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  本文關鍵詞： 噸酮 DNA作用 抗腫瘤活性 拓撲異構酶 抑制劑　出處：《河北大學》2014年碩士論文　論文類型：學位論文

【摘要】：惡性腫瘤已成為嚴重危害人類健康的主要疾病。隨著分子腫瘤學的發(fā)展，人類對惡性腫瘤發(fā)生、發(fā)展的機制逐步清晰�？鼓[瘤藥物的研發(fā)理念也發(fā)生了重大轉變—由傳統(tǒng)抗腫瘤藥物轉向靶向抗腫瘤藥物。DNA及其相關酶是抗腫瘤藥物的重要作用靶點，設計開發(fā)以DNA及其相關酶為靶點的抗腫瘤藥物極具發(fā)展前景。本工作選擇了具有良好生物和藥理活性的噸酮作為先導，合成了一系列帶有氨基側鏈的噸酮衍生物，并利用光譜技術、凝膠電泳分析、PCR實驗等方法系統(tǒng)地研究了它們和雙螺旋DNA的結合方式、結合強度以及對細胞增殖的影響與其側鏈結構因素等的關系。結果表明，柔性氨基側鏈的引入調(diào)控了化合物與DNA的結合方式和強度，并且不同的氨基側鏈可能改變化合物的極性，使化合物對腫瘤細胞增殖的抑制呈現(xiàn)出一定的差異。其中二甲胺基、吡咯烷基的引入顯著增強了噸酮與DNA的結合強度，并明顯提高了對腫瘤細胞的抑制能力。在此基礎上，利用凝膠電泳檢測了化合物對DNA拓撲異構酶(Topo)和Taq聚合酶活性的影響，結果顯示，化合物對DNA拓撲異構酶(Topo)和Taq聚合酶沒有抑制作用。 此外，還檢測并分析了課題組已有的抗腫瘤活性小分子CMCT、CMMT及51號硫色滿酮衍生物對DNA拓撲異構酶的抑制作用和機理。結果表明，，CMCT和CMMT是Top I的毒劑，且CMCT抑制作用強于CMMT；51號對Top I幾乎沒有抑制作用。CMCT是Top II的毒劑。
[Abstract]:With the development of molecular oncology, malignant tumor has become a major disease of human health. The mechanism of development has gradually become clear. The concept of development of antitumor drugs has also undergone a major change-from traditional anti-tumor drugs to targeted anti-tumor drugs. DNA and its related enzymes are important targets of antitumor drugs. The design and development of antitumor drugs targeting DNA and its related enzymes are very promising. In this work, a series of tonone derivatives with amino side chain were synthesized by selecting tonone with good biological and pharmacological activities as the lead. The binding mode of double helix DNA and the relationship between the binding strength and the influence of cell proliferation on the side chain structure were systematically studied by means of spectral technique and gel electrophoresis analysis. The introduction of the flexible amino side chain regulates the binding mode and intensity of the compound to DNA, and different amino side chains may change the polarity of the compound, and the inhibition of the compound on the proliferation of tumor cells is different. The introduction of pyrrolidine significantly enhanced the binding strength of tonone to DNA and the inhibition of tumor cells. On this basis, the effects of the compounds on the activity of DNA topoisomerase (Topo) and Taq polymerase were detected by gel electrophoresis. The results showed that the compounds had no inhibitory effect on DNA topoisomerase (Topo) and Taq polymerase. In addition, the inhibitory effect and mechanism of CMMT and thiolone derivatives on DNA topoisomerase were detected and analyzed. The results showed that CMCT and CMMT were toxic agents of Top I. The inhibitory effect of CMCT was stronger than that of CMMT.51 had little inhibitory effect on Top I. CMCT was a toxic agent of Top II.
【學位授予單位】：河北大學
【學位級別】：碩士
【學位授予年份】：2014
【分類號】：R917

【參考文獻】

相關期刊論文 前10條

1 甄啟雄,葉保輝,劉勁剛,計亮年,王雷;釕多吡啶配合物的合成及插入配體的位阻效應對鍵合DNA的影響[J];高等學�；瘜W學報;1999年11期

2 陳繪麗 ,楊頻;A Novel Cobalt(III) Mixed-polypyridyl Complex: Synthesis, Characterization and DNA Binding[J];Chinese Journal of Chemistry;2002年12期

3 李志良,陳建華,章開誠,李夢龍,俞汝勤;Schiff堿非鉑抗癌絡合物初步篩選的熒光法研究[J];中國科學(B輯 化學 生命科學 地學);1991年11期

4 黃鑫;劉玉欣;蘇立敏;郝德忠;崔世怡;楊更亮;;一種新硫色滿酮衍生物誘導人乳腺癌MCF-7細胞凋亡[J];科學通報;2012年08期

5 楊學東,徐麗珍,楊世林;遠志屬植物中釫酮類成分及其藥理研究進展[J];天然產(chǎn)物研究與開發(fā);2000年05期

6 宋玉民,康敬萬,高錦章,馮亞非;鈷(Ⅲ)配合物與DNA作用的研究[J];無機化學學報;2000年01期

7 易平貴,商志才,俞慶森;微量熱法研究 [Cu(phen)2]~(2+)、[Cu(bpy)_2]~(2+)與DNA的作用[J];無機化學學報;2001年01期

8 劉明華,卿晨,劉吉開,張雁麗,王蕾,紀舒昱;Albaconol的抗腫瘤活性及對DNA拓撲異構酶Ⅱ的影響[J];中國藥理學通報;2004年11期

9 譚慧心;;拓撲異構酶Ⅰ抑制劑研究進展[J];中國藥理學通報;2009年04期

10 張尊聽;陳莉莉;;白楊素衍生物的合成和晶體結構及與DNA的作用[J];藥學學報;2007年05期

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