氟喹诺酮C-3甲醛缩吲哚酮类衍生物的合成与生物活性研究

发布时间：2018-04-22 15:52

本文选题：喹诺酮 + 吲哚酮　；参考：《河南大学》2014年硕士论文

【摘要】：随着环境的恶化和生活节奏的加快,肿瘤的发生率逐年增加,进而带动了抗肿瘤药物的飞速发展。目前在临床使用的抗肿瘤药物虽然对肿瘤细胞有一定的杀灭作用,但因其选择性差、毒性较大,在杀灭肿瘤细胞的同时对正常细胞的伤害很大,如果能寻找到一些活性较好的靶向抗肿瘤候选化合物,将有望解决这一难题。氟喹诺酮类化合物作为临床广泛应用的的抗菌药物,其作用靶点为拓扑异构酶。研究发现,一些药物对肿瘤细胞的作用靶点和该类药物的抗菌作用靶点相似,因此许多氟喹诺酮化合物也具有一定的抗肿瘤活性,但因生物利用度、毒性、稳定性等原因,未能进入临床评价阶段。氟喹诺酮C-3位羧基虽是抗菌作用所必需的,但不影响药物的抗肿瘤活性,这为寻找有效的氟喹诺酮类抗肿瘤药物提供了有利的条件。吲哚类化合物因其广泛的生物活性在抗癌药物领域备受关注。将不同修饰基团引入吲哚结构中,能产生一系列具有抗癌活性的化合物,许多上市的药物如褪黑素、靛玉红、苏尼替尼等抗肿瘤药物都含有吲哚结构,这些化合物在临床上均有较好的治疗效果。为此,本文尝试以苏尼替尼为先导化合物,保留吲哚结构,利用活性拼接原理,将氟喹诺酮骨架与吲哚骨架通过羟醛缩合反应一系列氟喹诺酮-吲哚类查尔酮结构化合物,通过活性评价,得出构效关系,以期为进一步的研究提供数据支持。 1.目标化合物的设计和合成本文以喹诺酮类和吲哚酮为原料,以苏尼替尼为先导化合物,利用活性拼接原理,合成利一系列氟喹诺酮-吲哚类查尔酮目标化合物,其结构经HPLC-MS、IR、MS等光谱数据进行表征。 2.生物活性评价合成了15个目标化合物,并用MTT法测试其体外抗肿瘤活性。结果表明,测试化合物对人肝癌细胞都有一定的生长抑制活性,其中半数以上的化合物在浓度为10μmol/L下其抑制率大于70%。 3.结果与结论本文设计合成了15个氟喹诺酮-吲哚类查尔酮衍生物,经过HPLC-MS、IR、MS等光谱数据确证。体外抗肿瘤活性测试结果显示,所合成的目标化合物对人肝癌细胞有较强的生长抑制作用。氟喹诺酮与吲哚作为两个药效团拼合得到的氟喹诺酮-吲哚类查尔酮化合物作为有效的抗肿瘤先导物值得进一步研究。
[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.
【学位授予单位】：河南大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R914

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