博碩士論文 109223066 詳細資訊



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姓名 杜冠勳(Kuan-Hsun Tu)  查詢紙本館藏   畢業系所 化學學系
論文名稱
(Design and Synthesis of 2-Imino-1,2-Dihydro-Dipyrido[1,2-a:2′,3′-d]Pyrimidin-5-One Derivatives as Anti-cancer Drugs and Inhibitors)
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摘要(中) 受到資料庫中2-imino-1,2-dihydro-dipyrido[1,2-a:2′,3′-d] pyrimidin-5-one (IP) 抗癌活性的啟發，我們合成了一系列具有2-imino-1,2-dihydro-dipyrido[1,2-a:2′,3′-d] pyrimidin-5-one (IP) 的藥物GX002、GX003、GX004、GX006、GX007、GX008。接下來，我們進行了生物學研究，以測試它們對乳腺癌細胞的細胞毒性，並評估 GX006 的體內療效。一些 GX 化合物對三陰性乳腺癌細胞 MDA-MB-231 細胞具有良好的細胞毒性。綜上所述，GX化合物有一些對於三陰性乳癌細胞的增殖抑制是有效果的，在MDA-MB-21的細胞中，其IC50最低有到0.5至1μM。在這些化合物中，挑出GX006進行動物實驗，發現其對於腫瘤亦有不錯的抑制效果，表示這種藥物還具有潛力可開發出不同的結構來去測試對於癌細胞的治癒效果。
摘要(英) Inspired by the anti-cancer activity of 2-imino-1,2-dihydro-dipyrido[1,2-a:2′,3′-d] pyrimidin-5-one (IP) from in-house library, we synthesized a series of 2-imino-1,2-dihydro- dipyrido[1,2-a:2′,3′-d]pyrimidin-5-one (IP) containing compounds, GX002, GX003, GX004, GX006, GX007, GX008, with modifications of its functional groups. Next, we conducted biological study to test their cytotoxicity against breast cancer cells and evaluate the in vivo efficacy of GX006. Some of the GX compounds had good cytotoxicity to MDA-MB-231 cells, which are triple-negative breast cancer cells. Among of them, the IC50 value of cytotoxicity of the best one can reach around 0.5 to 1 μM. Furthermore, we chose the one, GX006, to the further animal study. The result showed that it can reduce the tumor growth significantly. In summary, this series of 2-imino-1,2-dihydro-dipyrido[1,2-a:2′,3′-d]pyrimidin -5-one containing compounds still have potential to develop into different candidates and study their inhibitory effect toward cancer cells.
關鍵字(中) ★ 抑制劑
★ 類似物
★ 抗癌藥物		 關鍵字(英) ★ inhibitors
★ deratives
★ anti-cancer drug
論文目次 中文摘要.....................................................................................................................................I
Abstract………………………………………………………………………………………..II
Contents……………………………………...……………………………………………….III
Scheme contents…………………………………………………………………………...…VI
Table contents………………………………………………………………………………..VII
Figure contents…………………………………………………………………………...…VIII
List of Abbreviation…………………………………………………………………………..IX
I. Introduction…………………………………………………………………………………1
1.1 Background……………………………………………………………………….…….1
1.2 Introduction of breast cancer…………………………………………………..………..2
1.2.1 Subtypes of breast cancer……………………………………………..…………..2
1.2.2 Triple-negative breast cancer (TNBC)……………………………………..……..3
1.2.3 Treatment of triple negative breast cancer (TNBC)……………………..………..3
1.3 Introduction of Human DNA Topoisomerase…………………………………………...6
1.3.1 Human DNA Topoisomerase……………………………………………………...6
1.3.2 Topoisomerase inhibitors………………………………………………………….8
1.3.3 Topoisomerase inhibit mechanism………………………………………………11
1.4 Literature review……………………………………………………………………....12
II. Results and Discussion…………………………………………………………………..15
2.1 Retrosynthetic Analysis of GX Compounds, IP-Containong Deratives..……………...15
2.2 Synthesis of cyano acetic acid linker and first step reagent…………………………...16
2.3 Synthesis of cyano amide and ester linker…………………………………….………17
2.3.1 Synthetic route of cyano amide 5………………………………………..………17
2.3.2 Synthetic route of cyano ester 6…………………………………………………17
2.4 Synthesis of anticancer drugs GX002-008…………………………………………….18
2.4.1 Synthetic route of GX002……………………………………………………….18
2.4.2 Synthetic route of GX003……………………………………………………….18
2.4.3 Synthetic route of GX004 and GX006………………………………………….20
2.4.4 Synthetic route of GX007……………………………………………………….21
2.4.5 Synthetic route of GX008……………………………………………….………22
2.5 In Vitro Studies of GX002-008…………………..………………………..…………..23
2.5.1 Cytotoxicity of GX002-008 on MDA-MB-231 cell proliferation………………24
2.6 Analysis of Structure Activity Relationship…………………………………………..26
2.7 In Vivo studies of GX006………………………………………………………….….27
III. Conclusion…………………………………………………………………………..…..28
IV. Material and Methods……………………………………………………………….…..29
4.1 General procedure……………………………………………………………………..29
4.2 Synthetic method………………………………………………………….…………..30
4.2.1 Preparation of cyclized linker………………………………………….………..30
4.2.2 Synthesis of first step reagent………………………………………….....……..32
4.2.3 Synthesis of intermediates of GX002-008………………………………………32
4.2.4 Preparation of GX002………………………………………………………...…36
4.2.5 Preparation of GX003…………………………………………………………...37
4.2.6 Preparation of GX004 ………………………………………………………......39
4.2.7 Preparation of GX006……………………………………………………...……41
4.2.8 Preparation of GX007…………………………………………………………...43
4.2.9 Preparation of GX008…………………………………………………………...45
4.3 Cell Line Used and Cell Culture………………………………………………...…….47
4.4 MTT Cytotoxicity Analysis………………………….………………………….……..47
4.5 Animal study…………………………………………………………………………..47
V. References……………………………………………………………………………….48
VI. Spectra Appendix………………………………………………………………..………52
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指導教授 李文山 侯敦仁(Wen-Shan Li Duen-Ren Hou) 審核日期 2022-9-27
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