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Title: | 設計與合成喹唑啉和喹啉衍生物作為蛋白激酶抑制劑及生物活性評估 Design, Synthesis, and Biological Evaluation of Quinazoline and Quinoline Derivatives as Kinase Inhibitors |
Authors: | 吳昆達 Kuen-Da Wu |
Advisor: | 陳基旺 Ji-Wang Chern |
Keyword: | ?唑?,??,表皮生長因子受體抑制劑,哺乳動物雷帕黴素靶蛋白抑制劑,丙烯醯胺,大環, quinazoline,quinoline,EGFR inhibitor,mTOR inhibitor,acrylamide,macrocycles, |
Publication Year : | 2018 |
Degree: | 博士 |
Abstract: | 本論文之研究主題為設計與合成一系列以喹唑啉和喹啉作為骨架的新穎衍生物,並探討其作為激酶抑制劑的生物活性。喹唑啉和喹啉的主結構廣泛應用於藥物設計上,尤其在表皮生長因子受體抑制劑與哺乳動物雷帕黴素靶蛋白抑制劑中尤為常見。利用文獻中已發表這兩類抑制劑的分子為設計基礎,找出其中結構高度相似的Torin 2 與Lapatinib,並以合併設計的方式開發出一系列表皮生長因子受體與哺乳動物雷帕黴素靶蛋白的雙重抑制劑。
在開發雙重抑制劑研究中,發現到4-取代-6-(1-甲基吡唑-4-取代)-喹唑啉和4-取代-6-(嘧啶-5-取代)-喹唑啉是具有開發潛力的骨架,並以此結果進一步發現分子25j同時具有對表皮生長因子受體和哺乳動物雷帕黴素靶蛋白的抑制效果。此項研究提供了具有表皮生長因子受體和哺乳動物雷帕黴素靶蛋白雙重抑制劑特性的新穎分子架構,並具有潛力可作為臨床治療藥劑。 在開發表皮生長因子受體抑制劑的研究中,我們發現到丙烯醯胺基能有效提高化合物Gefitinib和AZD3759在1-辛醇和pH7.4水溶液中的溶解度。也由於這項物理性質的提升,其結果也直接反應在抑制癌細胞增殖,特別是在表皮生長因子受體過度表現的A549細胞株中尤為顯著。其中以化合物2a對表皮生長因子受體和A549細胞株抑制最為突出。 在開發哺乳動物雷帕黴素靶蛋白抑制劑的研究中,利用新開發的合成途徑交聯四號與六號位喹啉形成大環分子,並進一步發現到化合物39以聚醚為鏈結,連結喹啉的四號與六號位所形成的二十一員環具有相當的抑制效果。此項研究提供了以喹啉為基礎結構的大環分子合成方法,並可作為哺乳動物雷帕黴素靶蛋白抑制劑開發的方向。 因此,本論文製備了兩種具有潛力可作為癌症治療的先導化合物。其中一個化合物25j具有表皮生長因子受體和哺乳動物雷帕黴素靶蛋白的雙重抑制性,另一個是具有二十一員環的化合物39能夠抑制哺乳動物雷帕黴素靶蛋白。此外,丙烯醯胺基在藥物的開發上,有助於改善分子的物化性質進而提升溶解度與細胞膜的穿透度。 The aim of this dissertation is to design, synthesize, and biologically evaluate novel kinase inhibitors with quinazoline and quinoline skeleton. Quinazoline and quinoline are considered to be ideal scaffolds for drug design. To develop a dual inhibitor, the key substructures of mTOR and EGFR inhibitors were merged using Torin 2 and Lapatinib as a lead, respectively. Two series of novel scaffold 4-substituted-6-(1-methylpyrazol-4-yl)quinazoline and 4-substituted-6-(pyrimidin-5-yl)quinazoline were synthesized and demonstrated the potential inhibition on these two enzyme. Compound 25j was identified as a dual inhibitor of the kinases mTOR and EGFR with IC50 values of 2.02 μM and 0.54 μM, respectively. This investigation provided a new scaffold for the development of potent mTOR and EGFR dual inhibitor as potential clinically therapeutic agent. For the development of EGFR inhibitors, an acrylamide group was added onto the EGFR inhibitors such as gefitinib and AZD3759 and the data were found to improve the solubility in 1-octanol and pH7.4 aqueous solutions. However, these physicochemical properties were directly corresponding to their cancer cell anti-proliferation assay. This series of compounds led to identification of compound 2a as potent inhibitor against EGFR with an IC50 value of 65.2 nM and against the A549 cell line with an IC50 value of 0.15 μM. For the development of mTOR inhibitors using macrocycles concept, a novel approach toward the synthesis of macrocycle ring based on quinoline as scaffold was established. We found out that compound 39 with 21-membered ring of polyether cross-linking 4- and 6-position of quinoline showed good activity against mTOR with an IC50 value of 8.89 μM. This study provided a new direction for the preparation of macrocycles base on quinoline as potential mTOR inhibitors. In summary, this dissertation has provided two new leads for the further development of potential anti-cancer agents. One is compound 25j as a dual inhibitor of the kinases mTOR and EGFR, and the other one is compound 39 with 21-membered ring macrocycle against mTOR. Besides, the physicochemical properties of acrylamide can be applied to be included in the molecule to improve solubility and cell permeability in the drug development. |
URI: | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/77814 |
DOI: | 10.6342/NTU201800891 |
Fulltext Rights: | 未授權 |
metadata.dc.date.embargo-lift: | 2028-01-01 |
Appears in Collections: | 藥學系 |
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ntu-106-2.pdf Restricted Access | 4.08 MB | Adobe PDF |
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