臺灣博碩士論文加值系統

薑黃素(curcumin)是從薑黃(Curcuma longa)的根莖中分離出來的一種成分。許多證據指出薑黃素可以降低一些阿茲海默氏症(Alzheimer’s disease, AD)症狀，包含了氧化傷害、發炎、老年斑塊(senile plaques, SPs)、神經糾結(neurofibrillary tangles, NFTs)、細胞循環失調和神經死亡。AD是一個複雜的疾病，有許多的病症，因此需要一個具有多種療效的藥物來治療，薑黃素是其中一個有潛力的AD治療藥物。
喹啉(quinoline)是一個好的金屬螯合試劑，也是潛在治療AD的藥物。由於喹啉和薑黃素的特性，有喹啉結構的薑黃素類似物可能可以提升金屬螯合能力和清除自由基的能力。因此，這論文中的主要目的即是在合成兩個末端都有個喹啉結構的薑黃素類似物。
在此合成研究中，首先以4-amino-3-methoxybenzoic acid為起始物，以Skraup方法來合成8-methoxy-6-quinolinecarboxylic acid；最後再利用6-quinolinecarbaldehyde和acetylacetone進行Knoevenagel縮合反應來合成含喹啉結構的薑黃素類似物。

Curcumin is isolated from the rhizome of Curcuma longa. Much evidence indicated that curcumin could be used as a therapeutic agent in the treatment of Alzheimer’s disease (AD) and could reduce the symptoms, including oxidative damage, inflammation, senile plaques, neurofibrillary tangles, cell cycle dysregulation and neuron damages. AD, a complex disease with multiple etiological factors, needs a multifunctional drug forits treatment. Curcumin is one of the potential drugs in the treatment of AD.
Some quinolines are known as good metal chelating agents and could also be used in potential remedy of AD. Owing to the characteristics of curcumin and quinolines, curcumin derivatives with quinoline structures may increase the metal chelating and radical scavenging abilities. Therefore, the main goal in this thesis is to synthesize the curcumin derivatives with two quinoline structures at both terminal positions.
In this study, 4-amino-3-methoxybenzoic acid was used as the starting material to prepare 8-methoxy-6-quinolinecarboxylic acid by Skraup method and a curcumin derivative was synthesized by Knoevenagel condensation of acetylacetone and a compound with 6-quinolinecarbaldehyde structure.

摘要 I
Abstract II
目錄 III
圖表目錄 IV
壹、緒論 1
貳、實驗儀器與藥品試劑 15
2-1 實驗儀器 15
2-2 溶劑 16
2-3 藥品試劑 17
參、研究方法 18
3-1 薑黃素類似物的逆合成分析 18
肆、實驗步驟 21
4-1 Methyl 8-methoxyquinoline-6-carboxylate (4) 21
4-2 (8-Methoxyquinolin-6-yl)methanol (5) 23
4-3 8-Methoxyquinoline-6-carbaldehyde (6) 24
4-4 薑黃素類似物1 25
伍、結果與討論 26
5-1 結構判定:薑黃素類似物1 26
5-2 結果 29
5-3 討論 33
陸、參考文獻 34
柒、圖表附錄 39

1.Cole, G. M.; Teter, B.; Frautschy, S. A. Adv. Exp. Med. Biol. 2007,
595, 197–212.
2.Butterfield, D. A.; Griffin, S.; Munch, G.; Pasinetti, G. M. Journal of Alzheimer’s disease 2002, 4, 193–201.
3.Heneka, M. T.; O’Banion, M. K. Journal of Neuroimmunology 2007, 184, 69–91.
4.Ulrich, J. D.; Holtzman, D. M. ACS Chem. Neurosci. 2016, 7, 420–427.
5.Herrup, K.; Yang, Y. Nat. Rev. Neurosci. 2007, 8, 368–378.
6.Webber, K. M.; Raina, A. K.; Marlatt, M. W.; Zhu, X.; Prat, M. I.; Morelli, L.; Casadesus, G.; Perry, G.; Smith, M. A. Mech. Ageing Dev. 2005, 126, 1019–1025.
7.Arendt, T.; Brückner, M. K. Biochim. Biophys. Acta 2007, 1772, 413–421.
8.Zhu, X.; Lee, H. G.; Perry, G.; Smith, M. A. Biochim. Biophys. Acta 2007, 1772, 494–502.
9.Nagy, Z. Biochim. Biophys. Acta 2007, 1772, 402–408.
10.Klein, J. A.; Ackerman, S. L. J. Chin. Invest. 2003, 111, 785–793.
11.Copani, A.; Caraci, F.; Hoozemans, J. J. M.; Calafiore, M.; Sortino, M. A.; Nicoletti, F. Biochim. Biophys. Acta 2007, 1772, 409–412.
12.Pastorino, L.; Sun, A.; Lu, P. J.; Zhou, X. Z.; Balastik, M.; Finn, G; Wulf, G.; Lim, J.; Li, S. H.; Li, X.; Xia, W.; Nicholson, L. K.; Lu, K. P. Nature 2006, 400, 528–534.
13.Seward, M. E.; Swanson, E.; Norambuena, A.; Reimann, A.; Cochran, J. N.; Li, R.; Roberson, E. D.; Bloom, G. S.; J. Cell Sci. 2013, 126, 1278–1286.
14.Xie, Y.; Hou, W.; Song, X.; Yu, Y.; Huang, J.; Sun, X.; Kang, R.; Tang, D. Nature 2016, 23, 369–379.
15.Smith, M. A.; Harris, P. L. R.; Sayre, L. M.; Perry, G. Proc. Natl. Acad. Sci. U. S. A. 1997, 94, 9866–9868.
16.Good, P. F.; Perl, D. P.; Bierer, L. M.; Schmeidler, J. Ann. Neurol. 1992, 31, 286–292.
17.Shin, R. W.; Kruck, T. P.; Murayama, H.; Kitamoto, T. Brain Res. 2003, 961, 139–146.
18.Bentué-Ferrer, D.; Tribut, O.; Polard, E.; Allain, H. CNS Drugs 2003, 17, 947–963.
19.Koch, H. J.; Szecsey, A.; Haen, E. Curr. Pharm. Design 2004, 10, 253–259.
20.Mandel, S.; Grünblatt, E.; Riederer, P.; Gerlach, M.; Levites, Y.; Youdim, M. B. CNS Drugs 2003, 17, 729–762.
21.Crapper, M. D. R.; Dalton, A. J.; Kruck, T. P.; Bell, M. Y.; Smith, W. L.; Kalow, W.; Andrews, D. F. Lancet 1991, 337, 1304–1308.
22.Ritchie, C. W.; Bush, A. I.; Mackinnon, A.; Macfarlane, S.; Mastwyk, M.; MacGregor, L.; Kiers, L.; Cherny, R.; Li, Q. X.; Tammer, A.; Carrington, D.; Mavros, C.; Volitakis, I.; Xilinas, M.; Ames, D.; Davis, S.; Beyreuther, K.; Tanzi, R. E.; Masters, C. L. Arch. Neurol. 2003, 60, 1685–1691.
23.Lannfelt, L.; Blennow, K.; Zetterberg, H.; Batsman, S.; Ames, D.; Harrison, J.; Masters, C. L.; Targum, S.; Bush, A. I.; Murdoch, R.; Wilson, J.; Ritchie, C. W. Lancet Neurol. 2008, 7, 779–786.
24.Ono, K.; Yoshiike, Y.; Takashima, A.; Hasegawa, K.; Naiki, H.; Yamada, M. Neurochem. 2003, 87, 172–181.
25.Yang, F.; Lim, G. P.; Begum, A. N.; Ubeda, O. J.; Simmons, M. R.; Ambegaokar, S. S.; Chen, P. P.; Kayed, R.; Glabe, C. G.; Frautschy, S. A.; Cole, G. K.; J. Biol. Chem. 2005, 280, 5892–5901.
26.Ono, K.; Hasegawa, K.; Naiki, H.; Yamada, M. Neurosci. Res. 2004, 75, 742–750.
27.Narlawar, R.; Baumann, K.; Schubenel, R.; Schmidt, B. Neurodegener. Dis. 2007, 4, 88–93.
28.Byun, J. H.; Kim, H.; Kim, Y.; Mook-Jung, I.; Kim, D. J.; Lee, W. K.; Yoo, K. H.; Bioorg. Med. Chem. Lett. 2008, 18, 5591–5593.
29.Byeon, S. R.; Lee, J. H.; Sohn, J. H.; Kim, D. C.; Shin, K. J.; Yoo, K. H.; Mook-Jung, I.; Lee, W. K.; Kim, D. J.; Bioorg. Med. Chem. Lett. 2007, 17, 1466–1470.
30.Anad, P.; Kunnumakkara, A. B.; Newman, R. A.; Aggarwal, B. B. Mol. Pharm. 2007, 4, 807–818.
31.Scapagnini, G.; Vasto, S.; Abraham, N. G.; Caruso, C.; Zella, D.; Fabio, G. Mol. Neurobiol. 2011, 44, 192–201.
32.Sreejayan, A.; Rao, M. N. J. Pharm. Pharmacol. 1997, 49, 105–107.
33.Tønnesen, H. H.; Másson, M.; Loftsson, T. Int. J. pharmaceut. 2002, 244, 127–135.
34.Sharma, R. A.; Gescher, A. J.; Steward, W. P. Eur. J. Cancer 2005, 41, 1955–1968.
35.Payton, F.; Sandusky, P.; Alworth, W. L. J. Nat. Prod. 2007, 70, 143–146.
36.Priyadarsini, K. I.; Maity, D. K.; Naik, G. H.; Kumar, M. S.; Unnikrishnan, M. K.; Satav, J. G.; Mohan, H. Free Radical Biol. Med. 2003, 35, 475–484.
37.Itokawa, H.; Shi, Q.; Akiyama, T.; Morris-Natschke, S. L.; Lee, K. H. Chin. Med. 2008, 3, Article 11.
38.Motterlini, R.; Foresti, R.; Bassi, R.; Green, C. J. Free Radic. Bio. Med. 2000, 28, 1303–1312.
39.Rajeswari, A. Eur. Rev. Med. Pharmacol. Sci. 2006, 10, 157–161.
40.Zhu, Y. G.; Chen, X. C.; Chen, Z. Z. Acta. Pharmacol. Sin. 2004, 25, 1606–1612.
41.Baum, L.; Ng, A. J. Alzheimers Dis. 2004, 6, 367–377.
42.Jiao, Y.; Wilkinson, J.; Pietsch, E. C.; Buss, J. L.; Wang, W.; Planalp, R.; Torti, F. M.; Torti, S. V. Free Radic. Bio. Med. 2006, 40, 1152–1160.
43.Barik, A.; Mishra, B.; Shen, L.; Mohan, H.; Kadam, R. M.; Dutta, S.; Zhang, H. Y.; Priyadarsini, K. I. Free Radic. Biol. Med. 2005, 39, 811–822.
44.Pedersen, U.; Rasmussen, P. B.; Lawesson, S. O. Liebigs Ann. Chem. 1985, 8, 1557–1569.
45.Lin, L.; Shi, Q.; Nyarko, A.K.; Bastow, K.F.; Wu, C. C.; Su, C. Y.; Shih, C. C. Y.; Lee, K. H.J. Med. Chem.2006, 49, 3963–3972.
46.Sharma, J.; Singh, A.; Sharma, R.; Singh, Y.; Teotia, U. V. S. Der Pharma. Sinica 2013, 4, 151–163.
47.Dedeoglu, A.; Cormier, K.; Payton, S.; Tseitlin, K. A.; Kremsky, J. N.; Lai, L.; Li, X. H.; Moir, R. D.; Tanzi, R. E.; Bush, A. I.; Kowall, N. W.; Rogers, J. T.; Huang, X. D. Exp. Gerontol. 2004, 39, 1641–1649.
48.Choi, J. S.; Braymer, J. J.; Nanga, R. P. R.; Ramamoorthy, A.; Lim, M. H. Proc. Natl. Acad. Sci. U.S.A. 2010, 107, 21990–21995.
49.Perez, L. R.; Franz, K. J. Dalton Trans. 2010, 39, 2177–2187.
50.Cavalli, A.; Bolognesi, M. L.; Minarini, A.; Rosini, M.; Tumiatti, V.; Recanatini, M.; Melchiorre, C. J. Med. Chem. 2008, 51, 347–372.
51.Bolognesi, M. L.; Cavalli, A.; Melchiorre, C. Neurotherapeutics 2009, 6, 152–162.