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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 陳基旺 | |
dc.contributor.author | Mei-Yun Lu | en |
dc.contributor.author | 呂美韻 | zh_TW |
dc.date.accessioned | 2021-06-08T06:11:21Z | - |
dc.date.copyright | 2011-10-07 | |
dc.date.issued | 2011 | |
dc.date.submitted | 2011-08-04 | |
dc.identifier.citation | 1.World Health Organization. World health statistics 2008. http://www.who.int/gard/news_events/World_Health_Statistics _2008/en/index.html
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A.; Newton, R., Harnessing the clinical efficacy of phosphodiesterase 4 inhibitors in inflammatory lung diseases: dual-selective phosphodiesterase inhibitors and novel combination therapies. Handb. Exp. Pharmacol. 2011, 204, 415-446. 53.Kita, T.; Fujimura, M.; Myou, S.; Watanabe, K.; Waseda, Y.; Nakao, S., Effects of KF19514, a phosphodiesterase 4 and 1 inhibitor, on bronchial inflammation and remodeling in a murine model of chronic asthma. Allergol. Int. 2009, 58, 267-275. 54.Yamamoto, S.; Sugahara, S.; Naito, R.; Ichikawa, A.; Ikeda, K.; Yamada, T.; Shimizu, Y., The effects of a novel phosphodiesterase 7A and -4 dual inhibitor, YM-393059, on T-cell-related cytokine production in vitro and in vivo. Eur. J. Pharmacol. 2006, 541, 106-114. 55.Vestbo, J.; Tan, L.; Atkinson, G.; Ward, J., A controlled trial of 6-weeks' treatment with a novel inhaled phosphodiesterase type-4 inhibitor in COPD. Eur. Respir. J. 2009, 33, 1039-1044. 56.Chapman, R. 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Design, synthesis and biological evaluation of 1-benzyl-4-phenyl -1H-quinazolin-2-one derivatives as phosphodiesterase inhibitors. Ph.D. Thesis, National Taiwan University, Taiwan, R. O. C., 2007. 61.Chang, C.-Y. Design and synthesis of 4-aryl-1-benzyl-1H-quinazolin-2-ones an dual phosphodiesterase 4 and 5 inhibitors. Master thesis, National Taiwan University, Taiwan, R. O. C., 2010. 62.Kerns, E. H.; Di, L., Drug-like properties: concepts, structure design and methods- from ADME to toxicity optimization. 1st ed.; Elsevier: 2008. 63.Information receved from the internet homepages of Molsoft. (http://www.molsoft.com/mprop/). 64.Prasad, K.; Lee, G. T.; Chaudhary, A.; Girgis, M. J.; Streemke, J. W.; Repic, O., Design of new reaction conditions for the Sugasawa reaction based on mechanistic insights. Org. Process Res. Dev. 2003, 7, 723-732. 65.Atechian, S.; Nock, N.; Norcross, R. D.; Ratni, H.; Thomas, A. W.; Verron, J.; Masciadri, R., New vistas in quinoline synthesis. Tetrahedron 2007, 63, 2811-2823. 66.Wang, J.; Discordia, R.; Crispino, G.; Li, J.; Grosso, J.; Polniaszek, R.; Truc, V., A mild and efficient synthesis of 4-aryl-quinolin-2(1H)-ones via a tandem amidation/Knoevenagel condensation of 2-amino-benzophenones with esters or lactones. Tetrahedron Lett. 2003, 44, 4271-4273. 67.Vrudhula, V. M.; Dasgupta, B.; Qian-Cutrone, J.; Kozlowski, E. S.; Boissard, C. G.; Dworetzky, S. I.; Wu, D.; Gao, Q.; Kimura, R.; Gribkoff, V. K.; Starrett, J. E.; John E. Starrett, J., Atropisomeric 3-( | |
dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/25385 | - |
dc.description.abstract | 本論文主旨為設計與合成一系列喹啉-2-酮衍生物作為潛能第四型與第五型磷酸二酯酶(PDE4/5)雙效抑制劑。早期研究發現1-(4-溴苯甲基)-4-(3-氯苯基)-7-甲氧基喹唑啉-2-酮 (10)為一新穎的PDE抑制劑,其對PDE4具有強效抑制作用(IC50 = 4 nM),且對PDE5亦有中等強度的抑制效果(IC50 = 512 nM);根據文獻指出PDE4/5雙效抑制劑對慢性阻塞性肺疾具有多重益處;然而,抑制腦部PDE4D似乎是PDE4抑制劑造成噁心、嘔吐的主要原因。為了發展出低血腦障壁穿透率的抑制劑以改善治療指數,本論文將以化合物10為起始模板進行結構修飾,置換喹唑啉-2-酮第三位置氮原子為碳原子並加入極性基團。喹啉-2-酮衍生物的製備,需先利用Sugasawa反應在苯胺的鄰位進行醯化以合成起始物2-胺基苯基苯甲酮18,再利用適當的鹼進行醯胺化及Knoevenagel縮和反應,所得到的中間產物再經過烷基化即可得到目標產物。根據初步的體外PDE酵素活性檢測結果,當化合物10的第三位置氮原子置換成碳原子所得到的化合物12a,對PDE4/5有相似程度的抑制活性,且對其他PDE家族具有明顯選擇性。當喹啉-2-酮第三位置加入羥乙基取代之後,所得到的化合物13a可提升PDE4/5的抑制活性,並可增加極性表面積(PSA);若將羥乙基替換成嗎福林或羧酸基團,則會成為選擇性PDE4抑制劑。在喹啉-2-酮第七位置加入甲氧基取代是保留PDE4/5抑制活性所必須的,但在第六位置加入取代基則會減弱PDE4的抑制活性。接著,分析喹啉-2-酮第一位置氮原子上取代基的構效關係,結果顯示加上4-溴苯甲基的表現最佳,但若加上具立體障礙的2,6-雙氯苯甲基,則會完全喪失PDE4/5的抑制活性。綜觀來說,本論文中的一系列1H-quinolin-2-one衍生物為具有潛力的PDE4/5雙效抑制劑,然而此類化合物對PDE4D有較好的抑制效果,可能會導致中樞神經副作用。此結果顯示引入極性官能基以改善副作用的設計策略是具有助益的。 | zh_TW |
dc.description.abstract | The aim of this thesis is to design and synthesize a series of 1H-quinolin-2-one derivatives as potential dual phosphodiesterase 4 and 5 (PDE4/5) inhibitors. In previous investigation, 1-(4-bromobenzyl)-4-(3-chlorophenyl)-7-methoxy-1H-quinazolin-2-one (10) was found to be a novel PDE inhibitor that inhibited PDE4 with a high potency (IC50 = 4 nM) and PDE5 with a moderate potency (IC50 = 512 nM). According to the literature, dual inhibitors of PDE4 and PDE5 would provide multiple benefits in COPD. However, PDE4D inhibition in human brain appears to be a major cause of nausea and emesis. In order to develop low blood-brain barrier penetration inhibitors with improved therapeutic ratio, compound 10 was chosen as lead compound. It was modified by displacing the nitrogen at 3-position of 1H-quinazolin-2-one ring to carbon and incorporating various polar groups on this position. In the preparation of 1H-quinolin-2-one derivatives, the required starting materials (2-aminophenyl)(phenyl) methanones 18 were obtained from ortho-acylation of anilines by Sugasawa reaction. Then, amidation and Knoevenagel condensation of 18 with suitable base gave an intermediate, which was alkylated to afford the target product. From preliminary results of in vitro PDE enzyme activity assay, 12a, the desaza-analog of 10 was found to possess a comparable activity against PDE4/5 to 10. Furthermore, it demonstrated a significant selectivity toward other PDE isoenzymes. When hydroxyethyl group was added on the 3-position of 1H-quinolin-2-one ring, the resulted compound 13a provided improvement in PDE4/5 inhibition. Additionally, the polar surface area was increased when compared to 10. Replacing the hydroxyethyl with morpholine or carboxylic acid resulted in selective PDE4 inhibitory activity. Introduction of methoxy to the 7-position of 1H-quinolin-2-one ring was necessary to keep PDE4/5 potency, while substitution at the 6-position was detrimental to PDE4 inhibitory activity. Next, the SAR of various nitrogen substituents on the 1-position of the 1H-quinolin-2-one ring was demonstrated that 4-bromobenzyl group was best. However, introduction of steric 2,6-dichlorobenzyl group to this position resulted in complete loss of PDE4/5 inhibitory activity. Taken together, a series of 1H-quinolin-2-one derivatives in this study were found to be potential PDE4/5 dual inhibitors. However, their relatively high PDE4D potency of these compounds may lead to CNS side effects. These results suggest that the strategy of incorporating various polar groups would be useful to improve adverse effects. | en |
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dc.description.tableofcontents | 圖目錄 iii
表目錄 iv 式目錄 v 縮寫表 vi 中文摘要 vii Abstract viii 第一章 緒論 1 1.1 慢性阻塞性肺疾 1 1.2 磷酸二酯酶 5 1.2.1 環狀核苷酸的訊息傳遞 5 1.2.2 磷酸二酯酶超家族的分類 6 1.3 磷酸二酯酶抑制劑於慢性阻塞性肺疾之應用 8 1.3.1 第四型磷酸二酯酶抑制劑 8 1.3.2 第一、第三、第五及第七型磷酸二酯酶抑制劑 11 第二章 實驗設計 13 2.1 設計動機 13 2.2 設計方法 15 第三章 結果與討論 19 3.1 標的化合物之合成 19 3.1.1 1-Benzyl-3-(2-hydroxyethyl)-4-phenyl-1H-quinolin-2-one衍生物之合成 19 3.1.2 1-(4-Bromobenzyl)-4-phenyl-1H-quinolin-2-one衍生物之合成 25 3.1.3 Carboxylic acid、morpholine及hydroxypropyl衍生物之合成 26 3.2 體外酵素活性評估 30 第四章 結論 36 第五章 實驗部分 38 5.1 檢驗方法與實驗儀器 38 5.2 試藥與溶劑 39 5.3 合成步驟 39 5.3.1 (2-Aminophenyl)(phenyl)methanone衍生物 39 5.3.2 3-(2-Hydroxyethyl)-4-phenyl-1H-quinolin-2-one衍生物 45 5.3.3 1-Benzyl-3-(2-hydroxyethyl)-4-phenyl-1H-quinolin-2-one衍生物 51 5.3.4 1-(4-Bromobenzyl)-4-phenyl-1H-quinolin-2-one衍生物 65 5.3.5 其他 72 5.4 體外酵素活性評估 80 第六章 參考文獻 81 第七章 附錄 88 | |
dc.language.iso | zh-TW | |
dc.title | 設計與合成喹啉-2-酮衍生物作為潛能第四型與第五型磷酸二酯酶雙效抑制劑 | zh_TW |
dc.title | Design and Synthesis of 1H-Quinolin-2-one Derivatives as Potential Dual Phosphodiesterase 4 and 5 Inhibitors | en |
dc.type | Thesis | |
dc.date.schoolyear | 99-2 | |
dc.description.degree | 碩士 | |
dc.contributor.oralexamcommittee | 王光昭,顧記華,忻凌偉,陳香惠 | |
dc.subject.keyword | 磷酸二酯酶,雙效抑制劑,慢性阻塞性肺疾,喹,啉,-2-酮, | zh_TW |
dc.subject.keyword | phosphodiesterases,dual inhibitors,COPD,1H-quinolin-2-one, | en |
dc.relation.page | 94 | |
dc.rights.note | 未授權 | |
dc.date.accepted | 2011-08-04 | |
dc.contributor.author-college | 醫學院 | zh_TW |
dc.contributor.author-dept | 藥學研究所 | zh_TW |
顯示於系所單位: | 藥學系 |
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