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研究生: 陳維家
Chen, Wei-Chia
論文名稱: 拓撲異構酶I抑制劑或鈣/鈣調蛋白依賴性蛋白激酶抑制劑的小分子化合物的設計合成和特性分析
Design, Synthesis, and Characterization of Small Molecules as Topoisomerase I Inhibitor or Calcium/calmodulin-dependent Protein Kinase Inhibitor
指導教授: 林文偉
Lin, Wen-Wei
李文山
Li, Wen-Shan
口試委員: 林文偉 李文山 林宜玲 邱勝賢 杜玲嫻
口試日期: 2022/01/19
學位類別: 博士
Doctor
系所名稱: 化學系
Department of Chemistry
論文出版年: 2022
畢業學年度: 110
語文別: 英文
論文頁數: 158
中文關鍵詞: 拓撲異構酶 I癌症鈣/鈣調蛋白依賴性激酶 II登革熱細胞存活試驗
英文關鍵詞: Topoisomerase I, Cancer, Calcium/calmodulin-dependent kinase II, Dengue fever, MTT assay
DOI URL: http://doi.org/10.6345/NTNU202200127
論文種類: 學術論文
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  • 利用有機合成的方式製備小分子藥物並通過構效關係(SAR)來優化結構是新藥開發的重要研究方式。本篇論文從以下兩個方向出發(1)使用拓撲異構酶 I (TOP1) 作為針對多種癌症的標靶蛋白(2)使用鈣/鈣調蛋白依賴性激酶 II (CaMKII) 作為針對登革熱病毒的標靶蛋白,合成了兩個系列的新型藥物。在第一部分,我們合成了一系列oxadiazolopyrazine的衍生物,發現其作用機制與市面上知名的TOP1抑制劑喜樹鹼相似。在這些物質中,7-fluoro-6-methoxy-9H-indeno[1,2-b][1,2,5]oxadiazolo[3,4-e]pyrazin-9-one (10)的抗癌效果最好,其針對 MDA-MB-231、BT549和MCF7細胞系的IC50分別是0.23 μM、0.19 μM 和0.25 μM。在第二部分中,我們關注在登革熱方面,它是一種屬於黃病毒科,目前最重要的蚊子傳播類疾病,每年會導致數萬人死亡。從我們合成的這些結構中,N-(4-cycloheptyl-4-oxobutyl)-4-methoxy-N-phenylbenzenesulfonamide (65) 顯示為具有最佳的抗病毒效果和最佳的CaMKII抑制效果,其EC50為1.52μM,並能顯著增加小鼠挑戰模型中的動物的存活時間。

    Using organic synthesis to make small molecule drugs and optimizing its structure via structure activity relationship (SAR) is an important research method in new drug development. Here, we synthesized two series of novel drugs by using topoisomerase I (TOP1) as a target protein against multiple cancers (part I) and calcium/calmodulin-dependent kinase II (CaMKII) as a target protein against dengue virus. (part II) In part I, we have synthesized a series of oxadiazolopyrazine analogues, and found that the mechanism of it is similar to that of camptothecin, a well-known TOP1 inhibitor in the market. Among these substances, 7-fluoro-6-methoxy-9H-indeno[1,2-b][1,2,5]oxadiazolo[3,4-e]pyrazin-9-one (10) shows the best anticancer effect, displayed IC50 = 0.23 μM, 0.19 μM, and 0.25 μM against MDA-MB-231, BT549, and MCF7 cell lines, respectively. In part II, we focus on dengue fever, which belongs to the Flaviviridae family, is an important mosquito-transmitted disease that causes tens of thousands of deaths every year. From these structures we synthesized, N-(4-cycloheptyl-4-oxobutyl)-4-methoxy-N-phenylbenzenesulfonamide (65) showed as the best CaMKII inhibitor with potent antiviral effect, displayed EC50 values of 1.52 M against DENV infections of human neuronal BE(2)C cells and increased animal survival time in mouse-challenge models significantly.

    1. Introduction 1 1-1 Cancer and Topoisomerases I 3 1-1.1 Introduction of Cancer 3 1-1.2 Introduction of Topoisomerases I 4 1-2 Dengue Fever and calcium/calmodulin-dependent protein kinase II 7 1-2.1 Introduction of Dengue Fever 7 1-2.2 Introduction of calcium/calmodulin-dependent protein kinase II (CaMKII) and its inhibitors. 8 2. Chemistry 11 2-1 Oxadiazolopyrazine Derivatives 11 2-1.1 Synthesis of Oxadiazolopyrazine Derivatives 1-9 11 2-1.2 Synthesis of Oxadiazolopyrazine Derivatives 10-18 12 2-1.3 Discussion of the Geometric on Friedel–Crafts Acylation 14 2-2 Benzenesulfonamide Derivatives 16 2-2.1 Retrosynthetic analysis of Benzenesulfonamide Derivatives 16 2-2.2 Synthesis of Benzenesulfonamide Derivatives 18 3. Result and Discussion 21 3-1 Oxadiazolopyrazine Derivatives 21 3-1.1 SAR Analysis of the Oxadiazolopyrazine Derivatives 21 3-1.2 Oxadiazolopyrazine Derivatives 10 showed the similar pattern compare to Camptothecin 24 3-1.3 Oxadiazolopyrazine Derivatives Induces DNA Damage 26 3-2 Benzenesulfonamide Derivatives 29 3-2.1 Structure–Activity Relationship Screening 29 3-2.2 Compound 9 Inhibits DENV-2 Infection In Vitro. 33 3-2.3 Compound 9 Improves the Survival Time of DENV-2- Infected Mice 34 4. Conclusion 36 5. Experimental Section 37 5-1 Chemistry 37 5-2 Synthesis 38 Reference 67 Appendixes 74

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