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研究生:吳佳欣
研究生(外文):Chia-Hsin Wu
論文名稱(外文):Design and Synthesis of Mono-, Di-, Tri- and Tetraindoles Derivatives as Novel Histone Deacetylase Inhibitors
指導教授:李文山李文山引用關係侯敦仁
指導教授(外文):Wen-Shan LiDuen-Ren Hou
學位類別:碩士
校院名稱:國立中央大學
系所名稱:化學學系
學門:自然科學學門
學類:化學學類
論文出版年:2020
畢業學年度:108
語文別:英文
論文頁數:110
中文關鍵詞:組織蛋白去乙醯酶抑制劑四吲哚衍生物抗三陰性乳癌藥物
外文關鍵詞:Histone deacetylase inhibitorTetraindole derivativesTNBC anticancer agent
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  • 被引用被引用:0
  • 點閱點閱:20
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在這次的研究中,我們設計合成了一系列的單,雙,三,和四吲哚的衍生物(CHW01-03, CHW05, CHW04 and AMB09-10),它們具有類似Vorinostat (suberanilohydroxamic acid)的側鏈,為FDA批准的HDAC抑制劑。在本篇論文中,我們設計和合成了一系列化合物,以測試其對組蛋白脫乙酰基酶(HDAC)的抑制和對TNBC癌細胞系MDA-MB-231的抑制生長的功能。在此系列化合物中,CHW03對MDA-MB-231細胞株具有最佳的抗增值能力,IC50值為1.4 µM。另外,關於組蛋白脫乙酰基酶抑制的進一步研究也正在研究中。
In this investigation, we discovered a series of mono-, di-, tri-, and tetraindoles derivatives (CHW01-03, CHW05, CHW04 and AMB09-10), possessing different number of indole rings and similar side chain like Vorinostat (SAHA), a HDAC inhibitor approved by FDA. Their inhibition of histone deacetylase (HDAC) and the inhibitory growth against TNBC cancer cell line MDA-MB-231 was evaluated. Among this series of compounds, CHW03 has the best antiproliferative activity against MDA-MB-231 cell line with an IC50 value of 1.4 µM. Further study in histone deacetylase inhibition is in progress.
Table of Contents
摘要 i
Abstract ii
誌謝 iii
Table of Contents iv
List of Figures vii
List of Tables viii
List of Schemes ix
List of Abbreviation x
Ⅰ. Introduction 1
1.1 Background 1
1.2 Introduction of triple negative breast cancer (TNBC) 2
1.2.1 Introduction of breast cancer 2
1.2.2 Introduction of triple negative breast cancer (TNBC) 3
1.2.3 Treatment of triple negative breast cancer (TNBC) 4
1.3 Introduction of tetraindole 8
1.3.1 Bio-inspired invention of tetraindole 8
1.3.2 Literature review of tetraindole 9
1.4 Introduction of Histone Deacetylase Inhibitor (HDACi) 10
1.4.1 Histone deacetylase inhibitor (HDACi) 10
1.4.2 Structure studies of histone deacetylase inhibitor (HDACi) 11
Ⅱ. Results and Discussion 12
2.1 Research Motivation 12
2.2 Retrosynthetic Analysis of Indole–Based HDAC Inhibitors 13
2.3 Synthesis of SAHA–Linker 3 15
2.4 Synthesis of Indole–based HDAC inhibitors 16
2.4.1 Synthetic route of AMB09 16
2.4.2 Synthetic route of AMB10 17
2.4.3 Synthetic route of CHW01 and CHW02 18
2.4.4 Synthetic route of CHW03 19
2.4.5 Synthetic route of CHW04 20
2.4.6 Synthetic route of CHW05 21
2.5 In Vitro Studies of AMB09-10, and CHW01-05 22
2.5.1 Cytotoxicity of AMB09-10 on MDA-MB-231 cell proliferation 22
2.5.2 Cytotoxicity of CHW01-05 on MDA-MB-231 cell proliferation 24
2.6 Preliminary Structure-Activity Relationship Studies 27
Ⅲ. Conclusions 28
Ⅳ. Materials and Methods 29
4.1 General Information 29
4.2 Experimental Method 30
4.2.1 Synthesis of SAHA–linker 3 30
4.2.2 Synthesis of AMB09 31
4.2.3 Synthesis of AMB10 35
4.2.4 Synthesis of CHW01 39
4.2.5 Synthesis of CHW02 41
4.2.6 Synthesis of CHW03 43
4.2.7 Synthesis of CHW04 46
4.2.8 Synthesis of CHW05 50
4.3 Cell Line Used and Cell Culture 52
4.4 MTT Cytotoxicity Analysis 52
Ⅴ. References 53
Ⅵ. Spectra Appendix 58

Ⅴ. References
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