潛力抗癌試劑巴比妥酸共軛衍生物之合成暨開發新穎鋯金屬有機骨架材料水相製備法

以作者查詢圖書館館藏

、以作者查詢臺灣博碩士

、以作者查詢全國書目

、勘誤回報

、線上人數：35

、訪客IP：3.133.118.122

姓名

郭紜維(Yun-Wei Kuo) 查詢紙本館藏

畢業系所

化學學系

論文名稱

潛力抗癌試劑巴比妥酸共軛衍生物之合成暨開發新穎鋯金屬有機骨架材料水相製備法

相關論文

★ 天然物 Faveline methyl ether 之合成研究	★ 人體突變生長激素受質膜內區段與半乳醣凝集素-12的表現、純化與結晶
★ 研究新型奈米粒子載體結合核糖核酸干擾調控在細胞內蛋白之表現	★ 具芳香環胺基酸與內環狀結構之中孔洞材料的合成、鑑定與應用
★ 以手性亞碸催化劑進行醛的不對稱乙基化反應之研究	★ 噁噻硼烷－氯化鎵錯合物催化不對稱 Diels-Alder 反應之研究
★ 開發心肌缺氧後再灌流傷害用藥與近紅外光染劑的高效率微脂體包覆方法	★ Total Synthesis of Pikrosalvin, Simplexene C, D and Synthetic Studies toward Swartziarboreol G and Simplexene B
★ Understanding the Depolymerization of Biomass-derived Polysaccharides: Recrystallization while Hydrolyzing Polysaccharides	★ 以手性有機硫催化劑進行不對稱環丙烷化反應並應用於合成吡咯類化合物之研究
★ 一、以掌性硫化合物進行不對稱 [4+1] 環化反應並應用在吲哚啉類化合物的合成研究二、掌性共價有機框架材料的設計與合成並應用在多烯環化反應	★ 第一章以手性硫催化劑進行不對稱 [4+1] 環化反應並應用於合成吲哚類化合物之研究第二章設計與合成手性共價有機骨架並應用至不對稱多烯環化反應
★ 以開環置換聚合反應合成手性共價有機框架材料並將其應用於不對稱催化多烯環化反應之研究	★ 利用光固化材料調控R3CE的界面共價修飾及其對三維細胞培養的影響
★ 流感病毒血球凝集素(II)膜外區域之物理化學特性分析	★ 中孔洞材料SBA-15及其官能基化衍生材料對溶液中污染物之吸附應用

檔案

[Endnote RIS 格式]

[Bibtex 格式]

[相關文章]

[文章引用]

[完整記錄]

[館藏目錄]

[檢視]

[下載]

本電子論文使用權限為同意立即開放。
已達開放權限電子全文僅授權使用者為學術研究之目的，進行個人非營利性質之檢索、閱讀、列印。
請遵守中華民國著作權法之相關規定，切勿任意重製、散佈、改作、轉貼、播送，以免觸法。

摘要(中)

Part I 潛力抗癌試劑巴比妥酸共軛衍生物之合成
　　隨著潛力藥物設計的蓬勃發展，經驗裡，雜環結構往往具有藥物活性且在多種疾病中都有潛力的抑制效果，正因為如此，藥物設計常以雜環作為基礎模板，篩選其衍生物是否能有更進一步的生物活性。
我們在過去的藥物研究重點期刊中發現含有巴比妥酸系列之雜環分子除了擁有相當的活性特性外，同時也注意到與雜環進行縮合反應之肉桂醛及胡椒醛的衍生物都有抗癌或是抗菌的能力，建立在這兩種醛類的基礎之下，我們推測此二醛結構的結合—3,4-亞甲基二氧基肉桂醛，在與巴比妥酸系列雜環進行結合時能有更卓越的藥性結果。
在本次的研究中我們成功了合成出3,4-亞甲基二氧基肉桂醛與巴比妥酸系列縮合反應之產物外，也針對其原始核心結構苯甲醛、肉桂醛等作同系列之反應探討，同時以醛及雜環做不同排列鍵結的各種小分子潛力藥物進行抗肝癌、抗肝纖維化能力的藥物活性檢測。
Part II 開發新穎鋯金屬有機骨架材料水相製備法
　　金屬有機骨架材料（MOFs），為一新型態之孔洞材料，其優異的孔洞性及高比表面積的優勢，使得MOFs在多方應用中皆有十分突出的表現，再加上MOFs具有相當良好的化熱穩定性，近期開始被大量研究及使用於石化工業上；同時，隨著環保意識的抬頭及工業成本上的考量，過去用來製備MOFs的溶劑熱合成法，也開始探討水相合成的可能性。在本實驗室過去的研究成果中，成功的在水相中製備出類沸石咪唑骨架材料-90（ZIF-90），同時使用ZIF-90包覆酵素並仍保有酵素活性，但由於ZIF-90的孔隙大小僅3.5 Å，較大的基質無法通過，因此我們極力尋求一個孔徑略大的酵素催化平台。
　　UiO-66，孔隙大小6.0 Å之金屬有機骨架材料，同時是目前MOFs結構熱穩定表現最優異之材料，根據軟硬酸鹼理論，高親電子性之鋯金屬易與羧酸基形成高強度鍵結，然而太強的鍵結使得材料無法有效形成結晶，故UiO-66多半在有機溶劑下合成。在實驗室過去的研究中，發現UiO-66的有機配體—對苯二甲酸中若苯環上具有推拉電子基，此推拉電子效應能影響鄰近羧酸官能基之電子密度，進而調控羧酸基與鋯金屬之間的鍵結強弱，促使較低鍵強之鍵結得以得到良好的結晶平衡，且藉由此結晶平衡，我們成功地發現了四氟對苯二甲酸在醋酸水相中有最適當的鍵結力，能在15分鐘內製備出UiO-66-F4。

摘要(英)

Part I Design and Synthesis of Barbiturate-Conjugated Derivatives as Potential Anti-Cancer Agents
Through high-throughput screening (HTS), extensively optimized drug discovery can be carried out these days. Aromatic and non-aromatic heterocyclic rings usually play key roles in interacting with the target biological macromolecules such as the active sites of enzymes. Based on the observations published, these heterocyclic rings can be a quick identification of “hits” to evaluate which heterocyclic derivatives can be the most potential structures in drug discovery.
With our investigation in this research, we have found that a series of barbiturate derivatives have quite potential bioactivities as pharmacophore. Besides, some published reports have mentioned the synthesized cinnamaldehydes or piperonals derivatives have great potential as anti-cancer or antibacterial agents. Herein, we have synthesized the conjugates of 3,4-methylenedioxycinnamaldehyde and barbiturate. By combining the bioactive aldehydes to barbiturates, the conjugates formed may have a more noticeable activity.
In this research, we have successfully synthesized a series of modified barbiturates by Knoevenagel condensation with 3,4-methylenedioxy- cinnamaldehyde and barbiturates. And we also synthesize the products with simpler aldehyde structure like benzaldehyde and cinnamaldehyde to discuss the differences. The bio-evaluation of these derivatives was also held to check their activities as anti-hepatoma and anti-fibrosis agent.
Part II Develop New Water-Based Synthesis of Zirconium-
Organic Framework
Metal-Organic Frameworks (MOFs) have numerous applications due to their good chemical/thermal stability, extraordinary porosity and high specific surface area. However, the synthetic methodologies for MOFs are limited in organic solvent system that may damage the environment. As a consequence, developing an environmental friendly approach for synthesizing MOFs is in urgent need. More specifically, inventing a method with water, an absolutely clean resource, as solvent to obtain MOFs is of great value, not to mention the possible huge impact water may have on the reaction. In our previous report, we successfully obtained ZIF-90 under water-based system. Besides, we demonstrated a de novo approach to acquire an enzyme@ZIF-90 composite with substrate selectivity and shielding capability. Nevertheless, the small aperture size of 3.5 Å in ZIF-90 restricted its catalysis ability--that is, the small size of window shields other oversized substrates as well as denaturants. Therefore, to solve the above problem, obtaining other MOFs with bigger size in aperture with water-based approach is what we are trying to do in this thesis.
UiO-66 with aperture size of 6.0 Å is the most thermal stable structure for MOFs. Our previous research revealed that different functional groups on benzene-1,4-dicarboxylic acid (BDC) could manipulate the bonding strength between Zr and carboxylate groups. Therefore, based on our previous results, we intend to optimize the synthetic condition of UiO-66 under water. Herein, we report the improved condition in which tetrafluoroterephthalic acid acted as organic linkers, and successfully synthesized UiO-66-F4 in minutes under acid aqueous solution.

關鍵字(中)

★ 巴比妥酸
★ 肝纖維化
★ 鋯
★ 金屬有機骨架材料
★ 水相製備

關鍵字(英)

論文目次

中文摘要 I
Abstract III
致謝詞 V
目錄 VI
圖目錄 VIII
表目錄 IX
Part I 潛力抗癌試劑巴比妥酸共軛衍生物之合成 1
第一章緒論 1
1-1 巴比妥酸系列之藥性 1
1-2 肉桂醛與胡椒醛與巴比妥酸系列 3
1-3 惡性腫瘤-肝癌 5
第二章結果與討論 8
2-1 化學部分-結果 8
2.1.1 核心結構-苯甲醛 8
2.1.2 核心結構-肉桂醛 9
2.1.3 核心結構-胡椒醛 10
2.1.4 核心結構-3,4-亞甲基二氧基肉桂醛 11
2-2 化學部分-討論 13
2.2.1 探討核心結構對於Knoevenagel condensation反應的差異 13
2.2.2 里賓斯基五規則（Lipinski′s rule of five） 15
2.2.3 E/Z標記的結構探討 16
2-3 藥物活性部分-結果與討論 18
2.3.1 抗肝癌活性測試 18
2.3.2 抗肝纖維化活性測試 18
第三章結論 21
實驗部分 21
Part II 開發新穎鋯金屬有機骨架材料水相製備法 29
第一章緒論 29
1-1 有機金屬骨架材料（Metal-Organic Frameworks） 29
1-2 水相合成有機金屬骨架材料 30
1-3 有機金屬骨架材料包覆酵素 30
1-4 鋯金屬有機骨架材料（Zirconium-Organic Framework） 31
第二章結果與討論 32
2-1 不同濃度有機羧酸下合成UiO-66-F4 32
2-2 不同合成時間在有機羧酸下合成UiO-66-F4 33
第三章結論 34
實驗部分 35
參考文獻 36
實驗光譜 40

參考文獻

(1) Wang, J.; O’Sullivan, S.; Harmon, S.; Keaveny, R.; Radomski, M. W.; Medina, C.; Gilmer, J. F. Journal of Medicinal Chemistry 2012, 55, 2154.
(2) Coggins, G. E.; Maddukuri, L.; Penthala, N. R.; Hartman, J. H.; Eddy, S.; Ketkar, A.; Crooks, P. A.; Eoff, R. L. ACS Chemical Biology 2013, 8, 1722.
(3) Wu, Y.; Karna, S.; Choi, C. H.; Tong, M.; Tai, H.-H.; Na, D. H.; Jang, C. H.; Cho, H. Journal of Medicinal Chemistry 2011, 54, 5260.
(4) Slepikas, L.; Chiriano, G.; Perozzo, R.; Tardy, S.; Kranjc-Pietrucci, A.; Patthey-Vuadens, O.; Ouertatani-Sakouhi, H.; Kicka, S.; Harrison, C. F.; Scrignari, T.; Perron, K.; Hilbi, H.; Soldati, T.; Cosson, P.; Tarasevicius, E.; Scapozza, L. Journal of Medicinal Chemistry 2016.
(5) Durham, T. B.; Klimkowski, V. J.; Rito, C. J.; Marimuthu, J.; Toth, J. L.; Liu, C.; Durbin, J. D.; Stout, S. L.; Adams, L.; Swearingen, C.; Lin, C.; Chambers, M. G.; Thirunavukkarasu, K.; Wiley, M. R. Journal of Medicinal Chemistry 2014, 57, 10476.
(6) Wu, F.; Jiang, H.; Zheng, B.; Kogiso, M.; Yao, Y.; Zhou, C.; Li, X.-N.; Song, Y. Journal of Medicinal Chemistry 2015, 58, 6899.
(7) Haldar, M. K.; Scott, M. D.; Sule, N.; Srivastava, D. K.; Mallik, S. Bioorganic & Medicinal Chemistry Letters 2008, 18, 2373.
(8) Ottanà, R.; Maccari, R.; Giglio, M.; Del Corso, A.; Cappiello, M.; Mura, U.; Cosconati, S.; Marinelli, L.; Novellino, E.; Sartini, S.; La Motta, C.; Da Settimo, F. European Journal of Medicinal Chemistry 2011, 46, 2797.
(9) Min, G.; Lee, S.-K.; Kim, H.-N.; Han, Y.-M.; Lee, R.-H.; Jeong, D. G.; Han, D. C.; Kwon, B.-M. Bioorganic & Medicinal Chemistry Letters 2013, 23, 3769.
(10) Pinson, J.-A.; Schmidt-Kittler, O.; Zhu, J.; Jennings, I. G.; Kinzler, K. W.; Vogelstein, B.; Chalmers, D. K.; Thompson, P. E. ChemMedChem 2011, 6, 514.
(11) Devi, P. B.; Samala, G.; Sridevi, J. P.; Saxena, S.; Alvala, M.; Salina, E. G.; Sriram, D.; Yogeeswari, P. ChemMedChem 2014, 9, 2538.
(12) Chinthala, Y.; Kumar Domatti, A.; Sarfaraz, A.; Singh, S. P.; Kumar Arigari, N.; Gupta, N.; Satya, S. K. V. N.; Kotesh Kumar, J.; Khan, F.; Tiwari, A. K.; Paramjit, G. European Journal of Medicinal Chemistry 2013, 70, 308.
(13) Jemal, A.; Bray, F.; Center, M. M.; Ferlay, J.; Ward, E.; Forman, D. CA: A Cancer Journal for Clinicians 2011, 61, 69.
(14) Ferlay, J.; Soerjomataram, I.; Dikshit, R.; Eser, S.; Mathers, C.; Rebelo, M.; Parkin, D. M.; Forman, D.; Bray, F. International Journal of Cancer 2015, 136, E359.
(15) 衛生福利部-103年死因統計結果分析, 2015.
(16) Friedman, S. L.; Sheppard, D.; Duffield, J. S.; Violette, S. Science Translational Medicine 2013, 5, 167sr1.
(17) Ellis, E. L.; Mann, D. A. Journal of Hepatology 2012, 56, 1171.
(18) Bissell, D. M. Exp Mol Med 2001, 33, 179.
(19) Wang, X. S.; Zeng, Z. S.; Li, Y. L.; Shi, D. Q.; Tu, S. J.; Wei, X. Y.; Zong, Z. M. Synthetic Communications 2005, 35, 1915.
(20) Tripathy, P. K. Asian Journal of Chemistry 2005, 17, 1207.
(21) Riveira, M. J.; Tekwani, B. L.; Labadie, G. R.; Mischne, M. P. MedChemComm 2012, 3, 1294.
(22) Al Nakib, T.; Bezjak, V.; Meegan, M. J.; Chandy, R. European Journal of Medicinal Chemistry 1990, 25, 455.
(23) Lipinski, C. A.; Lombardo, F.; Dominy, B. W.; Feeney, P. J. Advanced Drug Delivery Reviews 1997, 23, 3.
(24) Ohishi, Y.; Mukai, T.; Nagahara, M.; Yajima, M.; Kajikawa, N.; Miyahara, K.; Takano, T. Chemical & Pharmaceutical Bulletin 1990, 38, 1911.
(25) Chérouvrier, J.-R.; Carreaux, F.; Bazureau, J. P. Tetrahedron Letters 2002, 43, 3581.
(26) Bourahla, K.; Paquin, L.; Lozach, O.; Meijer, L.; Carreaux, F.; Bazureau, J. P. Molecules 2011, 16, 7377.
(27) Kumar, B. R. P.; Soni, M.; Kumar, S. S.; Singh, K.; Patil, M.; Baig, R. B. N.; Adhikary, L. European Journal of Medicinal Chemistry 2011, 46, 835.
(28) Carpino, G.; Morini, S.; Ginanni Corradini, S.; Franchitto, A.; Merli, M.; Siciliano, M.; Gentili, F.; Onetti Muda, A.; Berloco, P.; Rossi, M.; Attili, A. F.; Gaudio, E. Digestive and Liver Disease 2005, 37, 349.
(29) Alcerreca, G.; Sanabria, R.; Miranda, R.; Arroyo, G.; Tamariz, J.; Delgado, F. Synthetic Communications 2000, 30, 1295.
(30) Rahimov, A. I.; Avdeev, S. A. Russian Journal of General Chemistry 2009, 79, 2412.
(31) Durai Ananda Kumar, T.; Swathi, N.; Navatha, J.; Subrahmanyam, C. V. S.; Satyanarayana, K. Journal of Sulfur Chemistry 2015, 36, 105.
(32) Barreiro, E.; Casas, J. S.; Couce, M. D.; Sánchez, A.; Sordo, J.; Varela, J. M.; Vázquez-López, E. M. Crystal Growth & Design 2007, 7, 1964.
(33) Lamiri, M.; Bougrin, K.; Daou, B.; Soufiaoui, M.; Nicolas, E.; Giralt, E. Synthetic Communications 2006, 36, 1575.
(34) Mendgen, T.; Steuer, C.; Klein, C. D. Journal of Medicinal Chemistry 2012, 55, 743.
(35) Wang, C.; Ma, J. j.; Zhou, X.; Zang, X. h.; Wang, Z.; Gao, Y. j.; Cui, P. l. Synthetic Communications 2005, 35, 2759.
(36) Yang, D.-H.; Chen, Z.-C.; Chen, S.-Y.; Zheng, Q.-G. Journal of Chemical Research 2003, 2003, 330.
(37) Alizadeh, A.; Khodaei, M. M.; Eshghi, A. Canadian Journal of Chemistry 2010, 88, 514.
(38) Anuradha, V.; Srinivas, P. V.; Madhusudana Rao, J. Natural Product Research 2004, 18, 247.
(39) Yaghi, O. M.; Li, G.; Li, H. Nature 1995, 378, 703.
(40) Kitagawa, H. Nat Chem 2009, 1, 689.
(41) Barea, E.; Montoro, C.; Navarro, J. A. R. Chemical Society Reviews 2014, 43, 5419.
(42) Zhao, Z.; Ma, X.; Kasik, A.; Li, Z.; Lin, Y. S. Industrial & Engineering Chemistry Research 2013, 52, 1102.
(43) Li, S.-L.; Xu, Q. Energy & Environmental Science 2013, 6, 1656.
(44) Chen, E.-X.; Yang, H.; Zhang, J. Inorganic Chemistry 2014, 53, 5411.
(45) Bétard, A.; Fischer, R. A. Chemical Reviews 2012, 112, 1055.
(46) Vasconcelos, I. B.; Silva, T. G. d.; Militao, G. C. G.; Soares, T. A.; Rodrigues, N. M.; Rodrigues, M. O.; Costa, N. B. d.; Freire, R. O.; Junior, S. A. RSC Advances 2012, 2, 9437.
(47) Shieh, F.-K.; Wang, S.-C.; Leo, S.-Y.; Wu, K. C. W. Chemistry – A European Journal 2013, 19, 11139.
(48) Banerjee, R.; Phan, A.; Wang, B.; Knobler, C.; Furukawa, H.; O′Keeffe, M.; Yaghi, O. M. Science 2008, 319, 939.
(49) Shieh, F.-K.; Wang, S.-C.; Yen, C.-I.; Wu, C.-C.; Dutta, S.; Chou, L.-Y.; Morabito, J. V.; Hu, P.; Hsu, M.-H.; Wu, K. C. W.; Tsung, C.-K. Journal of the American Chemical Society 2015, 137, 4276.
(50) Cavka, J. H.; Jakobsen, S.; Olsbye, U.; Guillou, N.; Lamberti, C.; Bordiga, S.; Lillerud, K. P. Journal of the American Chemical Society 2008, 130, 13850.
(51) Schaate, A.; Roy, P.; Godt, A.; Lippke, J.; Waltz, F.; Wiebcke, M.; Behrens, P. Chemistry – A European Journal 2011, 17, 6643.

指導教授

謝發坤

審核日期

2016-8-26

推文