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中文論文名稱 抗癌試劑2-苯乙烯色素母酮及8-羥基喹啉衍生物的合成
英文論文名稱 Synthesis of 2-Styrylchromone and 8-Hydroxyquinoline Derivatives as Anticancer Agents
校院名稱 淡江大學
系所名稱(中) 化學學系碩士班
系所名稱(英) Department of Chemistry
學年度 98
學期 1
出版年 99
研究生中文姓名 張峻誼
研究生英文姓名 Chun-Yi Chang
學號 696161032
學位類別 碩士
語文別 中文
口試日期 2010-01-17
論文頁數 122頁
口試委員 指導教授-蕭永政
委員-蕭崇瑋
委員-鄧金培
中文關鍵字 2-苯乙烯色素母酮  曼尼希反應  8-羥基喹啉 
英文關鍵字 2-styrylchromone  Mannich-type reaction  8-hydroxyquinoline 
學科別分類 學科別自然科學化學
中文摘要 第一部分:我們合成了具有代表性的天然物結構所衍生出的2-苯乙烯色素母酮衍生物,利用了簡單的合成方法來合成,並作為新型抗癌試劑的模板,以測試其細胞毒殺性(cytotoxicity)及作用機轉。經由生物活性的試驗後證實化合物38可抑制子宮頸癌細胞(HeLa Cell)生長並誘導細胞凋亡(apoptosis),IC50值可達到4.9 μM。
第二部份:我們利用Mannich類型反應設計出8-羥基喹啉衍生物,並藉由修飾化合物90來合成出一系列8-羥基喹啉衍生物,來研究其分子結構與抗癌活性的關係(Structure-Activity Relationship)。經由生物活性的測試後證實可抑制一系列的癌細胞株生長。而最具抑制生長活性的化合物115,IC50值可達到0.7 μM。
英文摘要 The first part : A series of 2-styrylchromone analogs were synthesized and examined for their antiproliferative effects on a panel of carcinoma cells. Among the tested agents, only 34 exhibited a moderate activity with an IC50 value of 28.9 μM against PC-3 cells which indicates the selectivity of PC-3 cells in response to 2-styrylchromones. In addition, 38 demonstrated the most antiproliferative effect with an IC50 value of 4.9 μM against HeLa cells. Together, these results suggest a potential structural optimization and pharmacological study of 2-styrylchromones.

The second part : A series of Mannich-type reaction of 8-hydroxyquinoline derivatives are prepared which demonstrated apoptosis-inducing effect against HeLa cervical cancer cells. Among the tested compounds, 5-nitro-7-((4-tosylpiperazin-1-yl)methyl)quinolin-8-ol (115) exhibited the most anti-proliferative effect with an IC50 value of 0.7 μM. Further structure-activity relationship (SAR) study as well as pharmacological exploitation of this novel 8-hydroxyquinoline scaffold are underway.
論文目次 目錄
目錄 I
圖表目錄 IV
第一章 緒論 1
1-1 癌症的簡介 1
1-2 藥物的設計動機 3
第二章 2-苯乙烯色素母酮衍生物當作抗癌試劑之研究 6
2-1 色素母酮簡介 6
2-2 結果與討論 9
2-3 結構與活性關係 16
2-3-1 2-苯乙烯色素母酮衍生物抑制PC-3前列腺癌細胞生長
之構效關係 17
2-3-2 2-苯乙烯色素母酮衍生物抑制A549肺腺癌細胞生長
之構效關係 18
2-3-3 2-苯乙烯色素母酮衍生物抑制BT483乳癌細胞生長
之構效關係 19
2-3-4 2-苯乙烯色素母酮衍生物抑制HeLa子宮頸癌細胞生長
之構效關係 20
2-3-5 2-苯乙烯色素母酮衍生物抑制SKHep肝癌細胞生長
之構效關係 20
2-4 結論 21
第三章 8-羥基喹啉衍生物當作抗癌試劑之研究 22
3-1 簡介 22
3-1-1 曼尼希反應介紹 22
3-1-2 8-羥基喹啉簡介 25
3-2 結果與討論 28
3-3 結構與活性關係 41
3-3-1 8-羥基喹啉衍生物抑制HeLa子宮頸癌細胞生長
之構效關係 44
3-3-2 8-羥基喹啉衍生物抑制BT483乳癌細胞生長
之構效關係 48
3-3-3 8-羥基喹啉衍生物抑制SKHep肝癌細胞生長
之構效關係 49
3-3-4 8-羥基喹啉衍生物抑制CE81T食道癌細胞生長
之構效關係 49
3-4 結論 50
第四章 實驗部分 51
4-1 實驗儀器及測試方法 51
4-2 溶劑的乾燥 53
4-3 2-苯乙烯色素母酮衍生物之實驗步驟及光譜資料 54
4-4 8-羥基喹啉衍生物之實驗步驟及光譜資料 78
第五章 參考文獻 117


圖表目錄
Figure 2-1 Flavopiridol的結構 6
Figure 2-2 Hormothamnione與6-Desmethoxyhormothamnione的結
構 7
Figure 2-3 2-styrylchromone的架構 9
Figure 3-1 Quinoline和8-hydroxyquinoline的化學結構 25
Figure 3-2 8-hydroxyquinolines衍生物52和90的化學結構 27
Figure 3-3 7-(morpholinomethyl)quinolin-8-ol的化學結構 29
Figure 3-4 胺類化合物的化學結構 29
Figure 3-5 Sulfonyl chloride和sulfonamide的化學結構 30
Figure 3-6 8-hydroxyquinolines衍生物52和90的化學結構及對
HeLa細胞之生物活性值 32
Figure 3-7 8-hydroxyquinolines衍生物90的化學結構
修飾部位A-D 33
Scheme 2-1 2-methyl-5,7-dimethoxychromone的逆合成分析 9
Scheme 2-2 2-styrylchromone 22-33的合成路徑 11
Scheme 2-3 2-styrylchromone 34-38的合成路徑 13
Scheme 3-1 Iminium ion形成的反應機制 23
Scheme 3-2 Mannich Reaction產物形成的反應機制 24
Scheme 3-3 Hydroxy aromatic的Mannich reaction之化學反應式 28
Scheme 3-4 以一鍋式四元素合成8-羥基喹啉衍生物的化學
反應式 30
Scheme 3-5 Sulfonamide二聚物63形成的化學反應式 31
Scheme 3-6 經由一鍋式三元素合成8-羥基喹啉衍生物90-106 的化
學反應式 32
Scheme 3-7 所合成出Sulfonamide中間產物73-89 (二級胺)的化學
反應式 34
Scheme 3-8 Benzamide二聚物形成的化學反應式 37
Scheme 3-9 二級胺類化合物66的合成反應式 38
Scheme 3-10 Sulfonamide中間產物107(一級胺)的化學反應式 39
Scheme 3-11 8-hydroxyquinolines衍生物108-110的化學反應式 39
Scheme 3-12 8-hydroxyquinolines衍生物111-117的化學反應式 40
Table 2-1 2-styrylchromone衍生物22-33的化學結構 12
Table 2-2 Acetophenone 8-16的化學結構 14
Table 2-3 化合物17-21和34-38的化學結構 15
Table 2-4 所測試的2-styrylchromone衍生物22–38之IC50值 16
Table 3-1 所合成出Sulfonamide中間產物73-89 (二級胺)的化學結構 35
Table 3-2 8-hydroxyquinoline衍生物91-106的化學結構 36
Table 3-3 Mannich-type reaction加合物111-117的化學結構 40
Table 3-4 所測試的8-hydroxyquinoline衍生物91-106之
IC50值 42
Table 3-5 所測試的8-hydroxyquinoline衍生物108-117之
IC50值 43
參考文獻 (1) 中華民國行政院衛生署「中華民國96年死因統計」。
(2) 藥物化學(An introduction to medicinal chemistry,3/e)/ Graham L. Patrick原著;吳天賞編譯(台北市/藝軒/2007)
(3) 組合式新藥研發的近期發展/CHEMISTRY(THE CHINESE CHEM. SOC., TAIPEI)/孫仲銘/June. 2004 Vol. 62, No. 2, pp.187~212.
(4) Swanson J., Yirinec B., Burke E., Bushnell A. and Silverstein S. C., J. Cell Physiol. 1986, 128, 195-201.
(5) Schmid H.F., Chem. Org. Naturst.1954, 11, 124–179.
(6) Holdsworth D.K., Planta Med. 1972, 22 (1), 54–58.
(7) Ellis G.P., Chem. Heterocycl. Compd. 1977, 31, 455–480.
(8) Ghosal S.S., Shripati B., Mahendra P., Kumar Y., Phytochemistry 1982, 21 (12), 2943–2946.
(9) Edwards A.M., Howell J.B.L., Clin. Exp. Allergy 2000, 30 (6), 756–774.
(10) Pratt D.E., Betty M., J. Food Sci. 1964, 29 (1), 27–33.
(11) Donnelly D., Geoghegan R., O’Brien C., Philbin E., Wheeler T.S., J. Med. Chem. 1965, 8 (6), 872–875.
(12) Djerngou P.C., Gatsing D., Tehuendem M., Ngadjui B.T., Tane P., Ahmed A.A., Gamal-Eldeen A.M., Adoga G.I., Hirata T., Mabry T.J., Nat. Prod. Commun. 2006, 1 (11), 961–968.
(13) Reanmongkol W., Sanan S., Panichayupakaranant P., Kim K.-M., J. Pharm. Biomed. Anal. 2003, 41 (8), 592–597.
(14) Houghton P.J., Stud. Nat. Prod. Chem. 2000, 21, 123–155.
(15) Gamal-Eldeen A.M., Djemgou P.C., Tchuendem M., Ngadjui B.T., Tane P., Toshifumi H., Biosci. 2007,62 (5/6), 331–338.
(16) Ren W., Qiao Z., Wang H., Zhu L., Zhang L., Med. Res. Rev. 2003, 23 (4), 519–534.
(17) Kelland L.R., Expert Opin. Investig. Drugs 2000, 9, 2903–2911.
(18) Senderowicz A.M., Sausville E.A., J. Natl. Cancer Inst. 2000, 92, 376–387.
(19) Gerwick W.H., J. Nat. Prod. 1989, 52 (2), 252–256.
(20) Gerwick W.H., Lopez A., Van Duyne G.D., Clardy J., Ortiz W., Baez A., Tetrahedron Lett. 1986, 27 (18), 1979–1982.
(21) Doria G., Romeo C., Forgione A., Sberze P., Tibolla N., Corno M.L., Cruzzola G., Cadelli G., Eur. J. Med. Chem. 1979, 14, 347–351.
(22) Desideri N., Conti C., Mastromarino P., Mastropaolo F., Antivir. Chem. Chemother. 2000, 11, 373–381.
(23) Brion D., Le Baut G., Zammatio F., Pierre A., Atassi G., Belachm L., Chem. Abstr. 1991, 116, 106092k.
(24) Marinho J., Pedro M., Pinto D.C.G.A., Silva A.M.S., Cavaleiro J.A.S., Sunkel C.E., Nascimento M.S.J., Biochem. Pharmacol. 2008, 75 (4), 826–835.
(25) Momoi K., Soshiaki Y., Ishihara M., Satoh K., Kikuchi H., Hashimoto K., Yokoe I., Nishikawa H., Fujisawa S., Sakagami H., In Vivo 2005, 19 (1), 157–163.
(26) Filipe P., Silva A.M.S., Morliere P., Brito C.M., Patterson L.K., Hug G.L., Silva J.N., Cavaleiro J.A.S., Maziere J.- C., Freitas J.P., Santus R., Biochem. Pharmacol. 2004, 67 (12), 2207–2218.
(27) Gomes A., Fernandes E., Silva A.M.S., Santos C.M.M., Pinto D.C.G.A., Cavaleiro J.A.S., Lima J.L.F.C., Bioorg. Med. Chem. 2007, 15 (18), 6027–6036.
(28) Karton Y., Jiang J.- L., Ji X.- D., Melman N., Olah M.E., Stiles G.L., Jacobson K.A., J. Med. Chem. 1996, 39, 2293–2301.
(29) Fernandes E., Carvalho F., Silva A.M.S., Santos C.M.M., Pinto D.C.G.A., Cavaleiro J.A.S., Bastos M.L., J. Enzyme Inhib. Med. Chem. 2002, 17, 45–48.
(30) Cheema U.S., Gulati K.C., Venkataraman K., J. Chem. Soc. 1932, 925.
(31) Price W.A., Silva A.M.S., Cavaleiro J.A.S., Heterocycles 1993, 36 (11), 2601–2611.
(32) Christopher A.G., Perry T.K., Aloysius T.N., J. Nat. Prod. 2003, 66 (8), 1144–1146.
(33) Geissman T.A., J. Am. Chem. Soc. 1951, 73, 3514–3515.
(34) Ayyangar N.R., Khan R.A., Deshpande V.H., Tetrahedron Lett. 1988, 29 (19), 2347–2348.
(35) Mannich C., Krosche W., Archiv der Pharmazie 1912, 250, 647–667.
(36) Gao X., Hall D. G., J. Am. Chem. Soc. 2003, 125, 9308-9309.
(37) Dimmock J. R., Erciyas E., Raghavan S. K.,Kirkpatrick D. L., Pharmazie 1990, 45, 755-757.
(38) Shen A. Y., Hwang M. H., Rofflet S., Chen C. F.,Arch. Pharm. 1995, 328, 197-201.
(39) Nordenberg J., Novogrodsky A., Beery E., Patia M., Wasserman L., Warshawsky A., Eur. J. Cancer 1990, 26, 905-907.
(40) Ding W.-Q., Yu H.-J., Lind S. E., Cancer Lett. 2008, 271, 251-259.
(41) Ding W.-Q., Liu B., Vaught J. L., Yamauchi H., Lind S. E., Cancer Res. 2005, 65(8), 3389-3395.
(42) Mazumder, U. K., Gupta, M., Bhattacharya, S., Karki, S. S., Rathinasamy, S., Thangavel, S., Journal of Enzyme Inhibition and Medicinal Chemistry 2004, 19(2), 185-192.
(43) PHILLIPS, J. P., Chem. Rev. 1956, 56 (2), 271–297.
(44) Shen A.-Y., Wu S.-N., Chiu C.-T., Journal of Pharmacy and Pharmacology 1999, 51(5), 543-548.
(45) Huang P., Feng L., Oldham E. A., Nature 2000, 407, 390-395.
(46) Polette M., Nawrocki-Raby B., Gilles C., Clavel C. and Birembaut P., Crit. Rev. Oncol. Hematol. 2004, 49, 179–186.
(47) Cress W. D., Seto E., J. Cell Physiol. 2000, 184, 1-16.
(48) Hu G. F., J. Cell Biochem. 1998, 69, 326-335.
(49) Tramontini M., Synthesis 1973, 703.
(50) Tramontini M., Angliolini, L., Tetrahedron 1990, 46, 1791.
(51) Tramontini M., Angliolini L., Mannich Base: Chemistry and Uses; CRC Press: Boca Raton, 1994; pp 17-20.
(52) Thompson B. B., J. Pharm. Sci. 1968, 57, 715.
(53) Pochini A., Puglia G., Ungaro R., Synthesis 1983, 906.
(54) Cummings T. F., Shelton J. R., J. Org. Chem. 1960, 25, 419.
(55) Lukyanenko N. G., Pastushok V. N., Bordunov A. V., Synthesis 1991, 241.
(56) Chi K.-W., Ahn Y. S., Shim K. T., Park T. H., Ahn J. S., Bull. Korean Chem. Soc. 1999, 20(8), 973-976.
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