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研究生:陳惠亭
研究生(外文):Chen, Hui-ting
論文名稱:Indolo[2,1-b]quinazolin-6,12-dione衍生物作為抗癌藥物之設計與合成
論文名稱(外文):Design and Synthesis of Indolo[2,1-b]quinazolin-6,12-dione Derivatives as Potential Antitumor Agents
指導教授:陳基旺陳基旺引用關係
指導教授(外文):Chern, Ji-wang
學位類別:博士
校院名稱:國立臺灣大學
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:2000
畢業學年度:88
語文別:中文
論文頁數:230
中文關鍵詞:抗癌藥物多重抗藥性逆轉劑DNA結合劑參股螺旋
外文關鍵詞:TryptanthrinAntitumor agentmulti-drugs resistance (MDR)reversal agentDNA binderTriple helix
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本論文乃以天然物tryptanthrin (1) 為結構主體作為抗癌藥物之設計與合成,並探討其細胞毒性及作用機理。Tryptanthrin (indolo[2,1-b]quinazolin- 6,12-dione) 為含N-phenylquinazoline的四環共面結構;具有類似2-phenylnaphthalene之架構者,已被發現廣泛存於各種活性化合物中,若非共平面結構則使活性降低或甚至喪失。例如具2-phenyl-quinolone結構的抗癌化合物batracylin,可抑制多種癌細胞且有毒殺作用。因此引發我們對tryptanthrin進行結構修飾作為抗癌藥物之骨架並導入參股螺旋(triple helice) 穩定劑 benzo[e]pyridoindole (3)所具有的側鏈希望其能成為有潛力的DNA結合劑。運用文獻方法可便於合成tryptanthrin及其衍生物,但由於該分子對溶劑之溶解度不佳,使得直接對其進行官能基轉換困難,因此須先製備各類已進行烷基化的isatoic anhydrides和isatins再進一步縮合得到具側鏈取代的tryptanthrin衍生物。最後成功製備二十七種不同取代的tryptanthrin衍生物並進行生物活性測試。分別對HeLa,MCF7,MCF7/adr ,A498和Skov3等細胞株進行細胞毒性試驗,導入取代基確活性有所助益,除了2,3-dimethoxtryptanthrin (53) 及具側鏈的化合物205外。具dicyanomethylene取代的三衍生物中僅有6,12-Dihydro-6-(dicyanomethylene)-12-oxoindolo [2,1-b]quinazoline (72)具有活性;4-azatryptanthrin (70) 則對MCF7、MCF7/adr、A498和Skov3四種細胞株有較高的活性。其他不具細胞毒性之化合物則發現具有逆轉抗藥性之效。選取化合物1和2-chloro-6,12-dihydro-6-(dicyanomethylene)-12-oxoindolo [2,1-b]quinazoline (75) 作進一步的逆轉機轉探討,意外的發現兩類化合物具有不同的機制:化合物1主要抑制P-gp的過度表現而化合物75則影響mutidrug resistant-related protein (MRP) 之過度表現。另外,由電腦分子模擬觀察含不同側鏈取代之衍生物與DNA的結合情形,更以DNA熔點 (Tm) 測試探討具側鏈之衍生物 205的確對於DNA具有穩定作用更可提高參股螺旋DNA的安定性。綜合以上所言,tryptanthrins各類衍生物可經由結構修飾而達到抗癌效果,部分可直接抑制癌細胞生長或部分可作為逆轉抗藥性活性之發揮;更可透過極性側鏈的加成而對雙股或參股DNA具有穩定之功。顯然tryptanthrin及其衍生物極有潛力成為新一類抗癌藥物之前驅物。
This thesis is aimed to design and synthesize tryptanthrin and its analogs as potential anticancer agents. Tryptanthrin (1), indolo[2,1-b]quinazolin-6,12-dione, is a coplanar four-fused ring compound which contains N-phenylquinazoline skeleton similar to 2-phenylnaphthalene. It was illustrated that compounds containing coplanar 2-phenylnaphthalene skeletons exhibit different biological activities such as, ellipticine, camptothecin, while the bioactivities would be decreased or lost in unplanar structures. For example, batracylin, containing 2-phenyl-quinolone skeleton, inhibits the growth of several carcinoma cell growth. The results draw our attention to develop tryptanthrin and its derivatives as potent anticancer agents. Furthermore, the side chain of benzo[e]pyridoindole (3), a DNA binder, was also introduced to tryptanthrin derivatives in order to strengthen its ability of stabilizing of triple helices DNA. There are several methods available in the literature for the synthesis of tryptanthrin and its derivatives. However, the poor solubility is still the large obstruction of its synthesis. First of all, the desired alkyl isatoic anhydrides and isatins were synthesized. Thereafter, a condensation of the above two moieties gives desired tryptanthrin derivatives. In total, 27 different substituted tryptanthrins were synthesized for biological assay. In the cytotoxic assay against HeLa, MCF7, MCF7/adr, A498and Skov3 cell lines, most of the substituted tryptanthrin analogs shows the best cytotoxicity than tryptanthrin, but 2,3dimethoxytryptanthrin (53) and Tryptanthrin 205 are exception. 12-Dihydro-6-(dicyanomethylene)-12-oxoindolo [2,1-b]quinazoline (72) is the only one active agnet in three containing dicyanomethylene droup derivatives. 4-Azatryptanthrin (70) is more selectively against MCF7, MCF7/adr, A498 and Skov3 than HeLa cell. The other compounds without cytotoxicity are found to be reversal agents of some anticancer drugs and the further research result show that the reversal mechanism of 1 and 2-chloro-6,12-dihydro-6-(dicyanomethylene)-12-oxoindolo[2,1-b]quinazoline (75) are quite different. Compound 1 inhibits the overexpression of P-gp but 75 inhibits the overexpression of mutidrugs resistant-related protein (MRP). Moreover, both computer modeling and Tm experiment revealed that the substituted tryptanthrin analog 205 does stabilize not only duplex DNA but also triplex DNA. Overall, tryptanthrin derivatives demonstrate either the inhibition of cancer cell lines or reversion of mulitidrugs-resistant cancer cell lines, and the derivatives with polar side chain show the better ability to stabilize duplex or triplex DNA. Therefore, tryptanthrin and its analog are a new class of compounds possessing potential activity.
封面
章節目錄
中文摘要
Abstract
第一章序論
第二章Indolo[2,1-b]quinazolin-6,12-dione類似物作為抗癌藥物之合成與研究
第一節設計動機
第二節合成策略
第三節合成結果與討論
Indolo[2,1-b]quinazolin-6,12-dione及其衍生物之合成與討論
6,12-Dihydro-6-(dicyanomethylene)-12-oxoindolo[2,1-b]quinazoline及其類似物之合成與討論
6-Dihydrotryptanthrins之合成與討論
側鏈之Tryptanthrins之合成與討論
第四節細胞毒性測試討論
第五節實驗部份
第三章Tryptanthrin類似物作為MDR逆轉劑之研究
第一節多重抗藥性及多重抗藥性的逆轉作用
產生多重抗藥性之機轉
多重抗藥性的逆轉
第二節結果與討論
第四章Tryptanthin類似物作為DNA結合劑之研究
第一節設計動機
第二節電腦模擬探討
第三節DNA熔點測試與討論
第四節實驗部分
第五章結論
第六章參考文獻
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1. 陳英偉,<呼喚台灣的原鄉文化>,《現代美術》1996年10月。
2. 陳瑞文,<藝術批評的向度---阿多諾的美學架構>,《炎黃藝術》74期,1985年1月。
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11. 汪亞塵,<繪畫的鑑賞與批評>,《藝術家》251號。
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15. 王福東,<新生代美術再議>,《雄獅美術》259期,1992年10月。