臺灣博碩士論文加值系統

本論文主旨是設計與合成1-芳香基三氮肼[4,5-c]喹啉衍生物作為潛能抗癌試劑。Combretastatin A-4 (CA-4)為抗微管聚合抑制劑，而喹啉衍生物在各方面皆擁有不錯的生物活性，因此以喹啉為骨架，設計1-芳香基三氮肼[3,2-c]喹啉衍生物，迫使兩芳香環像CA-4中的順式結構。首先anthranilic acids和2-nitroacetaldehyde oxime進行反應形成2-(2-nitroethylideneamino)benzoic acid (2)，經環化及脫水反應得4-hydroxy-3-nitroquinoline (3)，化合物3經氯化反應後得4-chloro-3-nitroquinoline，再與不同取代基之苯胺進行取代反應得到4-arylanilino-3-nitroquinoline (4)，還原成氨基後再進行diazotization和cyclization得到一系列1-aryltriazolo[4,5-c]quinoline (6)衍生物。針對肺癌細胞株A549、大腸直腸癌細胞株HCT、肝癌細胞株HepG2、和胰腺癌細胞株PANC1作體外細胞毒性測試，以4-OMe取代之5b及3-OH-4-OMe取代之6g活性最佳，GI50值5b為0.088 μM (A549)、0.086 μM (HCT)、0.10 μM (HepG2)及5.93 μM (PANC1)，而6g之IC50值為0.70 μM (A549)、0.06 μM (HCT)、0.24 μM (HepG2)及0.45 μM (PANC1)。

This thesis is aimed at design and synthesis of 1-aryltriazolo[4,5-c]quinoline derivatives as potential anticancer agents. Combrestastatin A4 (CA-4) is a tubulin polymerization inhibitor, and quinoline derivatives are known to possess biological activities in many aspects. Thus, quinoline skeleton was chosen for the design of 1-aryltriazolo[3,2-c]quinoline derivatives to force the two aromatic rings in cis conformations as those in CA-4. Condensation of anthranilic acids with 2-nitroacetaldehyde oxime resulted in 2-(2-nitroethylideneamino)benzoic acid (2), which was cyclized and dehydrated to give 4-hydroxy-3-nitroquinoline (3). Compound 3 was chlorinated to afford 4-chloro-3-nitroquinoline, which was substituted by anilines to give 4-arylanilino-3-nitroquinolines (4). After reduction, diazotization, and cyclization, a series of 1-aryltriazolo[4,5-c] quinoline derivatives (6) were obtained. Target compounds were evaluated for their cytotoxicities against lung cancer (A549), colon cancer (HCT), liver hepatocellular carcinoma (hepG2), and pancreatic carcinoma carcinoma (PANC1) cell lines. Compound 5b with 4-OMe and 6g with 3-OH-4-OMe exhibited high potency. The values of IC50 were 0.088 μM (A549), 0.086 μM (HCT), 0.10 μM (HepG2), and 5.93 μM (PANC1) for 5b and 0.70 μM (A549), 0.06 μM (HCT), 0.24 μM (HepG2), and 0.45 μM (PANC1) for 6g.

第一章 緒論 1
第二章 實驗設計 17
第三章 結果與討論 19
3.1.1 2-Amino-4,5-dimethoxybenzoic acid (1b) 23
3.1.2 2-β-Nitroethylidenaminobenzoic acid (2) 23
3.1.3 4-Hydroxy-3-nitroquinoline (3) 24
3.1.4 4-Anilino-3-nitroquinoline衍生物 (4) 26
3.1.5 1-Arylimidazo[4,5-c]quinoline衍生物(5) 27
3.1.6 1-Aryltriazolo[4,5-c]quinoline衍生物 (6) 28
第四章 結論 34
第五章 實驗部分 37
5.1 實驗方法與實驗儀器 37
5.2 試藥、溶劑 37
5.3 合成步驟 38
第六章 參考資料 55

Information received from the Internet Homepages of the Department of Health, Taiwan, R. O. C. (http://www.doh.gov.tw)
Hartwell, L. H.; Weinert, T. A. Checkpoints: Controls that Ensure the Order of Cell Cycle Events. Science 1989, 246, 629-624
Alberts, B.; Johnson, A.; Lewis, J.; Raff, M.; Roberts, K.; Walter, P. The Mol. Biol. Cell, 5 th ed.; Garland Science: New York, 2002.
Mahmound, M. Effect of Nanoparticle on the Cell Life Cycle. Chem. Rev. 2011, 111, 3407-3432
Strachan, T.; Read, A. Human Molecular Genetics – 3th Ed.
Nogales, E.; Wolf, S. G.; Downing, K. A. Nature. 1998, 391, 199-203.
Klime-Smith, S. L; Walczak, C. E. Mitotic Spindle Assembly and Chromosome Segregation: Refocusing on Microtubule Dynamics. Molcu. Cell 2004, 15, 317-327.
Nogales, E.; Wang, H.-W.; Niederstrasser, H. Tubulin Rings: Which Way Do They Curve? Curr. Opin. Struct. Biol. 2003, 13, 256–261.
Kingston, D. G. I. Tubulin-Interactive Natural Products as Anticancer Agents. J. Nat. Prod. 2009, 72, 507–515
Datta, A.; Ali, S. M.; Zygmunt, J.; Vander Velde, D. G.; Georg, G. I. Structure-Activity Studies of Antitumor Taxanes: Synthesis of Novel C-13 Side Chain Homologated Tax01 and Taxotere Analogs. J. Med. Chem. 1994, 37, 2981-2984
Azevedo, W. F.; Leclerc, S.; Meijer, L.; Havlicek, L.; Strnad, M.; Kim, S. H. Inhibition of Cyclin-Dependent Kinases by Purine Analogues. Crystal Structure of Human CDK2 Complexed with Roscovitine. Eur. J. Biochem. 1997, 243, 518-526.
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.
Borzilleri, R. M.; Zheng, X.; Schmidt, R. J.; Johnson, J. A.; Kim, S.-H.; DiMarco, J. D.; Fairchild, C. R.; Gougoutas, J. Z.; Lee, F. Y. F.; Long, B. H.; Vite, G. D. A Novel Application of a Pd(0)-Catalyzed Nucleophilic Substitution Reaction to the Regio- and Stereoselective of Lactam Analogues of the Epothilone Natural Products. J. Am. Chem. Soc. 2000, 122, 8890–8897.
Gunasekera, S. P.; Gunasekera, M.; Longley, R. E. Discodermolide: a new bioactive polyhydroxylated lactone from the marine sponge Discodermia dissolute. J. Org. Chem. 1990, 55, 4912–4915.
Lindel, T. Jensen, P. R.; Fenical, W. Long, B. H. Casazza, A. M. Carboni, J. Fairchild, C. R. Eleutherobin, a New Cytotoxin that Mimics Paclitaxel (Taxol) by Stabilizing Microtubules. J. Am. Chem. Soc. 1997, 119, 8744–8745.
Svoboda, G. H.; Johnson, I. S.; Gorman, M.; Neuss, N. Current status of research on the alkaloids of Vinca rosea Linn. J. Pharm. Sci. 1962, 51, 707–720.
Dancey, J.; Steward, W. P. The role of vindesine in oncology – recommendations after 10 years' experience. Anti-Cancer Drugs 1995, 6, 625–36.
Dimitrios A.; Skoufiast and Leslie Wilson. Mechanism of Inhibition of Microtubule Polymerization by Colchicine: Inhibitory Potencies of Unliganded Colchicine and Tubulin-Colchicine Complexes. J. Med. Chem. 2002, 45, 1697-1711
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.
Pettit, G. R.; Singh, S. B.; Hamel, E.; Lin, C. M.; Alberts, D. S.; Garcia, K. D. Isolation and structure of the strong cell growth and tubulin inhibitor combretastatin A-4. Experientia 1989, 45, 209–211.
Pettit, G. R.; Toki, B. E.; Herald, D. L.; Boyd, M. R.; Hamel, E.; Pettit, R. K.; Chapuis, J. C. Antineoplastic Agents. 410. Asymmetric Hydroxylation of trans-Combretastatin A-4. J. Med. Chem. 1999, 42, 1459-1465.
Pettit, G. R.; Rhodes, M. R. Antineoplastic agents 389. New syntheses of the combretastatin A-4 prodrug. Anti-Cancer Drug Des. 1998, 13, 183– 191.
Kirwan, I. G.; Loadman, P. M.; Swaine, D. J.; Anthoney, D. A.; Pettit, G. R.; Lippert, J. W. 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.
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.; et al. Antineoplastic agents. 379. Synthesis of phenstatin phosphate. J. Med. Chem. 1998, 41, 1688-1695.
Jia Liu,; Can-Hui Zheng,; Xiao-Hui Ren,; Feng Zhou,; Wei Li,; Ju Zhu, Jia-Guo Lv,; You-Jun Zhou. Synthesis and Biological Evaluation of 1-Benzylidene-3,4-dihydronaphthalen-2-one as a New Class of Microtubule-Targeting Agents. J. Med. Chem. 2012, 55, 5720−5733
Liou, J.-P.; Wu, Z.-Y.; Kuo, C.-C.; Chang, C.-Y.; Lu, P.-Y.; Chen, C.-M.; Hsieh, H.-P.; Chang, J.-Y. Discovery of 4-Amino and 4-Hydroxy-1-aroylindoles as Potent Tubulin Polymerization Inhibitors. J. Med. Chem. 2008, 51, 4351–4355
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.
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.
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.
Bachman, G. B.; Welton, D. E.; Jenkins, G. L.; Christian, J. E. Quinoline derivatives from 3-nitro-4-hydroxyquinoline. J. Am. Chem. Soc. 1947, 69, 365-371.
Carlos Garcia-Echeve, Basel (CH); Hans-Georg Caprarp, Rheinfelden (CH); Paseal Furet, Thann (FR). 1H-imidazo[4,5-c]quinoline derivatuves in the treatment of protein kinase dependent diseases.; US 2005/0245562 A1
黃皓倫，碩士論文，靜宜大學應用化學研究所 (2008)。
蒲家弘，碩士論文，靜宜大學應用化學研究所 (2010)。
呂幸紋，推甄論文，靜宜大學應用化學陳香惠教授實驗室(2012)