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

陳維家(Chen Wei-Chia)

指導教授 ： 林文偉 ； 李文山

國立臺灣師範大學/理學院/化學系/博士(2022年)

https://doi.org/10.6345/NTNU202200127

摘要

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。

關鍵字

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

並列摘要

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.

並列關鍵字

Topoisomerase I ； Cancer ； Calcium/calmodulin-dependent kinase II ； Dengue fever ； MTT assay

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