臺灣博碩士論文加值系統

在本實驗室過去之研究中，磷酸化兩個極具發展潛力之2-arylquinoline (2AQ)類緣化合物，2-(2-fluorophenyl)-6,7-methylenedioxy-quinolin-4-one (2AQ-1)及2-(3-fluorophenyl)-5-hydroxy-6-methoxy-quinolin-4-one (2AQ-2)，並使之成為抗癌之候選藥物。為了開發更多新的2AQ類緣化合物之先導化合物，並且討論其結構與活性之相互關係。本研究合成了2-selenophenylquinolin-4-one和與之相關化合物做為標的化合物，並且以血癌細胞(HL-60 cells)、 肝癌細胞(Hep 3B cells)及肺癌細胞(H460 cells)等細胞株，進行了體外抗癌活性測試。比較其結果發現， 6,7-methylenedioxy-2-(substituted selenophenyl)quinolin-4-ones (52, 55, 58 and 70)及其2號位置上改變之等價異構物thiophenyl (53, 56, 59 and 71) 與furanyl (54, 57, 60 and 72)，有著結構與活性強弱之相關性順序如下： selenophenyl 衍生物 ?l thiophenyl 衍生物 > furanyl 衍生物。另外5,6-substituted-2-(substituted selenophenyl)quinolin-4-ones (61, 63, 65, 67, 68, 75, 77, 79, 73, 74 and 81) 也有著結構與活性強弱之相關性順序如下：5-hydroxy-6-methoxy 衍生物 > 6-methoxy 衍生物 > 5,6-dimethoxy 衍生物。在所有的受測化合物中，發現6,7-methylenedioxy-2-(5- methylselenophen-2-yl)quinolin-4-one (55)被發現為最具潛力之抗癌藥劑。在NCI 60株人類腫瘤細胞活性篩選中，化合物55在人類血癌HL-60細胞株上表現出了高選擇性細胞致毒活性。此外，由COMPARE分析結果發現，化合物55雖具有抗有絲分裂活性，但其作用模式不僅與傳統之抗有絲分裂試劑如：colchicine、vincristine、vinblastine及paclitaxel等不同，甚至與2AQ-1和 2AQ-2等具有和化合物55相同骨架化合物也不相同。因此，著者確認化合物55可做為先導化合物，並值得做進一步之優化。

In our prior work, the phosphorylation of two promising lead 2-arylquinoline (2AQ) analogues, 2-(2-fluorophenyl)-6,7-methylenedioxy-quinolin-4-one (2AQ-1) and 2-(3-fluorophenyl)-5-hydroxy-6-methoxy-quinolin-4-one (2AQ-2) led to the production of two anticancer drug candidates. In order to develop additional new lead compounds among 2AQ analogues and elucidate structure-activity relationships (SAR), 2- selenophenylquinoline and related compounds were synthesized as target compounds and evaluated for in vitro anticancer activity against HL-60, Hep 3B, and H460 cancer cell lines. Comparison of the 6,7-methylenedioxy-2- (substituted selenophenyl)quinolin-4-ones (52, 55, 58 and 70), with their thiophenyl (53, 56, 59 and 71) and furanyl isosteres (54, 57, 60 and 72) gave the following rank order of potency: selenophenyl derivatives ?l thiophenyl derivatives > furanyl derivatives. The anticancer activity of 5,6-substituted-2-(substituted selenophenyl)quinolin-4-ones (61, 63, 65, 67, 68, 75, 77, 79, 73, 74 and 81) was ranked in the following order: 5-hydroxy-6-methoxy derivatives > 6-methoxy derivatives > 5,6-dimethoxy derivatives. Among all tested compounds, 6,7-methylenedioxy-2-(5- methylselenophen-2-yl)quinolin-4-one (55) was found to be the most promising anticancer agent. In screening against NCI’s 60 human tumor cell line panel, compound 55 exhibited highly selective cytotoxicity activity against HL-60 leukemia. Furthermore, the results of COMPARE analysis suggested that 55 is an antimitotic agent with a different mechanism of action not only from the conventional antimitotic agents, such as colchicine, vincristine、vinblastine and paclitaxel, but also from 2AQ-1 and 2AQ-2, which have the same quinolin-4-one scaffold as 55. Therefore, compound 55 was identified as a new lead compound that merits further optimization.

目錄……I
縮寫表……VII
圖目錄……X
表目錄……XL
中文摘要……XLI
英文摘要……XLIII
第一章 緒論……1
一、抗癌藥物之概述……1
(一) 直接作用於核酸……1
(二) 作用於酶(enzyme)……2
(三) 賀爾蒙治療……3
(四) 作用於結構蛋白(structural proteins)……3
(五) 作用於訊息傳遞……4
二、 2-Phenylquinolin-4-one類化合物之研究概況……5
(一) 2-Phenylquinolin-4-one類生物鹼……5
(二) 2-Phenylquinolin-4-ones (2PQs)之化學合成方法……11
(三) 2-Phenylquinolin-4-one類緣化合物之抗癌活性……13
三、 五員雜環之基本性質……17
(一) 共振混成體(resonance hybrids)……18
(二) 振能(resonance energy)之大小……20
(三) 五員雜環C(2)－C(3)與C(3)－C(4)鍵長之比值……20
(四) 環狀電流(ring current)之比較……20
四、細胞週期(cell cycle)之概述……21
五、細胞凋亡(apoptosis)之概述……26
第二章 研究動機與目的……28
一、癌症死亡人數節節升高……28
二、抗癌藥物的缺點……30
(一) 抗藥性……30
(二) 副作用……31
三、新抗癌藥物的需求……31
四、2-phenylquinolin-4-one新骨架藥物的期待……32
第三章 結果與討論 ……35
一、 化學合成 ……35
(一) 標的化合物合成途徑之概述……35
(二) 起始化合物6-amino-3,4,5-substituted acetophenones
(1-4)之合成……40
1. 化合物6-amino-2,3-dimethoxyacetophenone (2)之合成 ……40
2. 化合物2-amino-5-methoxyacetophenone (3)之合成……41
3. 化合物2-mino-5-(pyrroylidin-1-yl)acetophenone (4)之
合成……41
(三) 起始化合物heterocyclic carboxylic acids (5-16)之合
成……42
1. 化合物selenophene-2-carboxylic acid (5)之合成……42
2. 化合物5-methyl selenophene-2-carboxylic acid (8)之
合成……42
3. 化合物5-chloroheterocyclic-2-carboxylic acids (11,
13)之合成 ……43
4. 化合物selenophene-3-carboxylic acid (14)之合成……
43
(四) 中間產物carboxamides (29-51)之合成……44
1.化合物N-(2-Acetyl-3,4-dimethoxyphenyl)-5-methyl-
selenophene-2-carboxamide (40)之合成……44
2.化合物N-(2-Acetyl-3,4-dimethoxyphenyl)-5-methyl-
selenophene-2-carboxamide (40)之結構解析……45
(五) 標的化合物quinolin-4-ones (52-74)之合成……47
1. 化合物5,6-Dimethoxy-2-(5-methylselenophen-2-yl)
quinolin-4-one (63)之合成……47
2. 化合物5,6-Dimethoxy-2-(5-methylselenophen-2-yl)
quinolin-4-one (63)之結構解析……48
(六) 標的化合物5-hydroxyquinolin-4-ones (75-81)之合成 ……50
1. 化合物5-Hydroxy-2-(5-methylselenophen-2-yl)-6-
methoxyquinolin-4-one (77)之合成……50
2. 化合物5-Hydroxy-2-(5-methylselenophen-2-yl)-6-
methoxyquinolin-4-one (77)之結構解析……51
(七) 標的化合物55的磷酸及其產物之結構解析……53
1. 化合物Dibenzyl 2-(5-methylselenophen-2-yl)-6,7-
methylene-dioxyquinolin-4-yl phosphate (82)之合成與
結構解析……54
2. 化合物6,7-methylenedioxy-2-(n-pentyl)quinolin- 4-
one (84)之合成與結構解析……57
二、 生物活性試驗結果……60
(一) 細胞生長抑制活性試驗……60
(二) 美國NCI 60株人類腫瘤細胞試驗與COMPARE……65
1. 美國NCI 60株人類腫瘤細胞試驗結果……65
2. COMPARE之結果與討論……76
(三) 抑制微管蛋白聚合 (Inhibition of tubulin assembly) ……86
(四) 藥理機轉……88
1. 化合物55於HL-60 cells之機轉探討……88
2. 化合物55於Hep 3B cells之機轉探討……92
(五) 動物試驗結果與討論……95
第四章 結論……98
第五章 實驗部分……100
一、 試藥與溶媒……100
(一) 化學合成……100
1. 試劑……100
2. 溶媒……101
二、重要儀器與實驗材料……102
(一) 重要儀器……102
(二) 實驗材料……104
三、化合物之製備 ……105
(一) 起始化合物之合成……105
(二) 中間產物carboxamides之合成……113
(三) 標的化合物quinolin-4-ones之合成 ……139
四、藥理試驗……171
(一) HL-60、Hep 3B、H460與Detroit 551之細胞培養及細胞生
長抑制活性試驗……171
(二) 60株人類腫瘤細胞抗增生活性試驗……172
(三) 抑制微管蛋白聚合……172
(四) HL-60與Hep 3B細胞抗增殖活性機轉……173
(五)、動物試驗 ……176
(六)、統計方法 ……176
參考文獻 ……177
附錄-圖譜 ……190

[1] G. L. Patrick, An Introduction to medicinal chemistry, fourth ed., Oxford University Press Inc. New York, 2009.
[2] 謝明杰, Phenylquinolone類緣化合物之合成及其抗血小板活性 中國醫藥學院藥物化學研究所博士論文, 1997.
[3] F.A. Steldt, K.K. Chen, The alkaloids of lunasia amara. J. Am. Pharm. Assoc. 32 (1943) 107-111
[4] S. Goodwin, A.F. Smith, A.A. Velasquez, E.C. Horning, Alkaloids of lunasia amara Blanco. Isolation studies. J. Am. Chem. Soc. 81 (1959) 6209-6213.
[5] R. Johnstone, J.R. Price, A.R. Todd, Alkaloids of the australian rutaceae: lunasia quercifolia. I. 7-Methoxy-1-methyl-2-phenyl-4-quinolone. Aust. J. Chem. 11 (1958) 562-574.
[6] H.C. Beyerman, R.W. Rooda, Alkaloids of Lunasia Amara-structure and synthesis of lunasia. I. Proceedings of the koninklijke nederlandse akademie van wetenschappen, series B: Physical Sci. 63 (1960) 427-431.
[7] O.O. Orazi, R.A. Corral, Plant studies. VIII. Isolation of tertiary bases from balfourodendron riedelianum. Anales de la Asociacion Quimica Argentina. 51 (1963) 174-179.
[8] F. Tillequin, M. Koch, T. Sevenet, Alkaloids from flindersia fournieri stem barks. Planta Medica 39 (1980) 383-387.
[9] V. I. Akhmedzhanova, I. A. Bessonova, S. Y. Yunusov, Alkaloids of haplophyllum leptomerum. I. Structure of leptomerine. Khimiya Prirodnykh Soedinenii 1 (1986) 84-86.
[10] A.R.P. Ambrozin, P.C. Vieira, J.B. Fernandes, M.F. das G. Fernandes da Silva, S. de Albuquerque, New pyranoflavones and trypanosomicidal activity of substances isolated from conchocarpus heterophyllus. Quimica Nova. 31 (2008) 740-743.
[11] A.P. Terezan, R.A. Rossi, R.N. A. Almeida, T.G. Freitas, J.B. Fernandes, M.F.das G. Fernandes da Silva, P.C. Vieira, O.C. Bueno, F.C. Pagnocca, J.R. Pirani, Activities of extracts and compounds from spiranthera odoratissima St. Hill. (rutaceae) on leaf-cutting ants and their symbiotic fungus. J. Brazil. Chem. Soci. 21 (2010) 882-886.
[12] N.K. Hart, S.R. Johns, J.A. Lamberton, J.R. Price, Alkaloids of the australian rutaceae: Lunasia quercifolia. IV. Identification of a minor constituent as 5-hydroxy-1-methyl-2-phenyl-4-quinolone and the preparation of an angular isomer of (-)-lunine. Aust. J. Chem. 21 (1968) 1389-1391.
[13] H.R. Arthur, H.T. Cheung, An examination of the Rutaceae of Hong Kong. VI. Graveoline a new alkaloid from ruta graveolens. Aust. J. Chem. 13 (1960) 510-513.
[14] A.Z. Gulubov, II.Z. Bozhkova, T.O. Sunguryan, Composition of Bulgarian medical plant Ruta graveolens. I. Alkaloid composition of ruta graveolens from bulgaria. Nauchni Trudove na Visshiya Pedagogicheski Institut, Plovdiv, Matematika, Fizika, Khimiya, Biologiya. 8 (1970) 125-128.
[15] D.M. Razakova, I.A. Bessonova, S.Yu. Yunusov, Alkaloids of haplophyllum dubium. Khimiya Prirodnykh Soedinenii. 6 (1979) 810-812.
[16] V.I. Akhmedzhanova, I.A. Bessonova, S.Y. Yunusov, Alkaloids of haplophyllum foliosum. Khimiya Prirodnykh Soedinenii. 6 (1980) 803-805.
[17] A. Ulubelen, H. Guner, M. Cetindag, Alkaloids and coumarins from the roots of ruta chalepensis var. latifolia. Planta Medica. 54 (1988) 551-552.
[18] K. El Sayed, M.S. Al-Said, F.S. El-Feraly, S.A. Ross, New Quinoline Alkaloids from ruta chalepensis. J. Nat. Prod. 63 (2000) 995-997.
[19] A.L. Hale, K.M. Meepagala, A. Oliva, G. Aliotta, S.O. Duke, Phytotoxins from the Leaves of ruta graveolens. J. Agricultural and Food Chem. 52 (2004), 3345-3349.
[20] A.M. Emam, E.S. Swelam, N.Y. Megally, Furocoumarin and quinolone alkaloid with larvicidal and antifeedant activities isolated from ruta chalepensis leaves. J. Nat. Prod. (Gorakhpur, India) 2 (2009) 10-22.
[21] Ha-Huy-Ke, M. Luckner, J. Reisch, 1-methyl-2-phenyl-3,6-dimethoxy- 4-quinolone, a new alkaloid from orixa japonica. Phytochem. (Elsevier) 9 (1970) 2199-2208.
[22] S. Funayama, R. Tanaka, Y. Kumekawa, T. Noshita, T. Mori, T. Kashiwagura, K.Murata, Rat small intestine muscle relaxation alkaloids from orixa japonica leaves. Bio. & Pharm. Bull. 24 (2001) 100-102.
[23] D.M. Razzakova, I.A. Bessonova, S.Y. Yunusov, Structure of folimidine. Khimiya Prirodnykh Soedinenii. 6(1972) 755-759.
[24] A. Ulubelen, B. Terem, E. Tuzlaci, K.F. Cheng, Y.C. Kong, Alkaloids and coumarins from ruta chalepensis. Phytochem. 25 (1986) 2692-2693.
[25] B.A. Barros-Filho, F.M. Nunes, M. da C.F. de Oliveira, M. Andrade- Neto, M.C. de Mattos, F.G. Barbosa, J. Mafezoli, Pirani, R. Jose, Secondary metabolites from esenbeckia almawillia kaastra (rutaceae). Quimica Nova. 30 (2007) 1589-1591.
[26] T.S. Wu, Alkaloids and coumarins of skimmia reevesiana. Phytochem. 26 (1987) 873-875.
[27] F.M. Oliveira, A.E.G. Santana, L.M. Conserva, J.G.S. Maia, G.M.P. Guilhon, Alkaloids and coumarins from esenbeckia species. Phytochem. 41 (1996) 647-649.
[28] B.A. Barros-Filho, F.M. Nunes, M. da C.F. de Oliveira, M. Andrade- Neto, M.C. de Mattos, F.G. Barbosa, J. Mafezoli, J.R. Pirani, Secondary metabolites from esenbeckia almawillia kaastra (rutaceae). Quimica Nova 30 (2007) 1589-1591.
[29] S. Funayama, T. Noshita, T. Mori, T. Kashiwagura, K. Murata, Quinoline alkaloids from orixa japonica (johzan)-isolation of an important biosynthetic intermediate. Tennen Yuki Kagobutsu Toronkai Koen Yoshishu 41 (1999) 451?{456.
[30] A.E.M. Khaleel, 2-Phenyl-4-quinolinone alkaloids from casimiroa edulis llave et lex (rutaceae). Monatshefte fuer Chemie 133 (2002) 183-187.
[31] A.S. Awaad, D.J. Maitland, S.M. Moneir, New antihypertensive alkaloids from casimiroa edulis fruits. Egyptian J. Biomed. Sci. 21 (2006) 14-22.
[32] Subehan; N. Takahashi, S. Kadota, Y. Tezuka, Cytochrome P450 2D6 inhibitory constituents of lunasia amara. Phytochem. Lett. 4 (2011) 30-33.
[33] S.C. Kuo, H.Z. Lee, J.P. Juang, Y.T. Lin, T.S. Wu, J.J. Chang, D. Lednicer, K.D. Pad, C.M. Lin, E. Hamel, K.H. Lee, 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. 36 (1993) 1146-1156.
[34] Y.Y. Lai, L.J. Huang, K.H. Lee, Z. Xiao, K.F. Bastow, T. Yamori, S.C. Kuo, Synthesis and biological relationships of 3'',6-substituted 2-phenyl- 4-quinolone-3-carboxylic acid derivatives as antimitotic agents, Bioorg. Med. Chem. 13 (2005) 265-275.
[35] L. Li, H.K. Wang, S.C. Kuo, T.S. Wu, D. Lednicer, C.M. Lin, E. Hamel, K.H. Lee, 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. 37 (1994) 1126-1135.
[36] Y. Xia, Z.Y. Yang, P. Xia, K.F. Bastow, Y. Nakanishi, P. Nampoothiri, E. Hamel, A. Brossi,K.H. Lee, Antitumor agents. Part 226: synthesis and cytotoxicity of 2-phenyl-4-quinolone acetic acids and their esters, Bioorg. Med. Chem. Lett. 13 (2003) 2891-2893.
[37] Y. Li, H. Fang, W. Xu, Recent advance in the research of flavonoids as anticancer agents. Mini. Rev. Med. Chem. 7 (2007) 663-678.
[38] K.H. Lee, K. Tagahara, H. Suzuki, R.Y. Wu, M. Haruna, I.H. Hall, H.C. Huang, K. Ito, T. Lida, J. S. Lai, Antitumor Agents 49: Tricin, kaempferol-3- O-P-D-glucopyranoside and (+)-nortrachelogenin, antileukemic principles from mikstoremia indica. J. Nat. Prod. 44 (1981) 530-535.
[39] M.T. Hung, A.W. Wood, H.L. Newmark, J.M. Snyer, H. Yagi, Jerina, A.H. Conney, Inhibition of the mutagenicity of bay-region diol-epoxides of polycyclic aromatic hydrocarbons by phenolic plant flavonoids. Carcinogenesis 4 (1983) 1631-1637.
[40] L.W. Wattenberg , J.L. Leong, Inhibition of the carcinogenic action of 7,12-dimethylbenz[a]anthracene by beta-naphthoflavone. Prod. 128 (1981) 940-943.
[41] L. Li, H.K. Wang, S.C. Kuo, T.S. Wu, A. Mauger, C.M. Lin, E. Hamel, K.H. Lee, Antitumor agents. 155. Synthesis and biological evaluation of 3′,6,7-substituted 2-phenyl-4-quinolones as antimicrotubule agents, J. Med. Chem. 37 (1994) 3400-3407.
[42] Y.H. Chang, M.H. Hsu, S.H. Wang, L.J. Huang, K. Qian, S.L. Morris- Natschke, E. Hamel, S.C. Kuo, K.H. Lee, Design and synthesis of 2-(3- benzo[b]thienyl)-6,7-methylenedioxyquinolin-4-one analogs as potent antitumor agents that inhibit tubulin assembly, J. Med. Chem. 52 (2009) 4883-4891.
[43] L.C. Chou, M.T. Tsai, M.H. Hsu, S.H. Wang, T.D. Way, C.H. Huang, H.Y. Lin, K. Qian, Y. Dong, K.H. Lee, L.J. Huang, S.C. Kuo, Design, synthesis, and preclinical evaluation of new 5,6-(or 6,7-)disubstituted-2- (fluorophenyl)quinolin-4-one derivatives as potent antitumor agents, J. Med. Chem. 53 (2010) 8047-8058.
[44] Y. Xia, Z.Y. Yang, P. Xia, K.F. Bastow, Y. Tachibana, S.C. Kuo, E. Hamel, T. Hackl, K.H. Lee, 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 antimitotic antitumor agents, J. Med. Chem. 41 (1998) 1155-1162.
[45] M.J. Hour, L.J. Huang, S.C. Kuo, Y. Xia, K. Bastow, Y. Nakanishi, E. Hamel, K.H. Lee, 6-Alkylamino- and 2,3-dihydro-3''-methoxy-2- phenyl-4-quinazolinones and related compounds: Their synthesis, cytotoxicity, and inhibition of tubulin polymerization, J. Med. Chem. 43 (2000) 4479-4487.
[46] Y. Xia, Z.Y. Yang, M.J. Hour, S.C. Kuo, P. Xia, K.F. Bastow, Y. Nakanishi, P. Namrpoothiri, T. Hackl, E. Hamel, H.K. Lee, Antitumor agents. Part 204: Synthesis and biological evaluation of substituted 2-arylquinazolinones, Bioorg. Med. Chem. 11 (2001) 1193-1196.
[47] M. Hadjeri, E.L. Peiller, C. Beney, N. Deka, M.A. Lawson, C. Dumontet, A. Boumendjel, Antimitotic activity of 5-hydroxy-7-methoxy-2-phenyl- 4-quinolones, J. Med. Chem. 47 (2004) 4964-4970.
[48] L.C. Chou, C.T. Chen, J.C. Lee, T.D. Way, C.H. Huang, S.M. Huang, C.M. Teng, T. Yamori, T.S. Wu, C.M. Sun, D.S. Chien, K. Qian, S.L. Morris-Natschke, E. Hamel, K.H. Lee, L.J. Huang, S.C. Kuo, Synthesis and preclinical evaluations of 2-(2-fluorophenyl)-6,7-methylene- dioxyquinolin-4-one monosodium phosphate (CHM-1－P-Na) as a potent antitumor agent, J. Med. Chem. 53 (2010) 1616-1626.
[49] K. Chen, S.C. Kuo, M.C. Hsieh, A. Mauger, C.M. Lin, E. Hamel, K.H. Lee, 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. 40 (1997) 2266-2275.
[50] K. Chen, S.C. Kuo, M.C. Hsieh, A. Mauger, C.M. Lin, E. Hamel, K.H. Lee, Antitumor agents. 178. Synthesis and biological evaluation of substituted 2-aryl-1,8-naphthyridin-4(1H)-ones as antitumor agents that inhibit tubulin polymerization, J. Med. Chem. 40 (1997) 3049-3056.
[51] S.X. Zhang, K.F. Bastow, Y. Tachibana, S.C. Kuo, E. Hamel, A. Mauger, V.L. Narayanan, K.H. Lee, Antitumor agents. 196. Substituted 2-thienyl- 1,8-naphthyridin-4-ones: Their synthesis, cytotoxicity, and inhibition of tubulin polymerization, J. Med. Chem. 42 (1999) 4081-4087.
[52] S.B. Bak, D. Christensen, W.B. Dixon, L. Hansen-Nygaard, J. Rastrup- Andersen, M. Schottlander, The complete structure of furan. J. mol. spectrosc. 9 (1962) 124.
[53] W.R. Harshbarger, S.H. Bauer, An electron diffraction study of the structure of thiophene, 2-chlorothiophene and 2-bromothiophene. Acta crystallographica. Section B 26 (1970) 1010.
[54] R.D. Brown, F.R. Burden, P.D. Godfrey, The microwave spectrum of selenophene , J. mol. spectrosc. 25 (1968) 415.
[55] J.A. Elvidge, Ring currents in furan, thiophen, and pyrrole and the aromaticities of these compounds, Chem. Commun. (1965) 160
[56] B. Grzelakowska-Sztabert, Cell cycle checkpoints--molecular background. Folia Morphologica (Warszawa) 63 (2004) 1-3.
[57] G. Brown, P.J. Hughes, R.H. Michell, Cell differentiation and proliferation--simultaneous but independent? Exp. Cell Res. 291 (2003) 282-288.
[58] J.R. Jackson, D.R. Patrick, M.M. Dar, P.S. Huang, Targeted anti-mitotic therapies: can we improve on tubulin agents? Nat. Rev. Cancer 7 (2007) 107-117.
[59] T. Hunter, J. Pines, Cyclins and cancer. II: Cyclin D and CDK inhibitors come of age. Cell 79 (1994) 573-582.
[60] D.O. Morgan, Principles of CDK regulation. Nature 374 (1995) 131-134.
[61] C. Swanton, Cell-cycle targeted therapies. Lancet. Oncology 5 (2004) 27-36.
[62] N. Kong, N. Fotouhi, P.M. Wovkulich, J. Roberts, Cell cycle inhibitors for the treatment of cancer. Drugs Fut 28 (2003) 881-896
[63] D. Hanahan, A. Weinberg R, The hallmarks of cancer. Cell 100 (2000) 57-70.
[64] M. Weller, K. Frei, P. Groscurth, P.H. Krammer, Y. Yonekawa, A. Fontana, Anti-Fas/APO-1 antibody-mediated apoptosis of cultured human glioma cells. Induction and147 modulation of sensitivity by cytokines. J. Clin. Invest. 94 (1994) 954-964.
[65] S. Nagata, Apoptosis by death factor. Cell 88 (1997)355-365.
[66] I. Budihardjo, H. Oliver, M. Lutter, X. Luo, X. Wang, Biochemical pathways of caspase activation during apoptosis. Annu.l Rev. Cell & Develop. Biol. 15 (1999) 269-290.
[67] M. MacFarlane, A.C. Williams, Apoptosis and disease: a life or death decision. EMBO reports 5 (2004) 674-678
[68] M.T. Tsai, Synthesis and anti-cancer activity of 5,6,7-substituted 2-fluorophenyl-4-quinolone derivatives, 中國醫藥大學藥學院藥物化學研究所碩士論文, 2009.
[69] H. Kagawa, A. Shigematsu, S. Ohta, Y. Harigaya, Preparative monohydroxyflavanone syntheses and a protocol for gas chromatography-mass spectrometry analysis of monohydroxyflavanones, Chem. Pharm. Bull. 53 (2005) 547–554.
[70] R.J. Robbins, D.M. Laman, D.E. Falvey, Substituent effects on the lifetimes and reactivities of arylnitrenium ions studied by laser flash photolysis and photothermal beam deflection, J. Am. Chem. Soc. 118 (1996) 8127–8135.
[71] S.K. Srivastava, A. Jha, S.K. Agarwal, R. Mukherjee, A.C. Burman, Synthesis and structure-activity relationships of potent antitumor active quinoline and naphthyridine derivatives. Anticancer Agents Med. Chem. 7 (2007) 685–709.
[72] M.H. Chen, Synthesis and cytotoxicity of 6-alkylamion-2-substituted phenyl-4-quinolone derivatives, 中國醫藥大學藥學院藥物化學研究所碩士論文, 2010.
[73] S.C. Kuo, C.M. Teng, K.H. Lee, L.J. Huang, L.C. Chou, C.S. Chang, C.M. Sun, T.S. Wu, S.L. Pan, T.D. Way, J.C. Lee, J.G. Chung, J.S. Yang, C.T. Chen, C.C. Huang, S.M. Huang, US 2010/0168064 A1.
[74] H. Gilman, A. David Shirley, Metalation of thiophene by n-butyllithium, J. Am. Chem. Soc. 71 (1949) 1870–1871.
[75] S. Tsuboi, S. Mimura, S.I. Ono, K. Watanabe, A. Takeda, Oxidation of 2,4-alkadienoic esters with selenium dioxide: a new synthesis of furans and selenophenes, Bull.Chem. Jpn. 60 (1987) 1807?{1812.
[76] L. Wen, S.C. Rasmussen, Synthesis and structural characterization of 2,5-dihalo-3,4-dinitrothiophenes, J. Chem. Crystal. 37 (2007) 387-398
[77] P. Franchetti, L. Cappellacci, G.A. Sheikha, H.N. Jayaram, V.V. Gurudutt, T. Sint, B.P. Schneider, W.D. Jones, B.M. Goldstein, G. Perra, A. De Montis, A.G. Loi, P. La Colla, M. Grifantini, Synthesis, structure, and antiproliferative activity of selenophenfurin, an inosine 5''- monophosphate dehydrogenase inhibitor analogue of selenazofurin, J. Med. Chem. 40 (1997) 1731–1737.
[78] G. Musumarra, D.F. Condorelli, A.S. Costa, M. Fichera, A multivariate insight into the in vitro antitumour screen database of the national cancer institute: classification of compounds, similarities among cell lines and the influence of molecular targets, J. Comput. Aided. Mol. Des. 15 (2001) 219–34.
[79] M. Cuendet, J. M. Pezzuto, Antitumor activity of bruceantin: an old drug with new promise. J. Nat. Prod. 67 (2004) 269?{72.
[80] H. Holcombe, I. Mellman, C. A. Jr Janeway, K. Bottomly, B. N. Dittel, The immunosuppressive agent 15-deoxyspergualin functions by inhibiting cell cycle progression and cytokine production following naive T cell activation. J. Immunol. 169 (2002) 4982-4989.
[81] M. Schmidt, H. Bastians, Mitotic drug targets and the development of novel anti-mitotic anticancer drugs. Drug Resist. Updat. 10 (2007) 162-181
[82] M.H. Hsu, S.C. Kuo, C.J. Chen, J.G. Chung, Y.Y. Lai, L.J. Huang, 1-(3,4-Dimethoxyphenyl)-3,5-dodecenedione (I6) induces G1 arrest and apoptosis in human promyelocytic leukemia HL-60 cells, Leuk. Res. 29 (2005) 1399-1406.
[83] M.H. Hsu, C.J. Chen, S.C. Kuo, J.G. Chung, Y.Y. Lai, C.M. Teng, S.L. Pan, L.J. Huang, YJC-1 induces mitotic phase arrest in A549 cells, Eur. J. Pharmacol. 559 (2007) 14-20.
[84] E. Hamel, Evaluation of antimitotic agents by quantitative comparisons of their effects on the polymerization of purified tubulin. Cell Biochem. Biophys. 38 (2003) 1-22.
[85] P. Verdier-Pinard, J.Y. Lai, H.D. Yoo, J. Yu, B. Marquez, D.G. Nagle, M. Nambu, J.D. White, J.R. Falck, W.H. Gerwick, B.W. Day, E. Hamel, Structure-activity analysis of the interaction of curancin A, the potent colchicines site antimitotic agents, with tubulin and effects of analogs on the growth of MCF-7 breast cnacer cells. Mol. Pharmacol. 53 (1998) 62-76.
[86] C.J. Chen, M.H. Hsu, L.J. Huang, T. Yamori, J.G. Chung, F.Y. Lee, C.M. Teng, S.C. Kuo, Anticancer mechanisms of YC-1 in human non-small- cell lung cancer cell line, NCI-H226, Biochem. Pharmacol. 75 (2008) 360-368.