本文選題：喹諾酮 + 吲哚酮　； 參考：《河南大學》2014年碩士論文

【摘要】：隨著環(huán)境的惡化和生活節(jié)奏的加快,腫瘤的發(fā)生率逐年增加,進而帶動了抗腫瘤藥物的飛速發(fā)展。目前在臨床使用的抗腫瘤藥物雖然對腫瘤細胞有一定的殺滅作用,但因其選擇性差、毒性較大,在殺滅腫瘤細胞的同時對正常細胞的傷害很大,如果能尋找到一些活性較好的靶向抗腫瘤候選化合物,將有望解決這一難題。 氟喹諾酮類化合物作為臨床廣泛應用的的抗菌藥物,其作用靶點為拓撲異構酶。研究發(fā)現(xiàn),一些藥物對腫瘤細胞的作用靶點和該類藥物的抗菌作用靶點相似,因此許多氟喹諾酮化合物也具有一定的抗腫瘤活性,但因生物利用度、毒性、穩(wěn)定性等原因,未能進入臨床評價階段。氟喹諾酮C-3位羧基雖是抗菌作用所必需的,但不影響藥物的抗腫瘤活性,這為尋找有效的氟喹諾酮類抗腫瘤藥物提供了有利的條件。 吲哚類化合物因其廣泛的生物活性在抗癌藥物領域備受關注。將不同修飾基團引入吲哚結構中,能產生一系列具有抗癌活性的化合物,許多上市的藥物如褪黑素、靛玉紅、蘇尼替尼等抗腫瘤藥物都含有吲哚結構,這些化合物在臨床上均有較好的治療效果。 為此,本文嘗試以蘇尼替尼為先導化合物,保留吲哚結構,利用活性拼接原理,將氟喹諾酮骨架與吲哚骨架通過羥醛縮合反應一系列氟喹諾酮-吲哚類查爾酮結構化合物,通過活性評價,得出構效關系,以期為進一步的研究提供數(shù)據(jù)支持。 1.目標化合物的設計和合成 本文以喹諾酮類和吲哚酮為原料,以蘇尼替尼為先導化合物,利用活性拼接原理,合成利一系列氟喹諾酮-吲哚類查爾酮目標化合物,其結構經HPLC-MS、IR、MS等光譜數(shù)據(jù)進行表征。 2.生物活性評價 合成了15個目標化合物,并用MTT法測試其體外抗腫瘤活性。結果表明,測試化合物對人肝癌細胞都有一定的生長抑制活性,其中半數(shù)以上的化合物在濃度為10μmol/L下其抑制率大于70%。 3.結果與結論 本文設計合成了15個氟喹諾酮-吲哚類查爾酮衍生物,經過HPLC-MS、IR、MS等光譜數(shù)據(jù)確證。體外抗腫瘤活性測試結果顯示,所合成的目標化合物對人肝癌細胞有較強的生長抑制作用。氟喹諾酮與吲哚作為兩個藥效團拼合得到的氟喹諾酮-吲哚類查爾酮化合物作為有效的抗腫瘤先導物值得進一步研究。
[Abstract]:With the deterioration of environment and the acceleration of life rhythm, the incidence of tumor increases year by year, which leads to the rapid development of antitumor drugs. Although the antitumor drugs currently used in clinical use have a certain killing effect on tumor cells, because of their poor selectivity and toxicity, they are harmful to normal cells while killing tumor cells. If we can find some active target antitumor candidate compounds, we hope to solve this problem. Fluoroquinolones are widely used as clinical antimicrobial agents, whose target is topoisomerase. Studies have found that some drugs have similar anti-tumor targets to tumor cells, so many fluoroquinolones also have anti-tumor activities, but due to bioavailability, toxicity, stability and other reasons, Failed to enter the stage of clinical evaluation. Although fluoroquinolone C-3 carboxyl group is necessary for antimicrobial action, it does not affect the antitumor activity of the drug, which provides favorable conditions for searching for effective fluoroquinolones antitumor drugs. Indole compounds have attracted much attention in the field of anticancer drugs because of their wide range of biological activities. Introducing different modified groups into the indole structure can produce a series of compounds with anticancer activity. Many antitumor drugs such as melatonin, indirubin and sulnitinib contain indole structure. These compounds have good therapeutic effect in clinic. Therefore, a series of fluoroquinolone-indole compounds were synthesized by condensation of fluoroquinolones and indoles by hydroxyaldehydes. Through the activity evaluation, the structure-activity relationship is obtained, in order to provide data support for further research. 1. Design and Synthesis of Target compounds In this paper, a series of fluoroquinolone-indole target compounds were synthesized by using quinolones and indole as raw materials and sulnitinib as lead compounds. The structures of these compounds were characterized by HPLC-MS IRMS and other spectral data. 2. Biological activity evaluation Fifteen target compounds were synthesized and their anti-tumor activity was tested by MTT method in vitro. The results showed that the tested compounds had a certain growth inhibitory activity on human hepatoma cells, and more than half of the compounds had inhibitory rates of more than 70% at the concentration of 10 渭 mol/L. 3. Results and conclusions Fifteen fluoroquinolone-indole derivatives were designed and synthesized. The results of antitumor activity test in vitro showed that the target compound had strong inhibitory effect on the growth of human hepatoma cells. Fluoroquinolone-indole as a combination of two pharmacophore groups of fluoroquinolone-indole chalcone compounds as an effective antitumor precursor worthy of further study.
【學位授予單位】：河南大學
【學位級別】：碩士
【學位授予年份】：2014
【分類號】：R914

【參考文獻】

相關期刊論文 前10條

1 張桂英,段朝軍,施家琦,冷愛民;消炎痛抗腫瘤作用及體外增敏作用的研究[J];湖南醫(yī)科大學學報;1997年06期

2 胡瑞定;俞慶森;易平貴;;四氯合鈀(Ⅱ)喹諾酮配合物的合成及與DNA的作用和抗增殖活性[J];化學學報;2009年14期

3 仲衛(wèi)國;許清華;孟繁德;;大青葉的研究進展[J];人參研究;2011年03期

4 展瑞巖;楊紅;張元新;葛雅琨;李世軍;施維;鄭昆;;蘇尼替尼對HeLa細胞增殖及3-磷酸甘油醛脫氫酶表達和活性的影響[J];中國生物制品學雜志;2013年03期

5 亢曉彬;馬勇;魏偉;;成人肝癌組織褪黑素受體的表達和結合特性[J];中國藥理學通報;2010年02期

6 季宇彬;周建華;左明新;尤啟冬;;新型TopoⅠ抑制劑CPUY013對胃腺癌細胞BGC823的體內外作用[J];藥學學報;2008年08期

7 胡國強;毋曉魁;王新;張智強;謝松強;黃文龍;張惠斌;;氟喹諾酮C3雜環(huán)取代衍生物的合成及抗腫瘤活性研究(I):環(huán)丙沙星噻二唑希夫堿[J];藥學學報;2008年11期

8 俞慶森，蔡國強，，朱龍觀;喹諾酮類C－2位構效關系的分子力學和量子化學研究[J];藥學學報;1994年08期

9 熊儉,劉婧,姜鳳超;3-取代2-吲哚酮類化合物的合成與抗腫瘤活性研究[J];醫(yī)藥導報;2005年05期

10 王華萍;孫遠;周游;尤啟冬;;優(yōu)勢結構4-喹諾酮類化合物抗腫瘤活性的研究進展[J];中國藥物化學雜志;2012年01期

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