含硒喹唑啉类衍生物的合成及生物活性研究

发布时间：2018-03-29 07:44

本文选题：喹唑啉　切入点：二硒钠　出处：《鲁东大学》2017年硕士论文

【摘要】：在六元含氮杂环系统中,喹唑啉骨架普遍存在于许多天然产物和合成材料中。这些化合物表现出多种非常良好的生物活性和药物功能,例如抗高血压、抗肿瘤、解热、利尿、止痛药、抗生素、抗兴奋剂和抗抑郁药,并且用作血管舒张剂。喹唑啉衍生物被发现具有生物活性多种多样,结构类型多变以及药用价值高等显著优点,是当前科学家研究热门方向之一。硒是人类健康最重要的必需微量营养素,硒化物的药用研究开发受到越来越多的关注。流行病学研究发现多器官癌风险增加与硒摄入量低或血浆硒水平降低密切相关。有机硒化合物被发现在抗炎、抗氧化、细胞保护、化学预防、抗抑郁和抗菌方面效果显著。因为它可以容易地被人类胃肠道吸收,并且对毒性作用显示出更高的阈值。为了开发出生物活性良好的衍生物,课题组已经合成出了多种喹唑啉衍生物。本论文选用邻氨基苯甲酸或取代邻氨基苯甲酸为原料,选用人体必需的微量元素硒作为配合元素,使喹唑啉环和硒有机结合,经闭环、氯化、与二硒化钠反应等,新合成出了喹唑啉二硒钠类衍生物1a-1f(6个),喹唑啉-4-硒钠3a以及二硒醚2a三种不同类型的含硒衍生物,经IR、1H NMR确证其结构。对部分所需化合物进行了有关反应方法和条件优化筛选,主要是对目标产物喹唑啉二硒钠的反应路线做了研究改进,对喹唑啉-4-硒钠的反应做了分析探究,另外还对部分中间体的合成进行了条件优化。对于本实验室已有的二喹唑啉二硒醚类衍生物的作用机理做了进一步深入探究。首先选用活性最好的二(喹唑啉-4-基)二硒醚,采用双标记流式细胞术测定A549(非小细胞肺癌细胞)细胞凋亡。经过系统分析我们认为二(喹唑啉-4-基)二硒醚(4a)主要是作用在G1或S期,从而使细胞逐渐走向凋亡。之后,我们使用生长速率法,对小麦赤霉病原菌(Gibberella zeae)、辣椒枯萎病原菌(Fusarium oxysporum)、苹果腐烂病原菌(Cytospora mandshurica Miura)这三种植物病原菌进行了初步抑菌活性的测试。实验数据说明全部测试物都展现出了一定的抑菌能力。特别需要注意的是,二(6-氯喹唑啉-4-基)二硒醚对小麦赤霉病原菌(Gibberella zeae)的抑制率为96.3%,远远高于商品药物恶霉灵(53.68%)。其它几个取代二硒醚也具有和恶霉灵相当抑制率,值得进一步深入研究。新合成的喹唑啉二硒钠类目标产物使用MTT比色法进行了抑制MDA-MB-231的体外抗癌活性测试。结果表明,化合物1f与1d在药剂浓度为10μM时体外作用72 h对MDA-MB-231的抑制率分别为99.19%和67.32%,全部远高于阳性对照组吉非替尼(Gefitinib),展示了喹唑啉二硒钠类非常高的抗癌活性。
[Abstract]:Quinazoline cytoskeleton is found in many natural products and synthetic materials in a six-element nitrogen-containing heterocyclic system. These compounds exhibit a variety of very good biological activities and drug functions, such as antihypertensive, antitumor, antipyretic, diuretic, diuretic, antipyretic, diuretic, antihypertensive, antipyretic, and diuretic. Analgesics, antibiotics, anti-stimulants, antidepressants, and as vasodilators. Quinazoline derivatives have been found to have a variety of biological activities, structural variety and high medicinal value. Selenium is the most important micronutrient in human health. More and more attention has been paid to the medicinal research and development of selenides. Epidemiological studies have found that the increased risk of multiple organ cancer is closely related to low selenium intake or a decrease in plasma selenium levels. Organic selenium compounds have been found in anti-inflammatory, antioxidant, and cellular protection. Chemical prevention, antidepressant and antimicrobial effects are significant because they can be easily absorbed by the human gastrointestinal tract and exhibit higher thresholds for toxicity. In this paper, o-aminobenzoic acid or substituted o-aminobenzoic acid was used as raw material, and selenium, a trace element necessary for human body, was selected as the coordination element to combine quinazoline ring with selenium. Three kinds of selenium-containing derivatives of quinazoline disselenide sodium derivatives 1a-1f, quinazoline -4-selenosodium 3a and diselenoether 2a were synthesized by chlorination and reaction with sodium diselenide. The structure of quinazoline sodium diselenide was confirmed by 1H NMR. The reaction methods and conditions of some needed compounds were optimized. The reaction route of quinazoline diselenide sodium was studied and improved, and the reaction of quinazoline -4selenite sodium was analyzed and explored. In addition, the conditions for the synthesis of some intermediates were optimized. The mechanism of action of diquinazoline diselenide derivatives in our laboratory was further explored. First, the most active bis (quinazoline -4-yl) diselenide was selected. The apoptosis of A549 (non-small cell lung cancer) cells was determined by double labeling flow cytometry. We think that the action of bis (quinazoline-4-yl) diselenoether 4a is mainly in G1 or S phase, which makes the cells apoptosis gradually. We use the growth rate method, The bacteriostatic activity of three plant pathogens, I. e., Gibberella zeaeae, Fusarium oxysporum and Cytospora mandshurica Miura, were tested. Bacteriological capacity. It is particularly important to note that, The inhibitory rate of dichloroquinazoline-4-yl) diselenide on wheat scab pathogen Gibberella zeaeis was 96.3g, which was much higher than that of commercial drug oxalaxelin 53.68.The other diselenides also had the same inhibitory rate as oxalazine. The new target product of quinazoline diselenide sodium has been tested by MTT colorimetry to inhibit the anticancer activity of MDA-MB-231 in vitro. The inhibitory rates of compound 1f and 1d on MDA-MB-231 were 99.19% and 67.32% respectively at the concentration of 10 渭 M for 72 h, all of which were much higher than those of the positive control group, Gefitinib, which showed that quinazoline diselenide sodium had very high anticancer activity.
【学位授予单位】：鲁东大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：O626

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