臺灣博碩士論文加值系統

本論文主旨是設計與合成1-芳香基吡咯[3,2-c]喹啉衍生物作為潛能抗癌試劑。本實驗室之前以喹啉為骨架，設計1-芳香基取代吡咯[3,2-c]喹啉衍生物，迫使兩芳香環為順式結構，發現此系列化合物對於癌細胞株具有不錯的活性。因此，本論文進一步改變芳香環上的取代基，同樣以合成1-arylpyrrolo[3,2-c]quinoline衍生物為主。將起始物2-acetylbutyrolactone與aniline進行縮合形成中間物，經氯化反應得4-chloro-3-(2-chloroethyl)-2- methylquinoline (1)和其6,8-dimethoxy取代之衍生物2，之後與不同取代基之苯胺及胺基吡啶進行取代反應，得到3-dihydropyrrolo[3,2-c]quinolines (3)和6,8-dimethoxy-2,3-dihydropyrrolo[3,2-c]quinoline (4)，最後利用鈀金屬催化劑脫氫，分別得到6和7系列芳香化之標的化合物。合成出之標的化合物均採SRB篩選方式，分別對肺癌細胞株A549、胃癌細胞株AGS及大腸直腸癌細胞株HT-29進行體外細胞毒性測試，發現在苯環上第三位置及第四位置分別接上羥基及甲氧基的化合物3a‧HCl、4a‧HCl、6a針對三種不同的癌細胞株有很高的抑制生長百分比。

This thesis is aimed at design and synthesis of 1-arylpyrrolo[3,2-c]quinoline derivatives as potential anticancer agents. We had been using quinoline ring as skeleton for the design of 1-arylpyrrolo[3,2-c]quinoline derivatives to force the two aromatic rings in cis conformations. Results of in vitro cytotoxicity presumed that this series of compounds have potentials as anticancer drugs. In this study, we change substituent on aryl ring to prepare a series new 1-arylpyrrolo[3,2-c]quinoline derivatives. The synthesis was initiated from the condensation of appropriate aniline and 2-acetylbutyrolactone. After one-pot chlorination, 4-chloro-3-(2-chloroethyl)-2-methyl substituted quinoline (1) and 6,8-dimethoxy derivatives 2 were substituted by various anilines and aminopyridines. Conversion of 2,3-dihydropyrrolo[3,2-c]quinolines (3) and 6,8-dimethoxy-2,3-dihydropyrrolo[3,2-c]quinoline (4) to the fully aromatic system could conveniently be accomplished by dehydrogenation over palladium catalyst to afford target compounds 6 and 7, respectively. All synthesized compounds were subjected to SRB assay for the in vitro cytotoxicity against lung cancer cell lines A549, stomach cancer cell line AGS, and colon cancer cell line HT-29. The results showed that 3-hydroxy-4-methoxy anilino substituted compounds 3a‧HCl, 4a‧HCl and 6a exhibited high inhibitory growth percentage to three cancer cell lines.

第一章 緒論 1
第二章 實驗設計 15
第三章 結果與討論 17
3.1 標的化合物合成 17
3.1.1 4-Chloro-3-(2-chloroethyl)-2-methylquinoline (1) 17
3.1.2 4-Chloro-3-(2-chloroethyl)-6,8-dimethoxy-2-methyl-quinoline (2) 17
3.1.3 1-Aryl-4-methyl-2,3-dihydropyrrolo[3,2-c]quinolines衍生物3及4 18
3.1.4 6,8-Dimethoxy-4-methyl-1-(pyridin-2-yl)-2,3-dihydro-1H-pyrrolo- [3,2-c]quinoline (5) 19
3.1.5 1-Aryl-4-methyl-pyrrolo[3,2-c]quinolines衍生物6及7 20
3.1.6 4-Methyl-1-(pyridin-2-yl)-2,3-dihydro-1H-pyrrolo[3,2-c] quinoline (10) 22
3.2 體外生物活性測試 30
第四章 結論 34
第五章 實驗部份 35
5.1 實驗方法與實驗儀器 35
5.2 試藥、溶劑 35
5.3 合成步驟 36
第六章 參考資料 61

Information Received from the Internet Homepages of the Department of Health, Taiwan, R. O. C. (http://www.doh.gov.tw)
Schafer, K.A. The Cell Cycle: a Review. Vet. Pathol. 1998, 35, 461–478.
Zhang, P. The Cell Cycle and Development: Redundant Roles of Cell Cycle Regulator. Curr. Opin. Cell Biol. 1999, 11, 655-662.
Lodish, H.; Berk, A.; Zipursky, S. L.; Matsudaira, P.; Baltimore, D.; Darnell, J. Molecular Cell Biology 2000, 4th Ed.; 1084; W.H. Freeman and Company, NY, New York.
Lodish, H.; Baltimore, D.; Berk, A.; Zipursky, S. L.; Matsudaira, P.; Darnell, J. Scientific American Books; Molecular Cell Biology 1995, 3rd Ed.; 1051.
Lillo, M. P.; Canadas, O.; Dale, R. E.; Acuna, A. U. Location and Properties of the Taxol Binding Center in Microtubules: A Picosecond Laser Study with Fluorescent Taxoids. Biochemistry 2002, 41, 12436-12449.
Pinney, K. G.; Mejia, M. P.; Villalobos, V. M.; Rosenquist, B. E.; Pettit, G. R.; Verdier-Pinard, P.; Hamel, E. Synthesis and Biological Evaluation of Aryl Azide Derivatives of Combretastatin A-4 as Molecular Probes for Tubulin. Bioorg. Med. Chem. 2000, 8, 2417-2425.
Jordan, M. A.; Wilson, L. Microtubules and Actin Filaments: Dynamic Targets for Cancer Chemotherapy. Curr. Opin. Cell Biol. 1998, 10, 123-130.
Attard, G.; Greystoke, A.; Kaye, S.; Bono, J. D. Upate on Tubulin-Binding Agents. Pathol. Biol. 2006, 54, 72-84.
Liu, C.; Strobl, J. S.; Bane, S.; Schilling, J. K.; McCracken, M.; Chatterjee, S. K.; Rayhana, R.-B.; Kingston, DG. I. Design, Synthesis, and Bioactivities of Steroid-Linked Taxol Analogues as Potential Targeted Drugs for Prostate and Breast Cancer. J. Nat. Prod. 2004, 67, 152-159.
Rice, A.; Liu, Y.; Michaelis, M. L.; Himes, R. H.; Georg, G. I.; Audus, K. L. Chemical Modification of Paclitaxel (Taxol) Reduces P-glycoprotein Interactions and Increases Permeation Across the Blood−Brain Barrier in Vitro and in Situ. J. Med. Chem. 2005, 48, 832-838.
Gerth, K.; Bedorf, N.; Hfle, G.; Irschik, H.; Reichenbach, H. Epothilones A and B: Antifungal and Cytotoxic Compound form Sorangium Cellulosum (Myxobacterium). Production, Physicochemical and Biological Properties. J. Antibiot. 1996, 49, 560-563.
Bollag, D. M.; McQueney, P. A.; Zhu, J.; Hensens, O.; Koupal, L.; Liesch, J.; Goetz, M.; Lazarides, E.; Woods, C. M. Epothilones, a New Class of Microtubule-Stabilizing Agents with a Taxol-Like Mechanism of Action. Cancer Res. 1995, 55, 2325-2333.
Shearwin, K. E.; Timasheff, S. N. Effect of Colchicine Analogues on the Dissociation of  Tubulin into Subunits: the Locus of Colchicine Binding. Biochemistry 1994, 33, 894–901.
Kingston DG. I. Tubulin-Interactive Natural Products as Anticancer Agents. J. Nat. Prod. 2009, 72, 507-515.
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.
Thorpe, P. E.; Chaplin, D. J.; Blakey. D. C. The First International Conference on Vascular Targeting: Meeting Overview. Cancer Res. 2003, 63, 1144-1147.
Kirwan, I. G.; Loadman, P. M.; Swaine, D. J.; Anthoney, D. A.; Pettit, G. R.; Lippert, JW. L.; Shnyder, S. D.; Cooper, P. A.; Bibby, M. C. Comparative Preclinical Pharmacokinetic and Metabolic Studies of the Combretastatin Prodrugs Combretastatin A4 Phosphate and A1 Phosphate. Clin. Cancer Res. 2004, 10, 1446-1453.
Ohsumi, K.; Nakagawa, R.; Fukuda, Y.; Hatanaka, T.; Morinaga, Y.; Nihei, Y.; Ohishi, K.; Suga, Y.; Akiyama, Y.; Tsuji, T. Novel Combretastatin Analogues Effective against Murine Solid Tumors: Design and Structure-Activity Relationships. J. Med. Chem. 1998, 41, 3022-3032.
Zhang, Q.; Peng, Y.; Wang, X. I.; Keenan, S. M.; Arora, S.; Welsh, W. J. Highly Potent Triazole-Based Tubulin Polymerization Inhibitors. J. Med. Chem. 2007, 50, 749-754.
Pettit, G. R.; Toki, B.; Herald, D. L.; Verdier-Pinard, P.; Boyd, M. R. Antineoplastic Agents. 379. Synthesis of Phenstation Phosphate. J. Med. Chem. 1998, 41, 1688-1695.
Kong, Y.; Wang, K.; Edler, M. C.; Hamel, E.; Mooberry, S. L.; Paige, M. A.; Brown, M. L. A Boronic Acid Chalcone Analog of Combretastatin A-4 as a Potent Anti-Proliferation Agent. Bioorg. Med. Chem. 2010, 18, 971-977.
Rappl, C.; Barbier, P.; Bourgarel-Rey, V.; Gregoire, C.; Gilli, R.; Carre, M.; Combes, S.; Finet, J. P.; Peyrot, V. Interaction of 4-Arylcoumarin Analogues of Combretastatins with Microtubule Network of HBL100 Cells and Binding to Tubulin. Biochemistry 2006, 45, 9210-9218.
Sun, C. M.; Lin, L. G.; Yu, H. J.; Cheng, C. Y.; Tsai, Y. C.; Chu, C. W.; Din, Y. H.; Chau, Y. P.; Don, M. J. Synthesis and Cytotoxic Activities of 4,5-Diarylisoxazoles. Bioorg. Med. Chem. Lett. 2007, 17, 1078-1081.
Wu, M. J.; Sun, Q. M.; Yang, C. H.; Chen, D. D.; Ding, J. Synthesis and Activity of Combretastatin A-4 Analogues: 1,2,3-Thiadiazoles as Potent Antitumor Agents. Bioorg. Med. Chem. lett. 2007, 17, 869-873.
Tron, G. C.; Pagliai, F.; DelGrosso, E.; Genazzani, A. A.; Sorba, G. Synthesis and Cytotoxic Evaluation of Combretafurazans. J. Med. Chem. 2005, 48, 3260-3268.
Shirai, R.; Okabe, T.; Iwasaki, S. Synthesis of Conformationary Restricted Combretastatins. Heterocycles 1997, 46, 145-148.
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.
Zhang, Q.; Peng, Y.; Wang, X. I.; Keenan, S. M.; Arora, S.; Welsh, W. J. Highly Potent Triazole-Based Tubulin Polymerization Inhibitors. J. Med. Chem. 2007, 50, 749-754.
Odlo, K.; Hentzen, J.; Chabert, J. F.; Ducki, S.; Sylte, I.; Skrede, M.; Florenes, V. A.; Hansen, T. V. 1,5-Disubstituted 1,2,3-Triazoles as Cis-restricted Analogues of Combretastatin A-4: Synthesis, Molecular Modeling and Evaluation as Cytotoxic Agents and Inhibitors of Tubulin. Bioorg. Med. Chem. 2008, 16, 4829-4838.
Ohsumi, K.; Hatanaka, T.; Fujita, K.; Nakagawa, R.; Fukuda, Y. Syntheses and Antitumor Activity of Cis-Restricted Combretastatins: 5-Membered Heterocyclic Analogues. Bioorg. Med. Chem. Lett. 1998, 8, 3153-3158.
吳澄迦，碩士論文，私立靜宜大學應用化學研究所 (2006)。
Nien, C. Y.; Chen. Y. C.; Kuo, C. C.; Hsieh H. P.; Chang, C. Y.; Wu, J. S.; Wu, S. Y.; Liou, J. P.; Chang, J. Y. 5-Amino-2-Aroylquinolines as Highly Potene Tubulin Polymerization Inhibitors. J. Med. Chem. 2010, 53, 2309-2313.
Ferlin, M. G.; Chiarelotto, G.; Gasparotto, V.; Via, L. D.; Pezzi, V.; Barzon, L.; Palu, G.; Castagliuolo, I. Synthesis and in Vitro and in Vivo Antitumor Activity of 2-Phenylpyrroloquinoline-4-ones. J. Med. Chem. 2005, 48, 3417-3427.
黃皓倫，碩士論文，靜宜大學應用化學研究所 (2008)。
Brown, T. H.; Ife, R. J.; Keeling, D. J.; Laing, S. M.; Leach, C. A.; Parsons, M. E.; Price, C. A.; Reavill, D. R.; Wiggall, K. J. Reversible Inhibitors of the Gastric (H+/K+)-ATPase. 1. l-Aryl-4-methylpyrrolo[3,2-c]quinolines as Conformationally Restrained Analogues of 4-(Ary1amino)quinolines. J. Med. Chem. 1990, 33, 527-533.
徐宜伶，碩士論文，靜宜大學應用化學研究所 (2010)。
Badaweyl, E. S.; Kappe, T. Potential Antineoplastics. Synthesis and Cytotoxicity of Certain 4-Chloro-3-(2-chloroethyl)-2-methylquinolines and Related Derivatives. Eur. J. Med. Chem. 1997, 32, 815-822.