N-(嘧啶-2-基)二氫吲哚-6-胺衍生物作為抗三陰性乳癌新型抗癌藥物的合成及生物活性研究

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姓名

賴盈汝(Ying-Ju Lai) 查詢紙本館藏

畢業系所

化學學系

論文名稱

N-(嘧啶-2-基)二氫吲哚-6-胺衍生物作為抗三陰性乳癌新型抗癌藥物的合成及生物活性研究
(Synthesis and Biological Activity Study of N-(Pyrimidin-2-yl)indolin-6-amine Derivatives as Novel Anticancer Agents Against Triple-Negative Breast Cancer Cells)

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至系統瀏覽論文 (2029-7-1以後開放)

摘要(中)

癌症多年來一直位居十大死因之列，其中乳腺癌是女性中最常見的癌症之一，也是女性癌症相關死亡的主要原因之一。乳腺癌可分為四個亞型之一是三陰性乳腺癌(TNBC)，其特點是高死亡率、高復發率、高轉移率和強烈的耐藥性，從而大大降低了治療的有效性。
本報告聚焦於一系列N-(pyrimidin-2-yl)indolin-6-amine衍生物的合成。我們根據化合物結構與生物活性之間的關係設計了所需的吲哚衍生物類似物。通過調整分子結構以增強化合物的生物活性，我們成功地確定並合成了化合物PN009。該化合物被發現對MDA-MB-231具有最強的活性，表明將branched adamantane引入到pyrimidin-6-yl位置有利於抑制癌細胞生長。此外，PN009還顯示可以減少癌細胞遷移並抑制細胞模型中的管狀結構形成。
總之，這種化合物在三陰性乳腺癌細胞(MDA-MB-231)中表現出抗增殖效果，IC50範圍大約在10-20 μM左右，我們對探索其作為新化學實體在藥物開發領域的潛力感到興奮。

摘要(英)

Cancer has consistently ranked among the top ten leading causes of death for many years, with breast cancer being one of the most prevalent cancers in women and a major contributor to female cancer-related fatalities. Breast cancer is divided into four subtypes, one of which is triple-negative breast cancer (TNBC), which is characterized by high mortality, high recurrence rate, high metastasis rate, and strong drug resistance, thus greatly reducing the effectiveness of treatment.
This report focuses on the synthesis of a series of N-(pyrimidin-2-yl)indolin-6-amine derivatives. The desired analogues of indoline derivatives are designed based on their relationship between compound structures and their biological activities. By adjusting molecular structures to enhance compound bioactivity, we successfully identified and prepared the compound PN009. It was found to be the most active compound against MDA-MB-231, suggesting that the introduction of branched adamantane substituent into position pyrimidin-6-yl would favor cancer cell growth inhibition. Alternatively, PN009 was shown to reduce cancer cell migration and inhibit tube formation in cell models.
In summary, this compound demonstrated anti-proliferative effects in triple-negative breast cancer cells (MDA-MB-231), the IC50 range is around 10-20 μM, and we are excited to explore its potential in the field of drug development as a new chemical entity.

關鍵字(中)

★ 三陰性乳腺癌

關鍵字(英)

★ Triple-Negative Breast Cancer

論文目次

中文摘要 i
Abstract ii
Table of Contents iii
List of Figures vi
List of Tables vii
List of Schemes viii
List of Abbreviation ix
Chapter I Introduction 1
1-1 Background 1
1-2 Introduction of Triple negative breast cancer (TNBC) 3
1-2-1 Types of breast cancer 3
1-2-2 Treatment of Triple negative breast cancer (TNBC) 5
1-3 Introduction of indoline 8
1-4 Introduction of pyrimidine 10
1-5 Introduction of angiogenesis 11
1-5-1 Angiogenesis in cancer 11
1-5-2 Inhibition of angiogenesis 12
Chapter II Result and Discussion 13
2-1 Research motivation 13
2-2 Synthesis strategy 14
2-2-1 Synthesis of PN001 14
2-2-2 Synthesis of PN002-PN012 15
2-2-3 Synthesis of PN013 17
2-2-4 Synthesis of PN014-PN016 18
2-2-5 Synthesis of PN017 19
2-3 Investigation of the selectivity of multiple halogens on pyrimidine 20
2-4 Biological experiments in vitro studies 22
2-4-1 Cytotoxicity of PN001-PN017 in MDA-MB-231 cell 22
2-4-2 Anti-migration effect of PN001-PN017 26
2-4-3 Cytotoxicity of PN007-PN009 and PN017 in HELA cell 28
2-4-4 Cytotoxicity of PN007-PN009 and PN017 in B16F10 cell 29
2-4-5 Cytotoxicity of PN007-PN009 and PN017 in M10 cell 30
2-4-6 Anti-angiogenic property of PN007-PN009 and PN017 31
2-4-7 Antiangiogenic properties of PN009 using mice aortic ring assay 33
Chapter III Conclusion 35
Chapter IV Material and Methods 36
4-1 General procedure 36
4-2 Synthetic method 37
4-2-1 General synthesis 37
4-2-2 Synthesis of intermediates of PN001 and PN003-PN016 39
4-2-3 Synthesis of PN001 40
4-2-4 Synthesis of intermediate of PN002 41
4-2-5 Synthesis of PN002 42
4-2-6 Synthesis of PN003 43
4-2-7 Synthesis of PN004 44
4-2-8 Synthesis of PN005 45
4-2-9 Synthesis of PN006 46
4-2-10 Synthesis of PN007 47
4-2-11 Synthesis of PN008 48
4-2-12 Synthesis of PN009 49
4-2-13 Synthesis of PN010 50
4-2-14 Synthesis of PN011 51
4-2-15 Synthesis of PN012 52
4-2-16 Synthesis of intermediate of PN013 53
4-2-17 Synthesis of PN013 54
4-2-18 Synthesis of intermediates of PN014-PN016 55
4-2-19 Synthesis of PN014 56
4-2-20 Synthesis of PN015 57
4-2-21 Synthesis of PN016 58
4-2-22 Synthesis of intermediate of PN017 59
4-2-23 Synthesis of PN017 60
4-3 Biological assays 61
4-3-1 Cell lines and cell cultures 61
4-3-2 MTT cytotoxicity assay 61
4-3-4 Transwell migration assay 61
Chapter V Reference 63
Chapter VI Spectra Appendix 68

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指導教授

李文山李文仁(Wen-Shan Li Wen-Ren Li)

審核日期

2024-7-18

推文