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研究生:林家暘
研究生(外文):LIN, CHIA-YANG
論文名稱:合成選擇性組蛋白去乙醯酶抑制劑作為阿茲海默症治療藥物
論文名稱(外文):Synthesis of selective HDAC inhibitors as a potential therapy for Alzheimer's disease
指導教授:胡明寬胡明寬引用關係
指導教授(外文):HU, MING-KUAN
口試委員:劉景平廖永豐
口試委員(外文):Liou, Jing-PingLiao, Yung-Feng
口試日期:2017-05-17
學位類別:碩士
校院名稱:國防醫學院
系所名稱:藥學研究所
學門:醫藥衛生學門
學類:藥學學類
論文種類:學術論文
論文出版年:2017
畢業學年度:105
語文別:中文
論文頁數:167
中文關鍵詞:組蛋白去乙醯酶抑制劑阿茲海默症
外文關鍵詞:selective HDAC inhibitorsAlzheimer's disease
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阿茲海默症 (Alzheimer’s disease, AD)是一種漸進性的神經退化疾病,失智症患者多數起因於此疾病。其病理特徵是腦部出現老年斑塊 (senile plaques)及神經細胞內的神經纖維糾結 (neurofibrillary tangles)。老年斑塊由β類澱粉胜肽 (β-amyloid, Aβ)堆積而成,而神經纖維糾結則是由過度磷酸化的tau蛋白 (phosphorylated-tau, p-tau)聚集纏繞而產生。依類澱粉蛋白假說,神經受損是由於Aβ的毒性造成,至於p-tau則是使微管失去構型,進而影響細胞內的運輸、訊息傳導及養分運輸而造成神經細胞死亡。
目前藥物開發以治療目標分為兩大類,第一類是以Aβ減少作為治療策略,如β分泌酶抑制劑、γ分泌酶抑制劑、Aβ單株抗體等。第二類則以減少不正常tau蛋白作為發展方向,如微管穩定劑、熱休克蛋白90抑制劑、組蛋白去乙醯酶 (histone deacetylases, HDACs)抑制劑等。此實驗係以7-氮雜吲哚 (7-azaindole)作為表面辨識區,合成一系列選擇性的HDAC抑制劑,並更換連接部位來探討結構與活性關係。
合成的化合物經由HDACs抑制實驗發現在HDAC6抑制上,POBen活性效價最強,而MOBen效價最差,但比較其他HDACs抑制實驗結果發現最具選擇性的卻是MOBen。惟合成的化合物抑制HDAC6能力均遠低於已發表化合物,故其結構須進一步修正以開發具有潛力藥物。

Alzheimer’s disease (AD) is a progressive neurodegenerative disease. It is the majority among dementia patients. The classical pathological hallmarks of AD are senile plaques and neurofibrillary tangles, which are located in the brain and neuronal cells. According to β-amyloid hypothesis, the toxic Aβ oligomers alter neuronal function and induce neuronal cells inflammation. Ultimately, the neuronal homeostasis is broken down and leads to clinical symptoms such as cognitive dysfunction and memory loss. Hyperphosphorylated taus tend to aggregate into neurofibrillary tangle and destabilize microtubules that are at the root of the tau pathology.
The development for the treatment of AD can be divided into two categories based on its pathological progression. One is aim to reduce Aβ quantity, such as β-secretase inhibitors, γ-secretase inhibitors, anti-Aβ monoclonal antibodies. The other is focusing on tau pathology, like heat shock protein 90 inhibitors, microtubules stabilizers, histone deacetylase 6 (HDAC 6) inhibitors. In this study, a series of new HDAC inhibitors were designed and synthesized by choosing 7-azaindole as the cap structure of the recognition space. Through screening on HDACs inhibition assay kit, the compound POBen is the most potent in the HDAC6 inhibition test among the tested compounds, while the compound MOBen is the weakest but most selective one. The results suggested that the skeleton of the linker portion can be optimized in further experiments to provide more potential candidates.
正文目錄 I
表目錄 III
圖目錄 III
附圖目錄 V
摘要 VIII
Abstract VIII
第一章、 緒論 1
第一節、阿茲海默症 3
壹、阿茲海默症簡介 3
貳、症狀 3
參、阿茲海默症診斷 4
肆、病理 7
伍、類澱粉蛋白假說 (Amyloid hyposis) 9
陸、AD治療與新藥開發方向 14
柒、組蛋白去乙醯酶 (histone deacetylases, HDACs)與AD 20
第二節、研究目的 29
第三節、研究方法 30
壹、美國食品藥物管理局(FDA)核准之HDACs抑制劑35 30
貳、已發表抑制HDAC6 小分子化合物 31
參、化合物構想與設計 33
第二章、材料與方法 35
第一節、儀器與材料 35
壹、實驗儀器 35
貳、試劑、溶劑及原料藥品 37
第二節、合成步驟與結構鑑定 40
第三節、HDACs活性抑制試驗 67
壹、HDACs活性抑制試驗 (pan-HDACs inhibition test) 67
貳、HDA6活性抑制試驗 (HDAC6 selective inhibition test) 69
參、HDA8活性抑制試驗 (HDAC8 selective inhibition test) 70
肆、HDAC2活性抑制試驗 (HDAC2 selective inhibition test) 70
第三章、實驗結果 71
第一節、化學合成結果 71
第二節、HDACs活性抑制 72
壹、HDACs活性抑制試驗 (pan-HDACs inhibition test) 72
貳、HDAC6活性抑制試驗 (HDAC6 selective inhibition test) 73
參、HDAC8活性抑制試驗 (HDAC8 selective inhibition test) 74
肆、HDAC2活性抑制試驗(HDAC2 selective inhibition test) 75
第四章、討論 76
第一節、化學合成 76
壹、N3還原成NH2 76
貳、合成流程選擇 77
參、Hydroxamic acid合成 78
第二節、生化活性 79
壹、化合物選擇性 79
貳、結構與活性關係 (structure activity relationship, SAR) 80
第五章、結論 81
第一節、實驗結果總結 81
第二節、臨床應用 82
第六章、參考文獻 84
附錄 88

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