合成……………………………………………………………...........47
圖五十 化合物17 NMR-2D圖譜1………………………………………………………52
圖五十一 化合物17 NMR-2D圖譜2………………………………………………………53
圖五十二 化合物29反應追蹤……………………………………………………………..59
圖五十三 化合物30NMR圖譜…………………………………………………………….60
圖五十四 化合物31 MS 圖譜……………………………………………………………...62
圖五十五 化合物20a UPLC 純度………………………………………………………….85
圖五十六 化合物20b UPLC 純度………………………………………………………….86
圖五十七 化合物20c UPLC 純度………………………………………………………….87
圖五十八 化合物20d UPLC 純度………………………………………………………….88
圖五十九 化合物20e UPLC 純度………………………………………………………….89
圖六十 化合物20f UPLC 純度………………………………………………………….90
圖六十一 化合物17之氫核磁共振圖……………………………………………………92
圖六十二 化合物18之氫核磁共振圖……………………………………………………..93
圖六十三 化合物19之氫核磁共振圖……………………………………………………..94
圖六十四 化合物20a之氫核磁共振圖…………………………………………………….95
圖六十五 化合物20b之氫核磁共振圖…………………………………………………….96
圖六十六 化合物20c之氫核磁共振圖…………………………………………………….97
圖六十七 化合物21之氫核磁共振圖……………………………………………………..98
圖六十八 化合物22之氫核磁共振圖……………………………………………………..99
圖六十九 化合物23之氫核磁共振圖……………………………………………………..100
圖七十 化合物20d之氫核磁共振圖……………………………………………………101
圖七十一 化合物20e之氫核磁共振圖…………………………………………………….102
圖七十二 化合物20f之氫核磁共振圖…………………………………………………….103
圖七十三 化合物20a之碳核磁共振圖…………………………………………………….104
圖七十四 化合物20b之碳核磁共振圖…………………………………………………….105
圖七十五 化合物20c之碳核磁共振圖…………………………………………………….106
圖七十六 化合物20d之碳核磁共振圖…………………………………………………….107
圖七十七 化合物20e之碳核磁共振圖…………………………………………………….108
圖七十八 化合物20f之碳核磁共振圖…………………………………………………….109
圖七十九 化合物20a之質譜圖………………………………………………………….....110
圖八十 化合物20b之質譜圖……………………………………………………………111
圖八十一 化合物20c之質譜圖…………………………………………………………....112
圖八十二 化合物20d之質譜圖………………………………………………………….....113
圖八十三 化合物20e之質譜圖………………………………………………………….....114
圖八十四 化合物20f之質譜圖……………………………………………………………..115
附路徑目錄
路徑一 化合物20a-20c的合成………………………………………….48
路徑二 化合物20d-20e的合成………………………………………….49
路徑三 化合物26合成…………………………………………………..49
路徑四 化合物30合成………………………………………………….50
路徑五 化合物17合成………………………………………………….51
路徑六 化合物18合成………………………………………………….54
路徑七 化合物19-20a-c合成…………………………………………55
路徑八 化合物21-22合成………………………………………………56
路徑九 化合物20d-f合成……………………………………………….57
路徑十 化合物24-26合成………………………………………………58
路徑十一 化合物27-29合成………………………………………………58
路徑十二 化合物31合成………………………………………………….61

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