本文選題：喹諾酮 + 吲哚酮　； 參考：《河南大學(xué)》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(jìn)而帶動(dòng)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(duì)腫瘤細(xì)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(xì)胞的同時(shí)對(duì)正常細(xì)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(yīng)用的的抗菌藥物,其作用靶點(diǎn)為拓?fù)洚悩?gòu)酶。研究發(fā)現(xiàn),一些藥物對(duì)腫瘤細(xì)胞的作用靶點(diǎn)和該類藥物的抗菌作用靶點(diǎn)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(jìn)入臨床評(píng)價(jià)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(lǐng)域備受關(guān)注。將不同修飾基團(tuán)引入吲哚結(jié)構(gòu)中,能產(chǎn)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(jié)構(gòu),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(dǎo)化合物,保留吲哚結(jié)構(gòu),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(yīng)一系列氟喹諾酮-吲哚類查爾酮結(jié)構(gòu)化合物,通過活性評(píng)價(jià),得出構(gòu)效關(guān)系,以期為進(jìn)一步的研究提供數(shù)據(jù)支持。 1.目標(biāo)化合物的設(shè)計(jì)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(dǎo)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(biāo)化合物,其結(jié)構(gòu)經(jīng)HPLC-MS、IR、MS等光譜數(shù)據(jù)進(jìn)行表征。 2.生物活性評(píng)價(jià) 合成了15個(gè)目標(biāo)化合物,并用MTT法測(cè)試其體外抗腫瘤活性。結(jié)果表明,測(cè)試化合物對(duì)人肝癌細(xì)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(jié)果與結(jié)論 本文設(shè)計(jì)合成了15個(gè)氟喹諾酮-吲哚類查爾酮衍生物,經(jīng)過HPLC-MS、IR、MS等光譜數(shù)據(jù)確證。體外抗腫瘤活性測(cè)試結(jié)果顯示,所合成的目標(biāo)化合物對(duì)人肝癌細(xì)胞有較強(qiáng)的生長抑制作用。氟喹諾酮與吲哚作為兩個(gè)藥效團(tuán)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(dǎo)物值得進(jìn)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(xué)位授予單位】：河南大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2014
【分類號(hào)】：R914

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