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研究生:吳澄迦
研究生(外文):Cheng-chia Wu
論文名稱:4-芳香羰基喹唑啉衍生物之設計與合成及其抗癌活性評估
論文名稱(外文):Design, Synthesis, and Evaluation of Anticancer Activity of 4-Arylcarbonylquinazoline Derivatives
指導教授:陳香惠
指導教授(外文):Grace-shiahuy Chen
學位類別:碩士
校院名稱:靜宜大學
系所名稱:應用化學研究所
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:2006
畢業學年度:94
語文別:中文
論文頁數:136
中文關鍵詞:細胞週期微管
外文關鍵詞:tubulinCA-4cell cycle
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本論文主旨為設計與合成一系列4-芳香羰基喹唑啉衍生物作為抗微管試劑。已有文獻報導出吲哚衍生物對抗微管聚合試劑與CA-4擁有相當的效果,結構上判斷,羰基連結二芳香環之間形成順式型態及環上的甲氧基是對抗微管試劑的設計必要的一環,因此,設計一系列喹唑啉衍生物,在第4位置接入芳香羰基,期盼擁有良好的生物活性。第四位置各種芳香羰機取代之喹唑啉衍生物6及6,7-雙取甲氧基喹唑啉7之合成均以aminobenzoate為起始物先以foramide進行縮合環化,再經氯化後,以各種取代基之benzaldehyde在強鹼下進行取代反應而得到最終產物6a-6o與7a-7o,其中7m與7n含有醚類化合物4-(3,4-difluorobenzyloxy)-6,7-dimethoxyquinazoline 8m及4-(2,4-dichlorobenzyloxy)-6,7-dimethoxyquinazoline 8n之副產物出現。合成的標的化合物均採SRB篩選方式,分別對胃癌細胞株AGS、肺癌細胞株A549、肝癌細胞株HepG2、大腸直腸癌細胞株HT-29和前列腺癌細胞株PC-3進行體外細胞毒性測試,結果發現均無生物活性。以理論計算方式鑑定結構構形,發現其構形為反式,因此進ㄧ步將衍生物7還原迫使結構更接近順式,針對還原後的衍生物9進行體外生物評估,期盼能擁有良好的抑制活性。
This thesis is aimed at design, synthesis, and evaluation of anticancer activity of 4-arylcarbonylquinazoline derivatives as antimicrotubule agents. The indole derivatives mimic CA-4 have been demonstrated to have great inhibitory activity against tubulin polymerization. Based on the structural features, it is essential for antimicrotubule agents to possess two aryl rings by carbonyl group in cis conformation and methoxy groups on the aryl rings. Therefore, we introduced 4-benzoyl substituents on quinazoline rings which were expected to possess biological activity. The synthesis of various benzoyl group substituents at the 4-position quinazoline (7) and 6,7-dimethoxyquinazoline (8) was initiated from the cyclization of aminobenzoate and foramide. After chlorination, various benzaldehydes were used to substitute the chloride under basic condition to give the target compounds 6a-6o and 7a-7o. For 7m and 7n, the byproducts, 4-(3,4-difluorobenzyloxy)-6,7-dimethoxyquinazoline 8m and 4-(2,4-dichlorobenzyloxy)-6,7-dimethoxyquinazoline 8n were also obtained. All synthesized compounds were subjected to SRB assay to test the in vitro cytotoxicity against stomach cancer cell line AGS, lung cancer cell lines A549, liver cancer cell line HepG2, colon cancer cell line HT-29, and prostate cancer cell line PC-3. However, all compounds were not active. On the basis of computational results, it was found that these compounds were in trans form. Thus, further reduction on derivatives 7 was carried out in order to approach the cis conformation for better biological activity.
目錄
第一章 緒論 1
第二章 實驗設計 18
第三章 結果與討論 19
3.1 標的化合物的合成 19
3.1.1 3H-Quinazolin-4-one (1)及6,7-dimethoxyquinazolin-4-one (2)的合成 19
3.1.2 4-Chloroquinazoline (3)及4-Chloro-6,7-dimethoxyquinazoline (4)的合成 20
3.1.3 N,N-Dimethylimidazolium iodide (5)催化劑的合成 21
3.1.4 4-Benzoylquinazoline衍生物6及7的合成 22
3.1.5 結構穩定度計算 23
3.1.6 4-Benzoyl-6,7-dimethoxyquinazolinne衍生物的還原 25
3.2 體外生物活性測試 26
第四章 結論 30
第五章 實驗部分 31
5.1 檢驗方法與實驗儀器 31
5.2 試藥、溶劑 31
5.3 合成步驟 31
第六章 參考資料 57
參考資料
Information receved from the Internet Homepages of the Department of Health, Taiwan, R. O. C. (http://www.doh.gov.tw)
Jordan, A.; Hadfield, J. A.; Lawrence, N. J.; McGown, A. T. Tubulin as a Target for Anticancer Drugs: Agents Which Interact with the Mitotic Spindle. Med. Res. Rev. 1998, 18, 259-296.
Compbell, T. B.; Reece, J. B. Biology 2002, 12, 215-231.
Desbène, S.; Renault, S. Drugs that Inhibit Tubulin Polymerization: The Particular Case of Podophyllotoxin and Analogues. Curr. Med. Chem. – Anti-Cancer Agents 2002, 2, 71-90.
Nam, N. H. Combretastatin A-4 Analogues as Antimitotic Antitumor Agents. Curr. Med. Chem. 2003, 10, 1697-1722.
Pineda, O.; Farra`s, J.; Maccari, L.; Manetti, F.; Botta, M.; Vilarrasaa, J.; Computational Comparison of Microtubule-Stabilising Agents Laulimalide and Peloruside with Taxol and Colchicine. Bioorg. Med. Chem. Let., 2004, 14, 4825–4829.
Rowinsky, E. K.; Donehower, R. C. Paclitaxel (Taxol). N. Engl. J. Med. 1995, 332, 1004–1014.
Shearwin, K. E.; Timasheff, S. N. Effect of Colchicine Analogues on the Dissociation of ab Tubulin into Subunits: the Locus of Colchicine Binding. Biochemistry 1994, 33, 894–901.
Perez-Ramirez, B.; Andreu, J. M.; Gorbunoff, M. J.; Timasheff, S. N. Stoichiometric and Substoichiometric Inhibition of Tubulin Self-Assembly by Colchicine Analogues. Biochemistry 1996, 35, 3277–3285.
Pryor, D. E.; O’Brate, A.; Bilcer, G.; Dı´az, J. F.; Wang, Y.; Wang, Y.; Kabaki, M.; Jung, M. K.; Andreu, J. M.; Ghosh, A. K.; Giannakakou, P.; Hamel, E. The Microtubule Stabilizing Agent Laulimalide Does Not Bind in the Taxoid Site, Kills Cells Resistant to Paclitaxel and Epothilones, and May Not Require Its Epoxide Moiety for Activity Biochemistry 2002, 41, 9109-9115.
Lin, C. M.; Singh, S. B.; Chu, P. S.; Dempcy, R. O.; Schmidt, J. M.; Pettit, G. R.; Hamel, E. Interactions of Tubulin with Potent Natural and Synthetic Analogues of the Antimitotic Agent Combretastatin: A Structure-Activity Study. Mol Pharmacol 1988, 34, 200-208.
Cushman, M.; Nagarathnam, D.; Gopal, D.; He, H. M.; Lin, C. M.; Hamel, E. Synthesis and Evaluation of Analogues of (Z)-l-(4-Methoxyphenyl)-2-(3,4,5-trimethoxyphenyl) etheanes Potential Cytotoxic and Antimitotic Agents. J. Med. Chem. 1992, 35, 2293-2306.
Bedford, S. B.; Quarterman, C. P.; Rathbone, D. L.; Slack, J. A.; Griffin, R. J.; Stevens, M. F. G. Synthesis of Water-soluble Prodrugs of the Cytotoxic Agent Combretastatin A4. Bioorg. Med. Chem. Lett. 1996, 6, 157-160.
Shirai, R.; Okabe, T.; Iwasaki, S. Synthesis of Conformationary Restricted Combretastatins. Heterocycles 1997, 46, 145-148.
Shirai, R.; Takayama, H.; Nishikawa, A.; Koiso, Y. Hashimoto, Y. Asymmetric Synthesis of Antimitotic Combretadioxolane with Potent Antitumor Activity Agent Multi-Drug Resistant Cells. Bioorg. Med. Chem. Lett. 1998, 8, 1997-2000.
Wang, L.; Woods, K. W.; Li, Q.; Barr, K. J.; McCroskey, R. W.; Hannick, S. M.; Gherke, L.; Credo, R. B.; Hui, Y. H.; Marsh, K.; Warner, R.; Lee, J. Y.; Zielinski-Mozng, N.; Frost, D.; Rosenberg, S. H.; Sham, H. L. Potent, Orally Active Heterocycle-Based Combretastatin A-4 Analogues: Synthesis, Structure-Activity Relationship, Pharmacokinetics, and In Vivo Antitumor Activity Evaluation. J. Med. Chem. 2002, 45, 1697-1711.
Li, Q.; Woods, K. W.; Claiborne, A.; Gwaltney, S. L. II.; Barr, K. J.; Liu, G.; Gehrke, L.; Credo, R. B.; Hui, Y. H.; Lee, J.; Warner, R. B.; Kovar, P.; Nukkala, M. A.; Zielinski, N. A.; Tahir, S. K.; Fitzgerald, M.; Kim, K. H.; Marsh, K.; Frost, D.; Ng, S. H.; Rosenberg, S.; Sham, H. L. Synthesis and Biological Evaluation of 2-Indolyloxazolines as a New Class of Tubulin Polymerization Inhibitors. Discovery of A-289099 as an Orally Active Antitumor Agent. Bioorg. Med. Chem. Lett. 2002, 12, 465-469.
Flynn, B. L.; Hamel, E.; Jung, M. K. One-Pot Synthesis of Benzo[b]furan and Indole Inhibitors of Tubulin Polymerization. J. Med. Chem. 2002, 45, 2670-2673.
Pinney, K. G.; Bounds, A. D.; Dingeman, K. M.; Mocharle, V. P.; Pettit, G. R.; Bai, R.; Hamel, E. A new Antitubulin Agent Containing Benzo[b] thiophene Ring System. Bioorg. Med. Chem. Lett. 1999, 9, 1081-1086.
Flynn, B. L.; Hamel, E.; Jung, M. K. One-Pot Synthesis of Benzo[b]furan and Indole Inhibitors of Tubulin Polymerization. J. Med. Chem. 2002, 45, 2670-2673.
Liou, J. P.; Chang, J. Y.; Chang, C. W.; Chang, C. Y.; Mahindroo, N.; Kuo, F. M.; Hsieh, H. P. Synthesis and Structure-Activity Relationships of 3-Aminobenzophenones as Antimitotic Agents. J. Med. Chem. 2004, 47, 2897-2905.
Aviv, G.; Jeffrey, C.; Harald A.; Gerald M.; Peter H.; Irit C.; Alexander L. Tyrphostins IV–Potent Inhibitor of EGF Receptor Kinase. Structure–Activity Relationship Study of 4-Anilidoquinazoline. Bio. Med. Chem. 1996, 4, 1203-1207.
Zoller, U. The Cheletropic Fragmentation of Hypervalent Three membered Thiaheterocyclic Intermediates. Tetrahedron 1988, 44, 7413-7426.
Miyashita, A.; Matsuda, H.; Iijima, C.; Higashino, T. Catalytic Action of Azolium Salts.Ⅰ. Aroylation of 4-Chloroquinazolines with Aromatic Aldehydes Catalyzed by 1,3-Dimethylbenzimidazolium Iodide. Chem. Pharm. Bull. 1990, 38, 1147-1152.
Miyashita, A.; Matsuda, H.; Iijima, C.; Higashino, T. Catalytic Action of Azolium Salts.Ⅱ. Aroylation of 4-Chloroquinazolines with Aromatic Aldehydes Catalyzed by 1,3-Dimethylbenzimidazolium Iodide. Chem. Pharm. Bull. 1992, 40, 43-48.
Kant, J.; Popp, F. D. Preparation and Reactions of Mono-Reissert Compounds and Analogs at the 3,4-Position of Quinazoline. J. Heterocyclic Chem. 1985, 22, 1313-1316.
Liu, G.; Yang, S.; Song, B.; Xue, W.; Hu, D.; Jin, L.; Lu, P. Microwave Assisted Synthesis of N-Arylheterocyclic Substituted- 4-aminoquinazoline Derivatives. Molecules 2006, 11, 272-278.
Miyashita, A.; Matsuda, H.; Suzuki, Y.; Iwamoto, K. I.; Higashino, T. Catalytic Action of Azolium Salts.Ⅳ. Preparation of 4-Aroylquinazolines and 4-Aroyl-1H-pyrazolo〔3,4-d〕pyrimidines by Catalytic Action of 1,3-dimethylimidazolium Iodide. Chem. Pharm. Bull. 1994, 42, 2017-2022.
Miyashita, A.; Matsuda, H.; Matsuoka, Y.; Iwamoto, K. I.; Higashino, T. An Approach to the Synthesis of a Papaverine Analogue Containing a Quinazoline Ring System. Heterocycles 1995, 40, 653-660.
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