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研究生:賴宥任
研究生(外文):LAI,YOU-REN
論文名稱:設計與合成新穎5,6-二氫-1H-吡唑並[4,5-d]噠嗪-4,7-二酮衍生物作為胱胺酸-麩胺酸轉運體抑制劑
論文名稱(外文):Design and synthesis of novel 5,6-dihydro-1H-pyrazolo[4,5-d]pyridazine-4,7-dione derivatives as cystine-glutamate antiporter inhibitors
指導教授:吳雨珊吳雨珊引用關係
指導教授(外文):WU,YU-SHAN
口試委員:楊定亞謝佳宏
口試委員(外文):YANG,DING-YAHHSIEH,CHIA-HUNG
口試日期:2020-07-23
學位類別:碩士
校院名稱:東海大學
系所名稱:化學系
學門:自然科學學門
學類:化學學類
論文種類:學術論文
論文出版年:2020
畢業學年度:108
語文別:中文
論文頁數:146
中文關鍵詞:胱胺酸-麩胺酸轉運體抑制劑胱胺酸麩胺酸
外文關鍵詞:cystine-glutamate antiporter inhibitorscystineglutamate
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System xc-轉運蛋白會將細胞內的麩胺酸(L-Glu)和細胞外的胱胺酸(L-Cys2)做1:1的交換,並將透過L-Cys2合成GSH來提升抗氧化能力,本研究參考 Patel 研究團隊所設計出的藥效基團模型和透過分析目前已發表過的抑制劑結構,設計出新穎的一系列以 pyrazole 為中心雜環為主體結構的9個衍生物,希望透過合成這些新的衍生物,能夠找到有效抑制神經興奮性毒性或是對於腦瘤治療有幫助的胱胺酸-麩胺酸轉運體的抑制劑。然而,這些衍生物都具有5,6-二氫-1H-吡唑並[4,5-d]噠嗪-4,7-二酮的結構,大部分的水溶性都極差,我們在9個衍生物中,發現了在長鏈導入疏水性基團的FM-GNXT和FM-MGNXT對於抑制system xc-效果較好,也找到了一個溶解度佳的衍生物FM-650F3NB,雖然其對於抑制system xc-抑制效果沒有那麼好,但溶解度良好,可以利於往後進一步的利用。
System xc- mediates the exchange of extracellular L-cystine and
intracellular L-glutamate across the cellular plasma membrane in a 1:1 ratio and through the entry of L-Cys2, GSH is synthesized in the cell to enhance antioxidant ability. In this study, we took pharmacophore model of isoxazole analogues proposed by Patel et. Al. as a guide to design and synthesize nine pyrazole derivatives as system xc- inhibitors.
These 5,6-dihydro-1H-pyrazolo[4,5-d]pyridazine-4,7-dione derivatives were shown to exhibit extremely poor solubility in water. Derivatives FM-GNXT and FM-MGNXT with hydrophobic groups in the long chain,were found to show better system xc- inhibition. FM-650F3NB, a derivative with better water solubility, was found to exhibit weaker inhibitory effect. FM-650F3NB thus serves as a good starting lead for an inhibitor with both good system xc- inhibition and water solubility.
中文摘要---------------------------------------------------------------I
Abstract-------------------------------------------------------------II
目錄--------------------------------------------------------------III_VI
圖目錄----------------------------------------------------------VII_VIII
表目錄----------------------------------------------------------------IX
圖譜目錄-----------------------------------------------------------X_XII
第一章 緒論-------------------------------------------------------1_2
1.1 麩胺酸與特異性受體---------------------------------------------2_3
1.2 System xc-轉運蛋白與GSH合成機制--------------------------------4_7
1.3 System xc-與興奮性毒性-----------------------------------------8
1.4 文獻探討與system xc-抑制劑-----------------------------------9_15
1.5 構校關係與藥效團模型-----------------------------------------16_18
1.6 藥物設計和修飾構思-------------------------------------------19_21
第二章 實驗材料與方法-----------------------------------------------22
2.1 化學試藥、溶劑與儀器介紹--------------------------------------22_23
2.2 化學試藥-------------------------------------------------------24
2.3 化學溶劑-------------------------------------------------------25
2.4 有機合成-------------------------------------------------------26
FM009-329 之合成方法-----------------------------------------------26
FM009-321 之合成方法-----------------------------------------------27
FM009-327 之合成方法-----------------------------------------------28
FM-08 之合成方法---------------------------------------------------29
FM-315 之合成方法--------------------------------------------------30
FM009-3291 之合成方法----------------------------------------------31
FM009-3211 之合成方法----------------------------------------------32
FM009-3271 之合成方法----------------------------------------------33
FM-081 之合成方法--------------------------------------------------34
FM-3151 之合成方法-------------------------------------------------35
FM009-3291-Cl 之合成方法-------------------------------------------36
FM009-3211-Cl 之合成方法-------------------------------------------36
FM009-3271-Cl 之合成方法-------------------------------------------37
FM-081-Cl 之合成方法-----------------------------------------------37
FM-3151-Cl 之合成方法----------------------------------------------38
FM-VI1 之合成方法--------------------------------------------------39
FM-650F 之合成方法-------------------------------------------------40
FM-VI2 之合成方法--------------------------------------------------41
FM-650F22 之合成方法-----------------------------------------------42
FM-NH2 之合成方法--------------------------------------------------43
FM-CNHU 之合成方法-------------------------------------------------44
FM-650F3 之合成方法------------------------------------------------45
FM-FNXT 之合成方法-------------------------------------------------46
FM-GNXT 之合成方法-------------------------------------------------47
FM-MFNXT 之合成方法------------------------------------------------48
FM-MGNXT 之合成方法------------------------------------------------49
FM-PHNXT 之合成方法------------------------------------------------50
FM-650F22NB 之合成方法---------------------------------------------51
FM-650F22PH 之合成方法---------------------------------------------52
FM-650F3NB 之合成方法----------------------------------------------53
FM-650F3PH 之合成方法----------------------------------------------54
2.5 細胞繼代與MTT 細胞毒性測試------------------------------------55_57
2.6 L-Glu 檢量線製作與前處理--------------------------------------57_59
第三章 結果與討----------------------------------------------------60
3.1 Piperazine 系列----------------------------------------------60_61
3.2 Aromatic 系列------------------------------------------------62_66
3.3 Piperidine 系列---------------------------------------------67_69
3.4 生物活性探討-------------------------------------------------70_74
第四章 結論--------------------------------------------------------75
4.1 未來展望-------------------------------------------------------76
4.2 參考文獻----------------------------------------------------77_80
4.3 圖譜附錄----------------------------------------------------81_130


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