臺灣博碩士論文加值系統

本研究主要探討具有DNA嵌入劑結構特徵之furocarbazole、benzimidazoisoquinolone及β-carboline類衍生物的合成與抗腫瘤活性的評估。研究結果發現，細胞毒殺活性主要取決於平面架構的furocarbazole與benzimidazoisoquinolone環上所導入的鹼性側鏈。具有propanylamine取代之furocarbazole衍生物(11d, 12d, 13d)有非常顯著的抗腫瘤活性，在4 μg/mL的濃度時能幾乎100% 抑制MCF-7(乳癌細胞)，NCI-H460(肺癌細胞)，SF-268(中樞神經癌細胞)的生長。Alkylamino取代能提高benzimidazoisoquinolone類衍生物的活性，18c具有最明顯效果。於C-1位置上取代之β-carboline類衍生物則顯示具有較弱的抗腫瘤活性。

Synthesis and antiproliferative evaluation of furocarbazole, benzimidazoisoquinolone, and β-carboline derivatives with the structural characteristics of DNA-intercalator are described. The results of this study indicate that the cytotoxic effect depends on the basic side chains inserted in the planar nucleus of furocarbazole, and benzimidazoisoquinolone. The propanylamine substituted of furocarbazole derivatives (11d, 12d, 13d), which show the most significant antiproliferative activity on the growth of MCF-7, NCI-H460, and SF-268 at a concentration of 4 μg/mL. The alkylamino substituted side chains of benzimidazoisoquinolone derivatives might facilitate the antiproliferative activity, 18c has particular effect. However, the substituents at position-1 of β-carboline derivatives displayed modest antiproliferative activity.

中文摘要 -----------------------------------------1
英文摘要 -----------------------------------------2
壹、緒言
一、前言 -------------------------------------3
二、研究動機 --------------------------------10
三、研究背景 --------------------------------15
貳、實驗方法 ------------------------------------22
參、實驗結果與討論 ------------------------------26
肆、藥理活性測試實驗方法與活性結果討論
一、實驗方式 --------------------------------43
二、活性結果與討論 --------------------------45
三、結論 ------------------------------------50
伍、實驗部份
一、溶劑及處理過程 --------------------------51
二、儀器及試藥 ------------------------------48
三、各化合物的製備 --------------------------55
陸、參考文獻 -----------------------------------103
附錄 -------------------------------------------108

1.簡伯武; 賴明德, 揭開細胞周期的奧秘-癌症治療的新希望Science Development 2002, 350, 52-55.

2.Laurence, H. H., DNA and its Assoicated Processies as Targets Cancer Therapy. Nat. Rev. Cancer 2002, 2, 188-200.

3.Braña, M. F.; Cacho, M.; Gradillas, A.; Pascual-Teresa, B. d.; Ramos, A., Intercalators as Anticancer Drugs. Curr. Pharm. Des. 2001, 7, 1745-1780.

4.Beatriz, M.; Wilmar, C. A.; Marc, M.; Rupert, O. l.; Joan, A.; Ernest, G.; Ricardo, P. R., DNA Interaction and Dual Topoisomerase I and II Inhibition Properties of the Anti-Tumor Drug Prodigiosin. Toxicol. Sci. 2005, 85, 870–879.

5.Taatjes, D. J.; Gaudiano, G.; Resing, K.; Koch, T. H., Redox Pathway Leading to the Alkylation of DNA by the Anthracycline, Antitumor Drugs Adriamycin and Daunomycin. J. Med. Chem. 1997, 40, 1276-1286.

6.Acton, E. M.; Narayanan, V. L.; Risbood, P. A.; Shoemaker, R. H.; Vistica, D. T.; Boyd, M. R., Anticancer Specificity of Some Ellipticinium Salts against Human Brain Tumors in vitro. J. Med. Chem. 1994, 37, 2185-2189.

7.Nagarajan, M.; Xiao, X.; Antony, S.; Kohlhagen, G.; Pommier, Y.; Cushman, M., Design, Synthesis, and Biological Evaluation of Indenoisoquinoline Topoisomerase I Inhibitors Featuring Polyamine Side Chains on the Lactam Nitrogen. J. Med. Chem. 2003, 46, 5712-5724.

8.Martínez, R.; García, L. C., The Search of DNA-Intercalators as Antitumoral Drugs: What it Worked and What did not Work. Curr. Med. Chem. 2005, 12, 127-151.

9.Lauria, A.; Diana, P.; Barraja, P.; Montalbano, A.; Dattolo, G.; Cirrincione, G.; Almerico, A. M., Docking of Indolo- and Pyrrolo-pyrimidines to DNA. New DNA Interactive Polycycles from Amino-Indoles/Pyrroles and BMMA. Arkivoc 2004, 5, 263-271.

10.de Pascual-Teresa, B.; Gallego, J.; Ortiz, A. R.; Gago, F., Molecular Dynamics Simulations of the Bis-Intercalated Complexes of Ditercalinium and Flexi-Di with the Hexanucleotide d(GCGCGC)2: Theoretical Analysis of the Interaction and Rationale for the Sequence Binding Specificity. J. Med. Chem. 1996, 39, 4810-4824.

11.Ito, C.; Furukawa, H., Chem. Pharm. Bull. 1990, 38, 1548-1550.

12.Yoshino, H.; Koike, K.; Nikaido, T., Synthesis and Antitumor Activity of Javacarboline. Heterocycles 1999, 51, 281-293.

13.He, L.; Chang, H. X.; Chou, T. C.; Savaraj, N.; Cheng, C. C., Design of Antineoplastic Agents Based on the ''2-Phenylnaphthalene-type'' Structural Pattern - Synthesis and Biological Activity Studies of 11H-indo[3,2-c]quinoline Derivatives. Eur. J. Med. Chem. 2003, 38, 101-107.

14.Harding, M. M.; Long, G. V.; Brown, C. L., Solution Conformation of the Antitumor Drug Streptonigrin. J. Med. Chem. 1993, 36, 3056-3060.

15.Sharma, V. M.; Prasanna, P.; Adi Seshu, K. V.; Renuka, B.; Laxman Rao, C. V.; Sunil Kumar, G., Novel Indolo[2,1-b]quinazoline Analogues as Cytostatic Agents: Synthesis, Biological Evaluation and Structure–Activity Relationship. Bioorg. Med. Chem. Lett. 2002, 12, 2303-2307.

16.Czoch, W. P.; Pognan, F.; Kaczmarek, L.; Boratynski, J., Synthesis and Structure-Activity Relationship of Methyl-Substituted Indolo[2,3-b] quinolines: Novel Cytotoxic, DNA Topoisomerase II Inhibitors. J. Med. Chem. 1994, 37, 3503-3510.

17.Bernardo, P. H.; Chai, C. L.; Heath, G. A.; Mahon, P. J.; Smith, G. D., Synthesis, Electrochemistry, and Bioactivity of the Cyanobacterial Calothrixins and Related Quinones. J. Med. Chem. 2004, 47, 4958-4963.

18.Bonjean, K.; De Pauw-Gillet, M. C.; Defresne, M. P.; Colson, P.; Houssier, C.; Dassonneville, L.; Bailly, C.; Greimers, R.; Wright, C.; Quetin-Leclercq, J.; Tits, M.; Angenot, L., The DNA Intercalating Alkaloid Cryptolepine Interferes with Topoisomerase II and Inhibits Primarily DNA Synthesis in B16 Melanoma Cells. Biochemistry 1998, 37, 5136-5146.

19.Via, L. D.; Gia, O.; Magno, S. M.; Settimo, A. D.; Marini, A. M.; Primofiore, G.; Settimo, F. D.; Salerno, S., Synthesis, in vitro Antiproliferative Activity and DNA-interaction of benzimidazoquinazoline Derivatives as Potential Anti-tumor Agents. Farmaco 2001, 56, 159-157.

20.Ishida, J.; Wang, H. K.; Oyama, M.; Cosentino, M. L.; Hu, C. Q.; Lee, K. H., Anti-HIV Activity of Harman, an Anti-HIV Principle from Symplocos setchuensis, and Its Derivatives. J. Nat. Prod. 2001, 64, 958-960.

21.Song, Y.; Wang, J.; Teng, S. F.; Kesuma, D.; Deng, Y.; Duan, J.; Wang, J. H.; Qib, R. Z.; Sima, M. M., beta-Carbolines as Specific Inhibitors of Cyclin-Dependent Kinases. Bioorg. Med. Chem. Lett. 2002, 12, 1129–1132.

22.Allen, M. S.; Tan, Y. C.; Trudel, M. L.; Narayanan, K.; Schindler, L. R.; Martin, M. J.; Schultz, C.; Hagen, T. J.; Koehler, K. F.; Codding, P. W.; Skolnick, P.; Cookt, J. M., Synthetic and Computer-Assisted Analyses of the Pharmacophore for the Benzodiazepine Receptor Inverse Agonist Site. J. Med. Chem. 1990, 33, 2343-2357.

23.Ishida, J.; Wang, H. K.; Bastow, K. F.; Chang, Q. H.; Lee, K. H., Antitumor Agents 201. Cytotoxicity of Harmine and b-Carboline Analogs. Bioorg. Med. Chem. Lett. 1999, 9, 3319-3324.

24.Hou, X. R.; Chen, Q.; Cao, R. H.; Peng, W. L.; Xu, A. L., A Comparative Molecular Field Analysis of Cytotoxic beta-Carboline Analogs. Acta Pharmacol. Sin. 2004, 7, 959-965.

25.Sakai, R.; Higa, T.; Jefford, C. W.; Bernardinelli, G., Manzamine A, a Novel Antitumor Alkaloid from a Sponge. J. Am. Chem. Soc. 1986, 108, 6404-6405.

26.Higa, T., PCT Int. Appl. (patent) 1998, WO 88/198 A1, 27.

27.Jones, S. F.; Burris, H. A., Topoisomerase I Inhibitors: Topotecan and Irinotecan. Cancer Pract. 1996, 4, 51-53.

28.Knölker, H. J.; Fröhner, W., Transition Metal Complexes in Organic Synthesis, Part 35.1 First Total Synthesis of Furostifoline. Tetrahedron Lett. 1996, 37, 9183-9186.

29.Beccalli, E. M.; Clerici, F.; Marchesini, A., A new Synthesis of Furostifoline. Tetrahedron 1998, 54, 11675-11682.

30.Hagiwra, H.; Choshi, T.; Nobuhiro, J.; Fujimoto, H.; Hibino, S., Novel Syntheses of Murrayaquinone A and Furostifoline through 4-Oxygenated Carbazoles by Allene-Mediated Electrocyclic Reactions Starting from 2-Chloroindole-3-carbaldehyde. Chem. Pharm. Bull. 2001, 49, 881-886.

31.Soós, T.; Timári, G.; Hajós, G., A Concise Synthesis of Furostifoline. Tetrahedron Lett. 1999, 40, 8607-8609.

32.Knölker, H. J.; Wang, H. K., Transition Metal Complexes in Organic Synthesis, Part 63; Convergent Iron-Mediated Syntheses of Furo[3,2-a]carbazole Alkaloid Furostifoline. Synthesis 2000, 14, 2131-2136.

33.Yasuhara, A.; Suzuki, N.; Sakamoto, T., A Concise Synthesis of Furostifoline by Tetrabutylammonium Fluoride-Promoted Indole Ring Formation. Chem. Pharm. Bull. 2002, 50, 143-145.

34.Robinson, B., Studies on the Fischer Indole Synthesis. Chem. Rev. 1969, 69, 227-250.

35.Ling, K. Q.; Chen, X. Y.; Fun, H. K.; Huang, X. Y.; Xu, J. H., Syntheses and Electronic Structures of Benzannelated Isoquinolinones and their Photoinduced Cycloaddition Reactions with Electron Deficient Alkenes. J. Chem. Soc. Perkin Trans. I 1998, 4147–4157.

36.Kraus, G. A.; Ridgeway, J., Total Synthesis of Coriandrin J. Org. Chem. 1994, 59, 4735-4737.

37.Ishii, H.; Ishikawa, T.; Takeda, S.; Ueki, S.; Suzuki, M., Cesium Floride-Mediated Claisen rearrangement of Aryl Propargyl Ether. Exclusive Formation 2-Methylarylfuran and Its Availability as a Masked Salicylaldehyde. Chem. Pharm. Bull. 1992, 40, 1148-1153.