本文關(guān)鍵詞： 噸酮 DNA作用 抗腫瘤活性 拓?fù)洚悩?gòu)酶 抑制劑　出處：《河北大學(xué)》2014年碩士論文　論文類型：學(xué)位論文

【摘要】：惡性腫瘤已成為嚴(yán)重危害人類健康的主要疾病。隨著分子腫瘤學(xué)的發(fā)展，人類對惡性腫瘤發(fā)生、發(fā)展的機(jī)制逐步清晰�？鼓[瘤藥物的研發(fā)理念也發(fā)生了重大轉(zhuǎn)變—由傳統(tǒng)抗腫瘤藥物轉(zhuǎn)向靶向抗腫瘤藥物。DNA及其相關(guān)酶是抗腫瘤藥物的重要作用靶點(diǎn)，設(shè)計開發(fā)以DNA及其相關(guān)酶為靶點(diǎn)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(dǎo)，合成了一系列帶有氨基側(cè)鏈的噸酮衍生物，并利用光譜技術(shù)、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(jié)合方式、結(jié)合強(qiáng)度以及對細(xì)胞增殖的影響與其側(cè)鏈結(jié)構(gòu)因素等的關(guān)系。結(jié)果表明，柔性氨基側(cè)鏈的引入調(diào)控了化合物與DNA的結(jié)合方式和強(qiáng)度，并且不同的氨基側(cè)鏈可能改變化合物的極性，使化合物對腫瘤細(xì)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(qiáng)了噸酮與DNA的結(jié)合強(qiáng)度，并明顯提高了對腫瘤細(xì)胞的抑制能力。在此基礎(chǔ)上，利用凝膠電泳檢測了化合物對DNA拓?fù)洚悩?gòu)酶(Topo)和Taq聚合酶活性的影響，結(jié)果顯示，化合物對DNA拓?fù)洚悩?gòu)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?fù)洚悩?gòu)酶的抑制作用和機(jī)理。結(jié)果表明，，CMCT和CMMT是Top I的毒劑，且CMCT抑制作用強(qiáng)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(xué)位授予單位】：河北大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2014
【分類號】：R917

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