槲皮素3、6或8位单取代衍生物的合成与抗肿瘤活性研究

发布时间：2018-02-10 23:02

本文关键词： 黄酮槲皮素衍生物槲皮素抗肿瘤 Suzuki偶联　出处：《天津科技大学》2014年硕士论文　论文类型：学位论文

【摘要】：槲皮素是自然界中最广泛存在的一种黄酮类天然产物,属于黄酮醇类化合物,以糖苷的形式存在于植物的叶、茎、花、果实中。近年来大量研究结果表明槲皮素具有扩张冠状血管、降低血脂、抗炎、抗氧化、抗癌变、抗糖尿病并发症等多种生理作用,激发人们对这类化合物越来越多的关注。目前这方面的研究主要集中在槲皮素羟基的衍生化,3位、6位或8位的碳-碳偶联衍生物的设计合成及生物活性研究鲜见报道。本文设计了3位、6位或8位单取代新颖槲皮素衍生物合成路线,以芦丁为原料,经过水解反应得槲皮素,对槲皮素的5个羟基进行选择性保护实现6位或8位的高选择性卤代,然后通过Suzuki偶联反应或Heck偶联反应等4-6步反应,以6%-34%的总产率获得了27个6位或8位单取代槲皮素衍生物。而3位衍生物的合成则是通过先对芦丁母环上4个羟基进行保护,然后水解脱掉糖苷后进行3位羟基三氟甲磺酰化,最后经Suzuki偶联反应或Heck偶联反应等4-5步反应以5%-31%的总产率得到了14个3位碳-碳偶联取代衍生物。这两种方法合成的关键中间体和目标化合物(41个)进行了1H-NMR,13C-NMR和MS的结构和纯度确认,其中有40种未见文献报道。本文还研究了温度、溶剂种类、碱、催化剂种类等反应条件对关键的Suzuki偶联或Heck偶联等反应产率的影响,优化了我们所设计的高效合成路线。三个系列41个目标化合物针对人白血病细胞K562、人肝癌细胞HepG2和人结肠癌细胞HT-29的抗肿瘤细胞活性测试结果表明：6位取代衍生物和3位取代衍生物对三种肿瘤细胞的增殖有一定的抑制作用,相比于槲皮素抗肿瘤活性有所提高,而8位衍生物的抗肿瘤活性最高,其中化合物1-5、1-7和1-8对人肝癌细胞HepG2的IC50值分别为0.38μM,0.83μM,0.75μM。
[Abstract]:Quercetin is one of the most widespread natural flavonoids in nature. It belongs to flavonol compounds and exists in leaves, stems and flowers in the form of glycosides. Fruit. In recent years, a large number of studies have shown that quercetin has a variety of physiological effects, such as dilating coronary blood vessels, lowering blood lipid, anti-inflammatory, anti-oxidation, anti-cancer, anti-diabetic complications, and so on. At present, the research on the derivatives of quercetin hydroxyl groups is mainly focused on the design, synthesis and biological activity of C-C coupling derivatives at 3, 6 or 8 positions of quercetin hydroxyl groups. In this paper, a novel synthetic route of monosubstituted quercetin derivatives at 3 or 8 sites has been designed. Quercetin was prepared by hydrolysis of rutin. The selective protection of 5 hydroxyl groups of quercetin was carried out to achieve high selective halogenation at 6 or 8 positions, and then 4-6 steps were obtained by Suzuki coupling reaction or Heck coupling reaction. Twenty-seven monosubstituted quercetin derivatives were obtained in 6- 34% yield, and the three derivatives were synthesized by protecting four hydroxyl groups from rutin ring, then hydrolyzing glucoside and then 3 hydroxyl trifluoromethyl sulfonylation. Finally, 14 C-C substituted derivatives at position 3 were obtained by 4-5 step reactions such as Suzuki coupling reaction or Heck coupling reaction with total yield of 5% -31%. The key intermediates and target compounds (41) synthesized by these two methods were studied by 1H-NMR13C-NMR and 1H-NMR13C-NMR and 1H-NMR13C-NMR and 1H-NMR13C-NMR respectively. The structure and purity of MS, The effects of reaction conditions, such as temperature, solvent, alkali and catalyst, on the yield of key Suzuki coupling or Heck coupling reactions were also studied. Three series of 41 target compounds targeting human leukemia cell line K562, human hepatoma cell line HepG2 and human colon cancer cell line HT-29 were tested for their antitumor activity. Compounds and 3-position substituted derivatives can inhibit the proliferation of three kinds of tumor cells. The antitumor activity of quercetin was higher than that of quercetin, and the antitumor activity of derivatives was the highest. The IC50 values of compounds 1-51-7 and 1-8 on HepG2 of human hepatoma cells were 0.38 渭 M, 0.83 渭 M and 0.75 渭 M. respectively.
【学位授予单位】：天津科技大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R914;R96

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