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研究生:陳香君
研究生(外文):Chern, Shiang-Jiun
論文名稱:新穎茚并[1,2-c]喹啉-11-酮衍生物之合成及其潛在抗癌活性評估
論文名稱(外文):Synthesis and Biological Evaluation of Novel Indeno[1,2-c]quinolin-11-one Derivatives as Potential Anticancer Agents
指導教授:黃旭山黃旭山引用關係
指導教授(外文):Huang, Hsu-Shan
口試委員:林敬哲顧記華林本元
口試日期:2013-05-21
學位類別:碩士
校院名稱:國防醫學院
系所名稱:藥學研究所
學門:醫藥衛生學門
學類:藥學學類
論文種類:學術論文
論文出版年:2013
畢業學年度:101
語文別:中文
論文頁數:166
中文關鍵詞:茚并[12-c]喹啉-11-酮抗癌
外文關鍵詞:Indeno[1,2-c]quinolin-11-oneAnticancer
相關次數:
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自1966年喜樹鹼 (camptothecin) 被發現以來,一系列indeno[1,2-c]quinolin-11-one衍生物被發現具有抑制第一型拓樸異構酶的活性。本篇論文的研究目的即在合成新穎且有效的小分子化合物,以期對癌症治療藥物的發展上有所幫助。於是合成26個具有四個平面環的結構並將不同的取代基團整合進來取代在C-6位置上,例如氨基和硫醇基。SRB實驗測試其抑制PC-3細胞株生長活性;topoisomerase I drug screening實驗測試其相較於camptothecin抑制topoisomerase I 活性;送交美國癌症研究中心測試60種不同癌症類型細胞株的體外細胞抗癌活性。SRB和topoisomerase I drug screening結果顯示SJ-11較camptothecin具強效的抑制topoisomerase活性;由美國癌症中心選中的14個化合物於單一劑量10μM下,其中SJ-3與SJ-10的mean GI% 分別為62.4, -14.37,進階被選為5個劑量的實驗。雖然我們對此類化合物具毒殺癌症細胞、抑制第一型拓樸異構酶的藥效機轉仍未完全了解,但這些衍生物仍然擁有明顯抑制癌細胞生長的能力、抑制第一型拓樸異構酶的活性。
Since the discovery of camptothecin in 1966, a series of indeno[1,2-c]quinolin-11-one derivatives had been found to be potential DNA topoisomerase I inhibition drugs. The purpose of this research is to synthesize novel and effective small molecular compounds and to evaluate their biological effects on antitumor activity for future drug development. Our study synthesized different amino and thiol side chains to substituents at C-6 of the pharmacorphore tetracyclic structure system. The obtained compounds were evaluated by sulforhodamine B (SRB) assay, topoisomerase I drug screening, and also evaluated for their in vitro antitumor activity through the National Cancer Institute (NCI) 60 cancerous cell lines panel assay. Results of SRB and topoisomerase I drug screening showed SJ-11 to have better cytotoxicity and inhibition of topoisomerase I than camptothecin. Results of NCI selected 14 compounds showed that SJ-3 and SJ-10 had potent anticancer activity (mean GI% = 62.4, -14.37, respectively) under one-dose (10 μM ) screening, and they were selected for further experimentation, utilizing a five-dose level screening. Although the exact pharmaceutical mechanisms of synthesized compounds are not well known, these derivatives still possess obvious cytotoxicity effects on cancerous cell lines, as well as inhibition of topoisomerase I activity.
總目錄
正文目錄 --------------------------------------------------------------------------------- II
表目錄 ----------------------------------------------------------------------------------- IV
圖目錄 ----------------------------------------------------------------------------------- V
附圖目錄 --------------------------------------------------------------------------------- VIII
中文摘要 --------------------------------------------------------------------------------- XI
英文摘要 --------------------------------------------------------------------------------- XII

正文目錄
第一章、緖論 ------------------------------------------------------------------------------ 1
第一節、 前言---------------------------------------------------------------------------- 1
壹、第一型拓樸異構酶 (Type I Topoisomerase) --------------------------------------------- 2
貳、第一型拓樸異構酶抑制劑 (Type I Topoisomerase Inhibitor) ------------------------------ 4
參、茚并異喹啉 / 茚并喹啉 (Indenoisoquinoline / Indenoquinoline) 衍生物文獻回顧------------- 7
第二節、 研究目的------------------------------------------------------------------------- 21
第三節、 藥物設計原理---------------------------------------------------------------------- 23
第二章、實驗部分---------------------------------------------------------------------------- 28
第一節、儀器與材料------------------------------------------------------------------------ 28
壹、實驗儀器----------------------------------------------------------------------------28
貳、化學試藥來源------------------------------------------------------------------------ 29
參、化學合成實驗方法 -------------------------------------------------------------------- 30
第二節、 藥理活性實驗 --------------------------------------------------------------------- 33
壹、Sulforhodamine B (SRB) Assay ----------------------------------------------------- 33
貳、Topoisomerase I Drug Screening --------------------------------------------------- 34
參、美國癌症研究中心(National Cancer Institute)癌細胞株毒殺試驗------------------------------37
第三章、實驗結果 --------------------------------------------------------------------------- 39
第一節、化學合成結果 ---------------------------------------------------------------------- 40
第二節、藥理實驗結果 -----------------------------------------------------------------------66
壹、Sulforhodamine B (SRB) Assay實驗結果----------------------------------------------- 66
貳、Topoisomerase I Drug Screening實驗結果--------------------------------------------- 68
參、美國癌症研究中心 (National Cancer Institute) 癌細胞株毒殺試驗實驗結果---------------------69
第四章、實驗討論---------------------------------------------------------------------------- 82
第一節、化學合成討論 ---------------------------------------------------------------------- 82
壹、TC-XCL-1 (6,9-dichloro-11H-indeno[1,2-c]quinolin-11-one) 衍生物的探討--------------- 82
貳、實驗過程中所使用的催化劑討論----------------------------------------------------------- 83
参、 側鏈取代基團的比較------------------------------------------------------------------ 86
第二節、 藥理結果討論 --------------------------------------------------------------------- 88
壹、Sulforhodamine B (SRB) Assay之實驗討論---------------------------------------------- 88
貳、Topoisomerase I Drug Screening之實驗討論-------------------------------------------- 90
參、美國癌症研究中心 (National Cancer Institute) 對癌細胞株篩選結 果討論--------------------- 91
第五章、 結論 ----------------------------------------------------------------------------- 92
第六章、參考文獻 --------------------------------------------------------------------------- 95

表目錄
表1、11H-indeno[1,2-c]quinolone-11-one derivatives抗癌活性分析------------------------------ 14
表2、化合物25g及其衍生物25h-i對leukemia cell的毒殺性------------------------------------------- 16
表3、化合物28j-o之IC50 cytotoxicity (μM) 及topo I activity---------------------------------- 18
表4、C-6取代的9-methoxy-11H-indeno[1,2-c]quinoline衍生物抗癌活性------------------------------ 27
表5、SRB assay 結果 (I)-------------------------------------------------------------------- 66
表6、SRB assay 結果 (II)------------------------------------------------------------------- 67
表7、化合物TC-XCL-1及SJ-1至SJ-25熔點及產率比較------------------------------------------------- 84

圖目錄
圖1、NSC 314622結構------------------------------------------------------------------------- 2
圖2、DNA的複製與拓樸異構酶之作用---------------------------------------------------------------- 3
圖3、Camptothecin結構----------------------------------------------------------------------- 5
圗4、 Camptothecin和Type I Topoisomerase之氫鍵作用-------------------------------------------- 6
圖5、Camptothecin-Type I Topoisomerase-DNA三複合體------------------------------------------- 6
圖6、 Topotecan結構------------------------------------------------------------------------- 7
圖7、Irinotecan結構------------------------------------------------------------------------- 7
圖8、TAS-103結構---------------------------------------------------------------------------- 7
圖9、 NSC 725776、NSC 724998結構------------------------------------------------------------- 9
圖10、由3-arylisoquinolines合成indeno[1,2-c]isoquinolines概要圖------------------------------- 9
圖11、化合物5-(2-aminoethylamino)-11H-indeno[1,2-c]isoquinolin-11-one合成步驟圖--------------- 11
圖12、MJ238結構----------------------------------------------------------------------------- 11
圖13、化合物5-(2-aminoethylamino)-11H-indeno[1,2-c]isoquinolin-11-one(compound 2) 與MJ238之
superimpose、docking------------------------------------------------------------------ 11
圖14、化合物5-(2-aminoethylamino)-11H-indeno[1,2-c]isoquinolin-11-one(compound 2) 之docking
model--------------------------------------------------------------------------------- 12
圖15、茚并喹啉 (indeno[1,2-c]quinoline) 衍生物合成步驟------------------------------------------ 13
圖16、化合物25g (TAS-103) 及其衍生物25h、25i合成步驟--------------------------------------------- 15
圖17、化合物25g及其衍生物25i抑制topoisomerase I之結果-------------------------------------------- 15
圖18、化合物28j-o、29j-o合成步驟--------------------------------------------------------------- 17
圖19、化合物28j-o、29j-k對於topoisomerase I之抑制情形-------------------------------------------- 18
圖20、化合物28o平行嵌合於DNA中------------------------------------------------------------------ 19
圖21、化合物28o正上方俯看圖--------------------------------------------------------------------- 20
圖22、化合物28o docking圖--------------------------------------------------------------------- 20
圖23、Quinoline、Indenoisoquinoline、Indenoquinoline結構-------------------------------------- 22
圖24、Indenoisoquinoline類衍生物-------------------------------------------------------------- 25
圖25、(i) Pfitzinger reaction 及 (ii) Friedel-Crafts acylation ------------------------------ 25
圖26、9-methoxy-11H-indeno[1,2-c]quinolone-11-one 衍生物合成圖--------------------------------- 26
圖27、MJ-238和DNA docking圖------------------------------------------------------------------- 26
圖28、TC-XCL-1 結構--------------------------------------------------------------------------- 27
圖29、化學合成之反應概要------------------------------------------------------------------------- 30
圖30、藥物抑制topoisomerase I的機轉------------------------------------------------------------- 36
圖31、被美國NCI機構初步篩選出之十四個化合物結構------------------------------------------------------ 38
圖32、被美國NCI機構篩選進入第二階段毒殺試驗之二個化合物結構---------------------------------------------38
圖33、SRB assay之toxicity趨勢圖---------------------------------------------------------------- 67
圖34、由SRB assay結果挑選四個化合物做topoisomerase I drug screening ------------------------------ 68
圖35、SJ-11做topoisomerase I drug screening dose dependent test ------------------------------ 68
圖36、TC-XCL-1 (NSC 773969)之NCI癌細胞株的毒殺試驗結果-------------------------------------------- 69
圖37、SJ-1 (NSC 772856) 之NCI癌細胞株的毒殺試驗結果----------------------------------------------- 70
圖38、SJ-2 (NSC 771781) 之NCI癌細胞株的毒殺試驗結果----------------------------------------------- 70
圖39、SJ-3 (NSC 772864) 之NCI癌細胞株的毒殺試驗結果----------------------------------------------- 71
圖40、SJ-6 (NSC 772860) 之NCI癌細胞株的毒殺試驗結果----------------------------------------------- 71
圖41、SJ-8 (NSC 771782) 之NCI癌細胞株的毒殺試驗結果----------------------------------------------- 72
圖42、SJ-9 (NSC 772857) 之NCI癌細胞株的毒殺試驗結果----------------------------------------------- 72
圖43、SJ-10 (NSC 772862) 之NCI癌細胞株的毒殺試驗結果---------------------------------------------- 73
圖44、SJ-12 (NSC 771783) 之NCI癌細胞株的毒殺試驗結果---------------------------------------------- 73
圖45、SJ-14 (NSC 772859) 之NCI癌細胞株的毒殺試驗結果---------------------------------------------- 74
圖46、SJ-16 (NSC 772861) 之NCI癌細胞株的毒殺試驗結果---------------------------------------------- 74
圖47、SJ-20 (NSC 772863) 之NCI癌細胞株的毒殺試驗結果---------------------------------------------- 75
圖48、SJ-23 (NSC 772858) 之NCI癌細胞株的毒殺試驗結果---------------------------------------------- 75
圖49、SJ-25 (NSC 765596) 之NCI癌細胞株的毒殺試驗結果---------------------------------------------- 76
圖50、TC-XCL-1、SJ-1、SJ-2 之NCI數據----------------------------------------------------------- 77
圖51、SJ-3、SJ-6、SJ-8 之NCI數據--------------------------------------------------------------- 78
圖52、SJ-9、SJ-10、SJ-12 之NCI數據------------------------------------------------------------- 79
圖53、SJ-14、SJ-16、SJ-20 之NCI數據------------------------------------------------------------ 80
圖54、SJ-23、SJ-25 之NCI數據------------------------------------------------------------------- 81
圖55、TC-XCL-1衍生物的探討---------------------------------------------------------------------- 82
圖56、TC-XCL-1進行親核性取代反應機制-------------------------------------------------------------- 83

附圖目錄
附圖1、化合物 TC-XCL-1 之1H-NMR, 13C-NMR圖譜---------------------------------------------------- 101
附圖2、化合物 TC-XCL-1 之MASS, IR圖譜----------------------------------------------------------- 102
附圖3、化合物 SJ-1 之1H-NMR, 13C-NMR圖譜-------------------------------------------------------- 103
附圖4、化合物 SJ-1 之MASS, IR圖譜--------------------------------------------------------------- 104
附圖5、化合物 SJ-2 之1H-NMR, 13C-NMR圖譜 ------------------------------------------------------- 105
附圖6、化合物 SJ-2 之MASS, IR圖譜--------------------------------------------------------------- 106
附圖7、化合物 SJ-3 之1H-NMR, 13C-NMR圖譜 ------------------------------------------------------- 107
附圖8、化合物 SJ-3 之MASS, IR圖譜--------------------------------------------------------------- 108
附圖9、化合物 SJ-4 之1H-NMR, 13C-NMR圖譜 ------------------------------------------------------- 109
附圖10、化合物 SJ-4 之MASS, IR圖譜-------------------------------------------------------------- 110
附圖11、化合物 SJ-5 之1H-NMR, 13C-NMR圖譜 ------------------------------------------------------ 111
附圖12、化合物 SJ-5 之MASS, IR圖譜-------------------------------------------------------------- 112
附圖13、化合物 SJ-6 之1H-NMR, 13C-NMR圖譜 ------------------------------------------------------ 113
附圖14、化合物 SJ-6 之MASS, IR圖譜-------------------------------------------------------------- 114
附圖15、化合物 SJ-7 之1H-NMR, 13C-NMR圖譜 ------------------------------------------------------ 115
附圖16、化合物 SJ-7 之MASS, IR圖譜-------------------------------------------------------------- 116
附圖17、化合物 SJ-8 之1H-NMR, 13C-NMR圖譜 ------------------------------------------------------ 117
附圖18、化合物 SJ-8 之MASS, IR圖譜-------------------------------------------------------------- 118
附圖19、化合物 SJ-9 之1H-NMR, 13C-NMR圖譜 ------------------------------------------------------ 119
附圖20、化合物 SJ-9 之MASS, IR圖譜-------------------------------------------------------------- 120
附圖21、化合物 SJ-10 之1H-NMR, 13C-NMR圖譜 ----------------------------------------------------- 121
附圖22、化合物 SJ-10 之MASS, IR圖譜------------------------------------------------------------- 122
附圖23、化合物 SJ-11 之1H-NMR, 13C-NMR圖譜 ----------------------------------------------------- 123
附圖24、化合物 SJ-11 之MASS, IR圖譜------------------------------------------------------------- 124
附圖25、化合物 SJ-12 之1H-NMR, 13C-NMR圖譜------------------------------------------------------ 125
附圖26、化合物 SJ-12 之MASS, IR圖譜------------------------------------------------------------- 126
附圖27、化合物 SJ-13 之1H-NMR, 13C-NMR圖譜 ----------------------------------------------------- 127
附圖28、化合物 SJ-13 之MASS, IR圖譜------------------------------------------------------------- 128
附圖29、化合物 SJ-14 之1H-NMR, 13C-NMR圖譜 ----------------------------------------------------- 129
附圖30、化合物 SJ-14 之MASS, IR圖譜------------------------------------------------------------- 130
附圖31、化合物 SJ-15 之1H-NMR, 13C-NMR圖譜 ----------------------------------------------------- 131
附圖32、化合物 SJ-15 之MASS, IR圖譜------------------------------------------------------------- 132
附圖33、化合物 SJ-16 之1H-NMR, 13C-NMR圖譜 ----------------------------------------------------- 133
附圖34、化合物 SJ-16 之MASS, IR圖譜------------------------------------------------------------- 134
附圖35、化合物 SJ-17 之1H-NMR, 13C-NMR圖譜 ----------------------------------------------------- 135
附圖36、化合物 SJ-17 之MASS, IR圖譜------------------------------------------------------------- 136
附圖37、化合物 SJ-18 之1H-NMR, 13C-NMR圖譜 ----------------------------------------------------- 137
附圖38、化合物 SJ-18 之MASS, IR圖譜------------------------------------------------------------- 138
附圖39、化合物 SJ-19 之1H-NMR, 13C-NMR圖譜 ----------------------------------------------------- 139
附圖40、化合物 SJ-19 之MASS, IR圖譜------------------------------------------------------------- 140
附圖41、化合物 SJ-20 之1H-NMR, 13C-NMR圖譜 ----------------------------------------------------- 141
附圖42、化合物 SJ-20 之MASS, IR圖譜------------------------------------------------------------- 142
附圖43、化合物 SJ-21 之1H-NMR, 13C-NMR圖譜 ----------------------------------------------------- 143
附圖44、化合物 SJ-21 之MASS, IR圖譜------------------------------------------------------------- 144
附圖45、化合物 SJ-22 之1H-NMR, 13C-NMR圖譜 ----------------------------------------------------- 145
附圖46、化合物 SJ-22 之MASS, IR圖譜------------------------------------------------------------- 146
附圖47、化合物 SJ-23 之1H-NMR, 13C-NMR圖譜 ----------------------------------------------------- 147
附圖48、化合物 SJ-23 之MASS, IR圖譜------------------------------------------------------------- 148
附圖49、化合物 SJ-24 之1H-NMR, 13C-NMR圖譜 ----------------------------------------------------- 149
附圖50、化合物 SJ-24 之MASS, IR圖譜------------------------------------------------------------- 150
附圖51、化合物 SJ-25 之1H-NMR, 13C-NMR圖譜 ----------------------------------------------------- 151
附圖52、化合物 SJ-25 之MASS, IR圖譜------------------------------------------------------------- 152
附圖53、化合物 TC-XCL-1 之NCI篩選數據 ----------------------------------------------------------- 153
附圖54、化合物 SJ-1 之NCI篩選數據 --------------------------------------------------------------- 154
附圖55、化合物 SJ-2 之NCI篩選數據 --------------------------------------------------------------- 155
附圖56、化合物 SJ-3 之NCI篩選數據 --------------------------------------------------------------- 156
附圖57、化合物 SJ-6 之NCI篩選數據 --------------------------------------------------------------- 157
附圖58、化合物 SJ-8 之NCI篩選數據 --------------------------------------------------------------- 158
附圖59、化合物 SJ-9 之NCI篩選數據 --------------------------------------------------------------- 159
附圖60、化合物 SJ-10 之NCI篩選數據 -------------------------------------------------------------- 160
附圖61、化合物 SJ-12 之NCI篩選數據 -------------------------------------------------------------- 161
附圖62、化合物 SJ-14 之NCI篩選數據 -------------------------------------------------------------- 162
附圖63、化合物 SJ-16 之NCI篩選數據 -------------------------------------------------------------- 163
附圖64、化合物 SJ-20 之NCI篩選數據 -------------------------------------------------------------- 164
附圖65、化合物 SJ-23 之NCI篩選數據 -------------------------------------------------------------- 165
附圖66、化合物 SJ-25 之NCI篩選數據 -------------------------------------------------------------- 166

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