臺灣博碩士論文加值系統

過去已合成出一系列3',6-substituted 2-phenyl-4-quinolone-3-carboxylic acids並評估其細胞致毒活性，結果顯示部分化合物具有明顯的活性，由於此項初步結果，因而從事2',6,7-substituted 2-phenyl-4-quinolone-3-carboxylic acids之合成。
首先substituted anilines 1-5和substituted benzoyl chlorides 6-10反應得到相對應的benzamides 11-24；接著將化合物11-24與PCl5進行氯化反應形成carboximidoyl chlorides，爾後再與sodium diethylmalonate反應而生成相對應的中間體；此相對應的中間體直接加熱環化即可獲得ethyl substituted 2-phenyl-4-quinolone-3-carboxylates 31-42；最後水解化合物31-42而得到標的化合物carboxylic acids 45-56。
檢視標的化合物45-56及其中間體的藥理活性，包括：細胞致毒活性、嗜中性白血球過氧化物形成之抑制活性、嗜中性白血球脫顆粒反應之抑制活性、肥胖細胞脫顆粒反應之抑制活性、TNF-α形成之抑制活性及一氧化氮形成之抑制活性，結果顯示部分化合物具有明顯的活性。其中，29, 30, 43, 44及56具有明顯的細胞致毒活性、32, 36及40具有明顯抑制嗜中性白血球過氧化物形成之活性、43及44具有優越的TNF-α形成之抑制活性。

In a previous paper, a series of 3',6-substituted 2-phenyl-4-quinolone-3-carboxylic acids were synthesized, and their cytotoxicity was evaluated. Some of 3',6-substituted 2-phenyl-4-quinolone-3-carboxylic acids showed significant activity. Encouraged by the initial result, 2',6,7-substituted 2-phenyl-4-quinolone-3-carboxylic acids were synthesized.
Reaction of substituted anilines 1-5 with substituted benzoyl chlorides 6-10 yielded the corresponding benzamides 11-24. Chlorination of compounds 11-24 with PCl5 afforded the carboximidoyl chlorides that treated with sodium diethylmalonate to give their corresponding intermediates. These intermediates were thermally cyclized into their corresponding ethyl substituted 2-phenyl-4-quinolone-3-carboxylates 31-42 that were hydrolyzed into the target compounds, carboxylic acids 45-56.
The target compounds 45-56 and their intermediates were examined for their cytotoxicity, inhibitory effect on neutrophil superoxide formation, neutrophil degranulation, mast cell degranulation, TNF-α formation and nitrile accumulation. Some of these compounds showed significant activities. Among them, 29, 30, 43, 44 and 56 exhibited significant cytotoxicity, 32, 36 and 40 exhibited significant inhibitory effect on neutrophil superoxide formation and 43, 44 exhibited potent inhibitory effect on TNF-α formation.

第一章 緒論 1
第一節 2-Phenyl-4-quinolone類緣化合物之研究概況 1
第二節 肥胖細胞與嗜中性白血球之生理功能 4
第三節 腫瘤壞死因子 7
第四節 小神經膠質細胞 9
第五節 研究動機與目的 10
第二章 結果與討論 11
第一節 化學合成 11
第二節 藥理活性試驗結果 53
(一) 細胞致毒活性 53
(二) 嗜中性白血球過氧化物形成之抑制活性 60
(三) 嗜中性白血球脫顆粒反應之抑制活性 61
(四) 肥胖細胞脫顆粒反應之抑制活性 74
(五) TNF-α形成之抑制活性 81
(六) 一氧化氮形成之抑制活性 87
第三章 結論 92
第四章 實驗部分 93
第一節 試藥與溶媒 93
第二節 重要儀器與實驗材料 95
第三節 各化合物之製備 97
第四節 藥理實驗簡介 145
參考文獻 150
圖譜 156

1. Cheng, C. C. A Common Structural Pattern Among Many Biologically Active Compounds of Natural and Synthetic Origin. Med. Hypotheses 1986, 20, 157-172.
2. Hung, M. T.; Wood, A. W.; Newmark, H. L.; Snyer, J. M.; Yagi, H.; Jerina, D. M.; Conney, A. H. Inhibition of the Mutagenicity of Bay-Region Diol?Epoxides of Polycyclic Aromatic Hydrocarbons by Phenolic Plant Flavonoids. Carcinogenesis 1983, 4, 1631-1637.
3. Wattenberg , L. W.; Leong, J. L. Inhibition of the Carcinogenic Action of 7,12-Dimethylbenz[a]anthracene by Beta-Naphthoflavone. Prod. 1981, 128, 940-943.
4. K. H. Lee; Tagahara, K.; Suzuki, H.; Wu, R. Y.; Haruna, M, Hall, I.H.; Huang, H.C.; Ito, K.; Iida, T; Lai, J. S. Antitumor Agents 49: Tricin, Kaempferol-3-O-β-D-glucopyranoside and (+)?Nortrachelogenin, Antileukemic Principles from Wikstoremia indica. J. Nat. Prod. 1981, 44, 530-535.
5. Xia, Y.; Yang, Z. Y.; Xia, P.; Bastow, K. F; Taxhibana, Y.; Kuo, S. C.; Hamel, E.; Hackl, T.; Lee, K. H. Antitumor agents. 181. Synthesis and biological evaluation of 6,7,2',3',4'?substituted 1,2,3,4-tetrahydro-2-phenyl-4-quinolones as a new class of antitmitotic antitmor agents. J. Med. Chem. 1998, 41, 1155-1162.
6. Kuo, S. C; Lee, H. Z.; Juang, J. P.; Lin, Y. T.; Wu, T. S.; Chang, J. J; Lendnicer, D.; Kenneth, P. D.; Lin, C. M.; Hamel E.; Lee, K. H. Synthesis and cytotoxicity of 1,6,7,8-substituted 2-(4'-substituted phenyl)-4-quinolones and related compounds: identification as antimitotic agents interacting with tubulin. J. Med. Chem. 1993, 36, 1146-1156.
7. Li, L.; Wang, H. K.; Kuo, S. C.; Wu, T. S.; Lendnicer, D.; Lin, C. M.; Hamel, E.; Lee, K. H. Antitumor agents. 150. 2',3',4',5',5,6,7-Substituted 2-phenyl-4-quinolones and related compounds: their synthesis, cytotoxicity, and inhibition of tubulin polymerization. J. Med. Chem. 1994, 37, 1126-1135.
8. Li, L.; Wang, H. K.; Kuo, S. C.; Wu, T. S.; Mauger, A. A.; Lin, C. M.; Hamel, E.; Lee, K. H. Antitumor agents. 155. Synthesis and biological evaluation of 3',6,7-substituted 2-phenyl-4-quinolones as microtubule agents. J. Med. Chem. 1994, 37, 3400-3407.
9. Neil, G. L.; Li, L. H.; Buskirk, H. H.; Moxley, T. E. Antitumor effects of the antispermatogenic agent, 2,3-dihydro-2-(1-naphthyl)-4-(1H)-quinazolinone. Cancer Chemother. 1972, 56, 163-173.
10. Yale, H. L; Kalkstein, M. Substituted 2,3-dihydro-4-(1H) quinazolinones. A new class of inhibitors of cell multiplication. J. Med. Chem. 1967, 10, 334-336.
11. Chen, K; Kuo, S. C.; Hsieh, M. C.; Mauger, A.; Lin, C. M.; Harnel, E.; Lee, K. H. Antitumor agents. 174. 2,3,4,5,6,7-Substituted 2-phenyl-1,8-naphthyridin-4-ones: their synthesis, cytotoxicity, and inhibition of tubulin polymerization. J. Med. Chem. 1997, 40, 2266-2275.
12. Chen, K.; Kuo, S. C.; Hsich, M. C.; Mauger, A.; Lin, C. M.; Hamel, E.; Lee, K. H. Antitumor agents. 178. Synthesis and biological evaluation of substituted 2-aryl1,8-naphthyridin-4(1H)-ones as antitumor agents that inhibit polymerization. J. Med. Chem. 1997, 40, 3049-3056.
13. Jiang, J. B.; Hesson, D. P.; Dusak, B. A.; Dexter, D. J.; Kang, G. L; Hamel, E. Synthesis and biological evaluation of 2-styryl-quinazolin-4(3H)-ones, a new class of antimitotic anticancer agents which inhibit tubulin polymerization. J. Med. Chem. 1990, 30, 1721-1728.
14. Adams, G. K.; Lichtenstein, L. M. In vitro studies of antigen-induced broncho spasm: effect of antihistamine and SRS-A antagonist on response to sensitized guinea pig and human airways to antigen. J .Immunol. 1979, 122, 555-562.
15. Schwartz, L. B.; Austen, K. F. Structural and function of the chemical mediators of mast cells. Prog. Allergy 1984, 34, 271-321.
16. Semb, A. G.; Vaage, J.; Mjos, O. D. Oxygen free radical producing leukocytes cause functional depression of isolated rat hearts: role of leukotrienes. J. Mol. Cell. Cardiol. 1990, 22, 555-563.
17. Harman, D.; Piette, L. H. Free radical theory of aging: free radical reactions in serum. J . Gerontol. 1966, 21, 560-565.
18. McCord, J. M. Free radicals and inflammation: protection of synovial fluid by superoxide dismutase. Science 1974, 185, 529-531.
19. Allen, R. E; Blake, D. R.; Nazhat, N. B.; Jones, P. Superoxide radical generation by inflamed human synovium after hypoxia. Lancet 1989, 2, 282-283.
20. Weissmann, G.; Smolen, J. E; Korzhak, H. M. Release of inflammatory mediators from stimulated neutrophils. N. Engl. J. Med. 1980, 303, 27-34.
21. Davies, M.; Barrett, A. L; Travis, J.; Sanders, E.; Coles, G. A. The degradation of human glomerular basement membrane with purified lysosomal proteinases: evidence for the pathogenetic role of the polymorphonuelear leukocyte in glomerulonephritis. Clin. Sci. Mol. Med. 1978, 54, 233-240.
22. Menninger, H.; Putzier, R.; Mohr, W.; Weissinghage, D.; Tillmann, K. Granulocyte elastase at the site of cartilage erosion by rheumatoid synovial tissue. J. Rheumatol. 1980, 39, 145-156.
23. Saklatvala, J.; Barrett, A. J. Identification of proteinases in rheumatoid synovium: detection of leukocyte elastase, cathepsin G and another serine proteinase. Biochem. Biophys. Acta. 1980, 615, 167-177.
24. Burde, R.; Seifert, R.; Buschauer, A.; Schultz, G. Histamine inhibits activation of human neutrophils and HL-60 leukemic cells via H2 receptors. Nauny-Schmiedeberg's Arch. Pharmacol. 1989, 340, 671-678.
25. Akinshola, B. E.; Verma, P.S.; Taylor, R. E. Effect of in vitro incorporation of prostanoid precursors, superoxide radical and hydrogen peroxide on platelet function. Thromb. Res. 1995, 79, 343-351.
26. Gutteridge, J. M.; Halliwell, B. The measurement and mechanism of lipid peroxidation in biological system. Trends. Biochem. Sci. 1990, 15, 129-135.
27. Parks, D. A.; Granger, D. N. Ischemia induced vascular changes: role of xanthine oxidase and hydroxyl radicals. Am. J. Physiol. 1983, 245, G285-G289.
28. McCord, J. M. Oxygen-derived free radicals in postischemic tissue injury. N. Engl. J. Med. 1985, 312, 159-163.
29. Dyke, H. J. and Montana, J. G. Update on the therapeutic potential of PDE4 inhibitors. Expert. Opin. Investig. Drugs. 2002, 11, 1-13.
30. Hofman, F. M.; Hinton, D. R.; Johnson K.; Merrill, J. E. Tumor necrosis factor identified in multiple sclerosis brain. J .Exp. Med. 1995, 170, 607-612.
31. Meda, L.; Cassatella, M. A.; Szendrei, G. I.; Otvos, L. Jr.; Baron, P.; Villalba, M.; Ferrari, D.; Rossi, F. Activation of microglial cells by β-amyloid protein and interferon-γ. Nature 1995, 374, 647-650.
32. Mallat, M.; Chamak, B. Brain macrophages: neurotoxic or neurotrophic effector cells. J. Leukoc. Biol. 1994, 56, 416-422.
33. Gehrmann, J.; Matsumoto, Y.; Kreutzberg, G. W. Microglia: intrinsic immunoeffector cell of the brain. Brain Res. Rev. 1995, 20, 269-280.
34. Gebicke-Haerter, P. J.; Bauer, L; Schobert, A.; Northoff, H. Lipopolysaccharide free conditions in primary astrocyte cultures allow growth and isolation of microglia cells. J. Neurosci.1989, 9, 183-194.
35. Minghetti, L.; Nicolini, A.; Polazzi, E.; Cruinon, C.; Maclotif, J.; Levi, G. Inducible nitric oxide synthase expression in activated rat microglial cultures is down-regulated by exogenous prostaglandin E2 and by cyclooxygenase inhibitors, Glia 1997, 19, 152-160.
36. Chao, C. C.; Hu, S.; Molitor, T. W.; Shaskan, E. G.; Peterson, P. K. Activated microglia mediate neuronal cell death injury via a nitric oxide mechanism. J mimunol. 1992, 149, 2736-2741.
37. Merrill, J. E.; Ignarro, L. J.; Sherman, M. P.; Melinek, J.; Lane, T. E.; Microglial cell cytotoxicity of oligodendrocytes is mediated through nitric oxide. J. Immunol. 1993, 151, 2132-2141.
38. Meda, L.; Cassatella, M. A.; Szendrei, G. I.; Otvos, L. Jr.; Baron, P.; Villalba, M.; Ferrari, D.; Rossi, F. Activation of microglial cells by β-amyloid protein and interferon-γ. Nature 1995, 374, 647-650.
39. Elderfield, R. C.; Gensler, W. J.; Bembry, T. H.; Kremer, C. B.; Head, J. D.; Brody, F.; Frohardt, R. Synthesis of 2-phenyl-4-chloroquinolines. J. Am. Chem. Soc. 1946, 68, 1272-1275.
40. 賴雅韻，中國醫藥學院藥物化學研究所博士論文，2002年。
41. He, Q.; Jiang, D. A Novel Aminosteroid is Active for Proliferation Inhibition and Differentiation Induction of Human Acute Myeloid Leukemia HL-60 Cells. Leuk. Res.1999, 23(4), 369-372.
42.Berridge, M. V.; Tan, A. S. Characterization of the Cellular Reduction of 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium Bromide (MTT): Subcellular Localization, Substrate Dependence, and Involvement of Mitochondrial Electron Transport in MTT Reduction. Arch. Biochem. Biophys. 1993, 303, 474-482.
43. J. P. Wang, S. L. Raung, Y. H. Kuo and C. M. Teng, Daphnoretin-induced respiratory burst in rat neutrophils is probably mainly through protein kinase C activation, Eur. J. Pharmacol 1995, 288, 341-348.
44. Markert, M.; Andrews, P. C.; Babior, B. M. Measurement of O2．- production by human neutrophils. The preparation and assay of NADPH oxidase-containing particles from human neutrophils. Methods Enzymo. 1984, 105, 358-365.
45. Newby, A. C. Role of adenosine deaminase, ecto-(5'-nucleo-tidase) and ecto-(non-specific phosphatase) in cyanide-induced adenosine monophosphate catabolism in rat polymorphonuclear leucocytes. Biochem. J. 1980, 186, 907-918.
46. Barrett, A. J. “A Laboratory Handbook”, Dingle, J. T. ed (Elsevier/NorthHolland, Amsterdam) 1972, 118-120.
47. Absolom, D.R. Basic methods for the study of phagocytosis. Methods Enzymol. 1986, 132, 95-180.
48. Wang, J. P.; Raung, S. L.; Hsu, M. F.; Lin, C. C. Inhibition by gomisin C (a lignan from Schizandra chinensis) of the respiratory burst of rat neutrophils. Br. J. Pharmacol. 1994, 113, 945-953.
49. McClain, D. E.; Donlon, M. A.; Chock, S.; Catravas, G. N. The effect of calmodulin on histamine release in the rat peritoneal mast cell. Biochem. Biophys. Acta. 1983, 763, 419.
50. Hanahae, T. H. P. Mechanism of histamine release from rat isolated peritoneal mast cells by dextran: the role of immunglobulin E. Agents Action 1984, 14, 468.
51. Johnson, A. R.; Erdos, E. G. Release of histamine from mast cell by vasoactive peptides.
Proc. Soc. Exp. Biol. Med. 1973, 142, l252-1256.
52. Hakanson, R.; Ronnberg, A. L. Improved fluorometric assay of histamine. Antlyt. Biochem. 1974, 60, 560-567.
53. Corradin, S. B.; Manuel, J.; Donini, S. D.; Quattrocchi, E.; RicciardiCastagnoi, P. Inducible nitric oxide synthase activity of cloned murine microglial cells. Glia 1993, 7, 255-262.
54. Minghetti, L.; Nicolini, A.; Polazzi, E.; Creminon, C.; Maclouf, J.; Levi, G.; Inducible nitric oxide synthase expression in activted rat microglial cultures is down-regulated by exogenous prostaglandin E2 and by cyclooxygenase inhibitors. Glia 1997, 19, 152-160.