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研究生:張昱勛
研究生(外文):Yu-Hsun Chang
論文名稱:2-(3-苯[b]噻吩)-6,7-亞甲二氧基喹啉-4-酮類緣物的設計、合成與抗癌活性、4-苯基-1H-苯[b][1,4]二氮雜環-2(3H)-酮衍生物的設計、合成與生物活性
論文名稱(外文):I. Design, synthesis and anticancer activity of 2-(3-Benzo[b]thienyl)-6,7-methylenedioxyquinolin-4-one analogs.II. Design, synthesis and biological activity of 4-phenyl-1H-benzo[b][1,4]diazepin-2(3H)-one derivatives.
指導教授:郭盛助郭盛助引用關係
學位類別:博士
校院名稱:中國醫藥大學
系所名稱:藥物化學研究所博士班
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:2009
畢業學年度:97
語文別:中文
論文頁數:299
中文關鍵詞:-4-酮凋亡微管
外文關鍵詞:2-phenyl-4-quinolonecombretastatin A-4apoptosismicrotubule
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Part I.
由於azo-flavonoids 的優異抗癌活性,本實驗室參考之前的實驗成果,整合2-(2-fluorophenyl)-6,7-methylenedioxyquinolin-4-one (CHM-2133)的6,7-methylenedioxy 基團結構與CoMFA 計算模型中的2位雜環概念,設計、合成出一系列新的2-aryl-6,7-methylenedioxyquinolin-4-one類緣物,之後以數種人類腫瘤細胞作為細胞毒性測試對象,建立出各個化合物結構和藥理活性間的關係。結果顯示,衍生物1、37及39展現出強效的抗癌能力,其中化合物1對Hep 3B 表現出選擇活性,而化合物37對HL-60、HCT-116、Hep 3B及KB-VIN等細胞呈現優異的抑制效果,至於化合物39則是對各個細胞株皆顯現出廣泛的毒殺作用,且IC50濃度介於0.07−0.19 μM間。而從微管的作用測試也證實,該系列新quinolone衍生物仍保有抗微管聚合的良好能力。

接續藥物結構和活性關係間的研究,CWC-8 (化合物39)被選為進一步探討抗癌活性機轉的藥物,過程中以U-2 OS骨癌細胞作為測試對象。根據MTT的結果顯示,CWC-8對U-2 OS的抑制有劑量及時間依存性的關係,其IC50濃度為4.97±0.24 μM,而在流式細胞儀的檢驗中,CWC-8也表現出它對細胞週期G2/M arrest與apoptosis的現象,之後於CDK1 kinase和western blotting試驗裡,則呈現CDK1酵素活性提昇、CDK1、Fas/CD95、FADD、cytosolic cytochrome c、caspase-8/-9/-3 active form、Apaf-1、AIF、Bax等蛋白質含量增加但Bcl-2下降之凋亡效果,此外,在caspase-8/-9/-3和其對應酵素抑制劑的混合試驗中,pan-caspase及caspase-8/-9/3 inhibitors皆有反轉CWC-8細胞毒性的能力。總合相關試驗的結果顯示,CWC-8擁有發展為抗癌藥物的潛在條件。

Part II.
蛋白質本身的mobility特性,長久以來在藥物設計領域中一直被忽略,構形誘導是ligand與目標蛋白相互作用時所形成的一種能量平衡過程,它在期間所產生的構形變化並不會自發性地出現在未和ligand結合時的平常狀態,由於蛋白質的這種彈性特性,普遍限制了現今合理藥物設計模式的發展。因此,我們在研究中提出,增加ligand結構彈性可以迎合目標蛋白變動性質的策略觀點,之後以本實驗室先前的抗腫瘤化合物2-phenyl-4-quinolones為基礎骨架,合成出相對具有flexibility特性之4-phenyl-1H-benzo[b][1,4]diazepin-2(3H)-one系列闊環衍生物。出乎預期的,該類化合物在體外細胞毒性篩選試驗結果中,並無明顯的抗癌活性,僅有化合物7-4、7-5、7-9、7-15、7-16、7-20及7-27等對HL-60細胞株展現程度上的抑制效果。雖說在抗癌測試上不盡理想,不過化合物7-4卻在random screening測試中另外發現其抑制細胞發炎的能力,它主要是是透過PKA-dependent pathway來達到抑制經fMLP誘導生成的superoxide anion,同時它還能活化protein phosphatase 2A酵素而使得phosphodiesterase 4之活性被抑制,進而提昇cAMP濃度的作用。
Part I.
As part of our continuing investigation of azo-flavonoid derivatives as potential anticancer drug candidates, a series of 2-aryl-6,7-methylenedioxyquinolin-4-one analogs was designed and synthesized. The design combined structural features of 2-(2-fluorophenyl)-6,7-methylenedioxyquinolin-4-one (CHM-2133), a previously discovered compound with potent in vivo antitumor activity, and 2-arylquinolin-4-ones identified by CoMFA models. The newly synthesized analogs were evaluated for cytotoxicity against several human cancer cell lines, and structure-activity relationship (SAR) correlations were established. Analogs 1, 37, and 39 showed potent cytotoxicity against different cancer cell lines. Compound 1 demonstrated selective cytotoxicity against Hep 3B (hepatoma) cells. Compound 37 was cytotoxic against HL-60 (leukemia), HCT-116 (colon cancer), Hep 3B (hepatoma), and SK-MEL-5 (melanoma) cells. Compound 39 exhibited broad cytotoxicity against all seven cancer cell lines, with IC50 values between 0.07−0.19 μM. Results from mechanism of action studies revealed that these new quinolone derivatives function as anti-tubulin agents.

Continuing with the screening result, CWC-8 (compound 39) was chosen to detect the mechanism of anticancer activity in the experiment. We have defined the viability inhibition and apoptotic mechanisms of CWC-8 on human osteogenic sarcoma U-2 OS cells. According to the MTT assay, the cell viability was inhibited by CWC-8 in a dose- and time-dependent manner, with an IC50 of 4.97±0.24 μM. CWC-8 treatment induced G2/M arrest and apoptosis in U-2 OS cells by cell cycle and flow cytometry analysis. Western blotting and CDK1 kinase assay showed that CWC-8 treatment caused a time-dependent increase of Cyclin B and CDK1 protein levels and activity during G2/M arrest. CWC-8 treatment also caused a time-dependent increase in Fas/CD95, FADD, cytosolic cytochrome c, caspase-8/-9/-3 active form, Apaf-1, AIF, Bax protein levels, and decrease in Bcl-2 protein level. CWC-8 also promoted caspase-8/-9 and -3 activities; however, pretreatment of cells with pan-caspase, caspase-8/-9 and -3 inhibitors led to reduced cell growth inhibition action. Taken together, these findings show CWC-8 could be a potential candidate for cancer therapy.

Part II.
The intrinsic mobility of proteins has often been ignored in drug design field. Conformational induction is the energy balance process in which ligand converts protein into a conformation that would not spontaneously adopt in its unligated state. This flexible property of protein limits the development of rational drug design model nowadays. Therefore, we proposed a concept that describes raise of ligand flexibility is the strategy to accommodate protein mobility. In this study, we synthesized a series of 4-phenyl-1H-benzo[b][1,4]diazepin-2(3H)-one derivatives which are more flexible than our previous antitumor compound− 2-phenyl-4-quinolones. Unexpectedly, the cytotoxicity screening result shows little activity of these derivatives. Only 7-4, 7-5, 7-9, 7-15, 7-16, 7-20 and 7-27 compounds exhibt the potency to inhibt HL-60 cell line. Despite the unideal outcome in anti-cancer test, we acquired the anti-inflammation activity of compound 7-4 via random screening insteadly. It inhibited fMLP-induced superoxide anion production through a PKA-dependent pathway and increased cAMP by activating protein phosphatase 2A, which subsequently inhibited phosphodiesterase 4.
附圖目錄................................................................................................................................. 5
縮寫表................................................................................................................................... 13
Part I 2-(3-Benzo[b]thienyl)-6,7-methylenedioxyquinolin-4-one類緣物的設計、合成與抗癌活性............................................................................................................................... 14
中文摘要............................................................................................................................... 15
Abstract ................................................................................................................................. 16
第一章 緒論.......................................................................................................................... 18
第一節 癌症治療之發展概況 ......................................................................................... 18
第二節 細胞凋亡(Apoptosis)現象與癌細胞的增殖能力.............................................. 19
第三節 微管概述 ............................................................................................................. 21
第四節 2-Aryl-4-quinolones相關研究與其抗癌活性之探討....................................... 24
第五節 加速先導藥物開發的電腦輔助軟體 ................................................................. 25
一、Target structure-based程式的Rational Drug Design應用原理.......................26
二、Ligand-based程式的藥效基團找尋原理.........................................................28
第二章 研究動機與目的...................................................................................................... 30
第三章 實驗器材與方法...................................................................................................... 32
第一節 化學合成器材 ..................................................................................................... 32
一、化學反應試劑 ....................................................................................................32
二、純化耗材和分析儀器 ........................................................................................32
第二節 化學合成方法 ..................................................................................................... 32
一、Arylcarbonyl chlorides (14−24, 61−64)原料的製備.........................................34

二、Carboxamides (25−35, 55, 65−68)中間體的製備.............................................34
三、以方法A.製備2-aryl-6,7-methylenedioxyquinolin-4-ones (1, 37−44) ............34
四、以方法B.製備2-aryl-6,7-methylenedioxyquinolin-4-ones (1, 36, 39, 45, 69, 70)及4-methyl-6,7-methylenedioxy-3-(1-naphthyl)quinolin-2-one (56)...........35
五、去乙醯化產物46−53的意外生成條件............................................................35
第三節 藥理實驗步驟 ..................................................................................................... 35
一、3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays.35
二、Sulforhodamine B (SRB) assays ........................................................................36
三、Tubulin assays ....................................................................................................36
四、The human osteogenic sarcoma cell (U-2 OS)細胞毒性試驗...........................36
五、Propidium iodide (PI)染色法偵測細胞週期與細胞凋亡現象.........................37
六、CWC-8藥理機轉之tubulin濁度試驗.............................................................37
七、Western blotting assay ........................................................................................37
八、Caspase-8、-9和-3的酵素活性測試...............................................................38
九、CDK1 kinase酵素活性測試..............................................................................38
十、統計學分析 ........................................................................................................38
第四章 結果與討論.............................................................................................................. 39
第一節 化合物的物理性質及光譜資訊 ......................................................................... 39
一、Carboxamides (25−35, 55, 65−68).....................................................................39
二、以方法A.製備2-aryl-6,7-methylenedioxyquinolin-4-ones (1, 37−44) ............45
三、以方法B.製備2-aryl-6,7-methylenedioxyquinolin-4-ones (1, 36, 39, 45, 69, 70)........................................................................................................................48
四、Deacetylation products 46−53............................................................................51
第二節 化合物的結構與體外細胞毒性試驗之探討 ..................................................... 63
一、Carboxamides (25−35、55、65−68).................................................................63

二、Deacetylation化合物(46−53) ............................................................................65
三、2-Aryl-6,7-methylenedioxyquinolin-4-ones (1, 36−45, 56, 69−70) 的IC50 (μM)體外細胞毒性與抗微管試驗.....................................................................65
第三節 以NCI COMPARE程式分析相關化合物之作用機轉.................................... 70
一、COMPARE原理................................................................................................70
二、Combretastatin、2-arylquinolin-4-ones、2-arylnaphthyridin-4-ones與2-(3-Benzo[b]furyl)- 6,7-methylenedioxyquinolin-4-one (化合物37)的COMPARE差異分析.........................................................................................72
第四節 化合物39 (CWC-8)生化藥理機轉.................................................................... 85
一、CWC-8 對U-2 OS細胞的毒性試驗...............................................................85
二、CWC-8對U-2 OS細胞週期與微管聚集之抑制試驗....................................86
三、CWC-8對細胞週期相關蛋白之影響試驗.......................................................88
四、CWC-8所造成的U-2 OS細胞凋亡現象和相關蛋白之表現研究................89
五、CWC-8對U-2 OS細胞凋亡酵素(caspase)影響之檢定試驗..........................90
六、抗微管藥物和內在凋亡路徑間的關連 ............................................................92
七、CWC-8對外在凋亡路徑的影響.......................................................................93
八、經CWC-8試驗推論U-2 OS為type II cell .....................................................93
第五章 結論.......................................................................................................................... 96
Part II 4-phenyl-1H-benzo[b][1,4]diazepin-2(3H)-one衍生物的設計、合成與生物活性............................................................................................................................................... 98
中文摘要............................................................................................................................... 99
Abstract ............................................................................................................................... 100
第一章 緒論........................................................................................................................ 101

第一節蛋白質的彈性(flexibility)觀念與藥物設計..................................................... 101
第二章 研究動機與目的.................................................................................................... 105
第三章 實驗器材與方法.................................................................................................... 107
第一節 化學合成器材 ................................................................................................... 107
一、化學反應試劑 ..................................................................................................107
二、純化耗材和分析儀器 ......................................................................................107
第二節 化學合成方法 ................................................................................................... 107
一、Substituted ethyl benzoylacetates的製備........................................................109
二、Substituted 4-phenyl-1H-benzo[b][1,4]diazepin-2(3H)-ones的製備, ...........109
三、反應失敗之七環benzazepine (scheme 3)與八環benzodiazocine (scheme 4)的合成方法....................................................................................................... 110
第三節 藥理實驗步驟 ................................................................................................... 110
第四章 結果與討論............................................................................................................ 111
第一節 化合物的物理性質及光譜資訊 ....................................................................... 111
第二節 化合物7-5和7-6的結構解析......................................................................... 123
一、8-Chloro-4-(3-chlorophenyl)-1H-benzo[b][1,4]diazepin-2(3H)-one (7-5) ......124
二、7-Chloro-4-(3-chlorophenyl)-1H-benzo[b][1,4]diazepin-2(3H)-one (7-6) ......131
三、其它同分異構物的分別 ..................................................................................138
第三節 化合物的結構與體外細胞毒性試驗之探討 ................................................... 138
第四節 化合物7-4之抗發炎活性................................................................................ 144
第五章 結論........................................................................................................................ 147
參考文獻.............................................................................................................................. 148
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1. 一、3',6-Substituted2-Phenyl-4-quinolone-3-carboxylicacid衍生物之合成及其抗癌、抗血小板、抗過敏與抗發炎活性二、生薑成分Gingerdione及Ferulamide衍生物之抗癌活性與抗幽門桿菌活性
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