發(fā)布時間：2018-02-24 01:10

  本文關鍵詞： EGFR抑制劑 抗癌 分子模擬 細胞遷移 構(gòu)效分析 吡唑環(huán) 噻唑環(huán) 萘酚環(huán) 1 4二氧八環(huán) 咖啡酸酰胺　出處：《南京大學》2014年博士論文　論文類型：學位論文

【摘要】：癌癥是世界上首位導致死亡的因素,在美國每一年因為癌癥死亡的人數(shù)大約占總死亡人數(shù)的25%,不僅如此每年新增癌癥患者的人數(shù)也不斷增加。隨分子生物學的研究發(fā)展,對于癌癥的發(fā)病機理和其在產(chǎn)生和發(fā)展的過程中起到重要作用的特異性的酶有了更加深入的了解,使得這些特異酶作為研制抗癌藥物的分子靶標成為了可能。表皮生長因子受體EGFR (epidermal growth factor receptor)在腫瘤細胞的增殖、血管生成、腫瘤侵襲、轉(zhuǎn)移及細胞凋亡的抑制等方面起到重要的作用,大量的研究表明EGFR可作為治療癌癥的分子靶標,像EGFR抑制劑埃羅替尼和吉非替尼就是非常成功的抗癌藥物。本篇論文我們設計了兩個系列共45個全新的化合物,并對它們進行了抗增殖、抑制EGFR、毒性、凋亡和抑制細胞遷移等生物活性的檢測,研究表明這些化合物可能是通過抑制抑制EGFR,起到抗腫瘤效果的。 (1)由于吡唑、噻唑和萘酚環(huán)具有低毒和顯著地生物活性,我們在此基礎上合成出同時含有吡啶、噻唑和萘酚環(huán)的化合物(la-7a,1b-7b,1c-7c,1d-7d)通過元素分析、H-NMR、ESI-MS分析確定了這些新化合物的結(jié)構(gòu),通過單晶X-射線結(jié)構(gòu)分析確定了1d和5d化合物的三維空間結(jié)構(gòu)�？乖鲋澈鸵种艵GFR的活性結(jié)果顯示這些化合物較好的抗癌活性,其中化合物7d抗Hela癌細胞和抑制EGFR活性最好,對應的IC50值為0.86μM和0.12μM,同時構(gòu)效分析表明苯環(huán)上的取代基種類對化合物的生物活性影響較大。實驗結(jié)果顯示EGFR抑制活性和抗增殖活性具有一定的相關性,表明這個系列化合物的抗增殖活性可能是通過抑制EGFR的活性產(chǎn)生的。另外細胞毒性和抑制Hela細胞遷移測試表明7d沒有毒性并且能夠較好地抑制Hela細胞遷移。分子模擬顯示7d中的萘環(huán)與EGFR中的氨基酸LYS721形成了兩個p-π鍵,提高了抗癌活性。 (2)合成了含有苯并1,4二氧八環(huán)的咖啡酸酰胺,并對化合物進行結(jié)構(gòu)鑒定,包括1H NMR、ESI-MS、元素分析以及晶體結(jié)構(gòu)測定,合成出的17個化合物均為首次報道。對合成出的化合物的抗增殖和抑制EGFR活性檢測顯示大部分的化合物具有很強的抗癌活性,尤其是D9(IC50=0.79μM對HepG2和IC50=0.36μM對EGFR)。構(gòu)效分析表明苯并1,4二氧八環(huán)結(jié)構(gòu)和苯胺上苯環(huán)的對位的取代基種類對于化合物的生物活性影響很大,同時在細胞凋亡、細胞毒性和抑制HepG2細胞的測試中化合物均顯示出很好的活性。分子模擬顯示D9與EGFR中的氨基酸MET793和LEU1001形成了兩個氫鍵,增加了粘合力提高了抗癌活性。 這兩個系列化合物的研究表明7d和D9有望成為以EGFR為靶點的新型抗癌藥物先導化合物。
[Abstract]:Cancer is the first cause of death in the world. Cancer accounts for about 25 of the total deaths in the United States every year, and the number of new cancer patients increases every year. We have a deeper understanding of the pathogenesis of cancer and the specific enzymes that play an important role in the development and development of cancer. This makes it possible for these specific enzymes to be used as molecular targets for the development of anticancer drugs. Epidermal growth factor receptor, EGFR epidermal growth factor receptor, proliferates, angiogenesis, and invades tumor cells. Metastasis and inhibition of apoptosis play an important role. A large number of studies have shown that EGFR can be used as a molecular target for the treatment of cancer. Erotini and gefitinib, EGFR inhibitors, are very successful anticancer drugs. In this paper, we designed two series of 45 new compounds, and carried out anti-proliferation, inhibition of EGFR, toxicity. The detection of biological activities such as apoptosis and inhibition of cell migration suggests that these compounds may have antitumor effects by inhibiting EGFR. (1) due to the low toxicity and remarkable biological activity of pyrazole, thiazole and naphthol rings, we have synthesized compounds containing pyridine, thiazole and naphthol ring, which are composed of pyridine, thiazole and naphthol ring. The structures of these compounds have been determined by elemental analysis with H-NMRESI-MS. The three-dimensional spatial structures of 1-d and 5-d compounds were determined by single crystal X-ray structure analysis. The results of anti-proliferation and inhibition of EGFR activity showed that these compounds had better anticancer activity, of which 7d had the best antitumor activity against Hela cancer cells and the best inhibition of EGFR activity. The corresponding IC50 values were 0.86 渭 M and 0.12 渭 M. meanwhile, the structural activity analysis showed that the substituents on the benzene ring had a great influence on the bioactivity of the compounds. The experimental results showed that the inhibitory activity of EGFR and the anti-proliferation activity of the compounds were related to each other. The results indicated that the antiproliferative activity of this series of compounds may be produced by inhibiting the activity of EGFR. In addition, the cytotoxicity and inhibition of Hela cell migration test showed that the antiproliferative activity of this series of compounds was not toxic at 7 days and could inhibit the migration of Hela cells well. The simulation shows that the naphthalene ring in 7 d and the amino acid LYS721 in EGFR form two p- 蟺 bonds. The anti-cancer activity was improved. The caffeic acid amide containing benzo 1o 4 dioxo octamer was synthesized and its structure was identified, including 1H N MRN ESI-MS, elemental analysis and crystal structure determination. For the first time, 17 compounds were synthesized. The detection of the antiproliferation and inhibition of EGFR activity of the synthesized compounds showed that most of the compounds had strong anticancer activity. In particular, the structure-activity analysis of HepG2 and IC50=0.36 渭 M in D9 / IC50 / 0.79 渭 M and IC50=0.36 渭 M showed that the structure of benzo 1 / 4 dioxo 8 ring and the type of p-substituents of benzene ring on aniline had a great influence on the bioactivity of the compounds, and apoptosis was also observed in the cells. Molecular simulation showed that D9 formed two hydrogen bonds with amino acid MET793 and LEU1001 in EGFR and increased adhesion to enhance anticancer activity. The studies of these two series of compounds indicate that 7d and D9 are expected to be the leading compounds of new anticancer drugs targeting EGFR.
【學位授予單位】：南京大學
【學位級別】：博士
【學位授予年份】：2014
【分類號】：R914

【參考文獻】

相關期刊論文 前5條

1 Ming-Dong Lu;Xiao Zhou;Yao-Jun Yu;Pi-Hong Li;Wei-Jian Sun;Cheng-Guang Zhao;Zhi-Qiang Zheng;Tao You;Fei-Hai Wang;;Synthesis and in vitro biological evaluation of nitric oxide-releasing derivatives of hydroxylcinnamic acids as anti-tumor agents[J];Chinese Chemical Letters;2013年05期

2 趙春貴,張立偉,王暉,黃登宇;肉桂酸及其衍生物抗氧化活性研究[J];食品科學;2005年01期

3 李娜;魏學;范會濤;畢亮;李向陽;楊松;胡德禹;宋寶安;;2-氰基-3-(4-甲基苯并[d]噻唑-2-氨基)-3-苯基丙烯酸酯類化合物的合成及抗病毒活性[J];有機化學;2011年08期

4 ;Targeted cancer therapies based on antibodies directed against epidermal growth factor receptor:status and perspectives[J];Acta Pharmacologica Sinica;2007年09期

5 任曉嵐,汪鑫,李志裕,尤啟冬;表皮生長因子受體(EGFR)酪氨酸激酶抑制劑的研究進展[J];中國新藥雜志;2005年07期

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本文編號：1528305