Design and Synthesis of Mono-, Di-, Tri- and Tetraindoles Derivatives as Novel Histone Deacetylase Inhibitors

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吳佳欣(Chia-Hsin Wu) 查詢紙本館藏

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化學學系

論文名稱

(Design and Synthesis of Mono-, Di-, Tri- and Tetraindoles Derivatives as Novel Histone Deacetylase Inhibitors)

★ Synthesis and biological evaluation of pyrazole derivatives as antitumor agents

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摘要(中)

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。

摘要(英)

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.

關鍵字(中)

★ 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

關鍵字(英)

★ Histone deacetylase inhibitor
★ Tetraindole derivatives
★ TNBC anticancer agent

論文目次

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

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指導教授

李文山侯敦仁(Wen-Shan Li Duen-Ren Hou)

審核日期

2020-7-28

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