臺灣博碩士論文加值系統

Akt，又名為蛋白質激酶B (PKB，protein kinase B)是一種蛋白質轉錄因子，而Akt的活化可以引發一連續的生理反應，除了抑制細胞凋亡外，會進一步造成細胞不正常增生、抑制細胞分化、血管新生與惡性轉移等作用。本篇論文是藉2006年亞培(Abbott)公司發表的Akt抑制劑SS3與PKA的結合作用力作為參考設計，並合成以吲哚(indoles)為主要架構的抑制藥物。另外對FGFR與GSK-3β的分子資料庫進行虛擬藥物篩選，延伸合成苯並咪唑 (benzimidazoles)、胺嘌呤(purines)及鄰苯二甲內酯(Isobenzofuranone)衍生物並進行生物活性的探討。生物活性結果顯示由苯並咪唑 (benzimidazoles)衍生的化合物6201、6204、6208、6209、6210和6212與胺嘌呤(purines)衍生的化合物6306、6308和6309具有減少Akt被磷酸化的效果；另外再經由ELISA分析，定量出被磷酸化過後的Akt並且與控制組比較後，找到其中的化合物6208、6209和6212在抑制Akt活化的效果最好，將來可以預期新的Akt抑制劑。

Protein kinase B/Akt is a central node of the PI3K/Akt signaling pathway that is believed to be the most frequently mutated or overexpressed signaling abnormality in human cancers. In this study, we have taken SS3, an Akt inhibitor developed by Abbott Laboratory, as a lead compound, designed and synthesize indole derivatives according to its interaction with PKA. By virtual screening a FGFR/GSK-3β compound library, we have also designed and synthesized benzimidazole, purine and isobenzofuranone derivatives which showed good binding with PKA. While benzimidazole derivatives 6201 6204 6208 6209 6210 6212, and purine derivatives 6306 6308 6309 all demonstrated some ability to decrease Akt1 phosphorylation, compound 6212 was found to be the most active compound that can potentially be developed into a new Akt inhibitor.

目錄
摘要..............................II
Abstract..............................III
目錄..............................IV
圖目錄..............................VIII
表目錄..............................XII
縮寫表..............................XIII
第一章 緒論..............................1
1.1前言..............................1
1.2 PI3K..............................3
1.3 Akt蛋白家族..............................5
1.4研究動機與實驗設計..............................8
第二章 實驗部分..............................16
2.1化學試藥、溶劑與儀器介紹..............................16
2.1.1化學試藥..............................16
2.1.1化學溶劑..............................19
2.1.1儀器介紹..............................19
2.2分子對接實驗方法..............................20
2.1.1 PKA結構比對..............................20
2.1.1分子對接軟體操作..............................21
2.3有機合成方法..............................22
2.3.11-(6-bromo-4-nitroindol-2-yl)-2-phenylethanone..............................22
(6101A) 4-Bromo-2,6-dinitrotoluene..............................23
(6101B) (E)-2-(4-bromo-2,6-dinitrophenyl)-N,N-dimethyl-ethenamine..............................24
(6101C) 6-bromo-4-nitroindole..............................25
(6101D) 6-bromo-4-nitro-1-(phenylsulfonyl)-1H-indole..............................26
2.3.2 1,3-dihydro-1H-benzimidazol-2-one衍生物..............................27
(6201A) 3-(benzyloxy)benzaldehyde..............................29
(6201) (E)-5-(3-(benzyloxy)benzylideneamino)-1H-benzimidazol-2(3H)-one..............................30
(6202) 5-(3-(benzyloxy)benzylamino)-1H-benzimidazol-2(3H)-one..............................31
(6203A) 4-(benzyloxy)benzaldehyde..............................32
(6203) (E)-5-(4-(benzyloxy)benzylideneamino)-1H-benzimidazol-2(3H)-one..............................33
(6204) 5-(4-(benzyloxy)benzylamino)-1H-benzimidazol-2(3H)-one..............................34
(6205) 5-(4-(dimethylamino)benzylamino)-1H-benzimidazol-2(3H)-one..............................35
(6206) 5-((1H-indol-6-yl)methylamino)-1H-benzimidazol-2(3H)-one..............................36
(6207) 5-(3-methoxybenzylamino)-1H-benzimidazol-2(3H)-one..............................37
(6208a) (E)-5-(2-nitrobenzylideneamino)-1H-benzimidazol-2(3H)-one..............................38
(6208) 5-(2-nitrobenzylamino)-1H-benzimidazol-2(3H)-one..............................39
(6209a) (E)-5-(3-nitrobenzylideneamino)-1H-benzimidazol-2(3H)-one..............................40
(6209) 5-(3-nitrobenzylamino)-1H-benzimidazol-2(3H)-one..............................41
(6210) 5-(4-nitrobenzylamino)-1H-benzimidazol-2(3H)-one..............................42
(6211) 5-(benzylamino)-1H-benzimidazol-2(3H)-one..............................
(6212) 5-(3-hydroxybenzylamino)-1H-benzimidazol-2(3H)-one..............................44
(6213) 5-(4-hydroxybenzylamino)-1H-benzimidazol-2(3H)-one..............................45
(6214) 5-(4-methoxybenzylamino)-1H-benzimidazol-2(3H)-one..............................46
2.3.3 Purine衍生物..............................47
(6301) 4-(9H-purin-6-ylamino)phenol..............................48
(6302) N-phenyl-9H-purin-6-amine..............................49
(6303) N-(4-methoxyphenyl)-9H-purin-6-amine..............................50
(6304) N1,N1-dimethyl-N4-(9H-purin-6-yl)benzene-1,4-diamine..............................51
(6305) 3-(9H-purin-6-ylamino)phenol..............................52
(6306) N-(3-methoxyphenyl)-9H-purin-6-amine..............................53
(6307) 5-(9H-purin-6-ylamino)-1H-benzimidazol-2(3H)-one..............................54
(6308) 3-(9H-purin-6-ylamino)benzoic acid..............................55
(6309) N-(4-nitrophenyl)-9H-purin-6-amine..............................56
(6310) N-(3-(trifluoromethyl)phenyl)-9H-purin-6-amine..............................57
(6311) 5-(9H-purin-6-ylamino)-2-hydroxybenzoic acid..............................58
2.3.4 Isobenzofuranone衍生物..............................59
(6401a) Phthalidyl-acetic acid ethyl ester..............................60
(6401b) Phthalide-3-acetic acid..............................61
(6401) N-(furan-2-ylmethyl)-2-(3-oxo-1,3-dihydroisobenzofuran-1-yl)acetamide..............................62
第三章 結果與討論..............................64
3.2有機合成探討..............................64
3.1.1 1-(6-bromo-4-nitroindol-2-yl)-2-phenylethanone..............................64
3.1.2 1,3-Dihydro-1H-benzimidazol-2-one derivatives..............................69
3.1.3 Purine derivatives..............................75
3.1.4 Isobenzofuranone derivatives..............................78
3.2分子對接結果..............................83
3.3生物活性測試結果..............................88
3.3.1 1-(6-bromo-4-nitroindol-2-yl)-2-phenylethanone..............................88
3.3.2 Purine derivatives and Isobenzofuranone..............................90
3.3.3 Western Blot定量及ELISA結果..............................91
3.4生物活性測試與分子對接結果比對..............................94
第四章 結論..............................98
未來展望..............................101
參考文獻..............................105
圖譜..............................110

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