负载铜催化的反应及在药物合成中的应用

发布时间：2018-03-21 08:12

本文选题：负载铜催化剂　切入点：点击化学　出处：《浙江工业大学》2016年博士论文　论文类型：学位论文

【摘要】：在药物的研发过程中,化合物库的构建对药物筛选及构效关系的研究起着非常重要的作用。新的化学技术和方法的发展为快速构建化合物库提供了保障,而催化反应技术是实现这一目标的重要技术之一。应用催化反应可方便完成对药物分子的结构修饰、改造以及高效的合成目标分子。铜作催化剂具有价廉、易得、毒性小等特性,尤其是将其进行负载后,极易分离,从而实现了回收和套用,这使它在制药中的应用更有优势。本文制备了两种天然多糖负载的铜催化剂,并针对这两种负载铜催化剂在药物研究中的应用开展了以下工作:1.制备了纤维素负载铜催化剂,用XPS、TEM、ICP-AES等对催化剂进行了表征,然后将负载催化剂应用到了糖基叠氮和端基炔的环加成反应中。纤维素负载铜可以在水中高收率的催化合成糖基三氮唑类化合物,反应无需其它的配体或碱,且催化剂回收方便,可以循环使用。应用该方法合成了5个含有齐多夫定结构的喹诺酮衍生物,并进行了抗肿瘤活性筛选。纤维素负载铜催化反应为构建糖基三氮唑化合物库提供了一种有效方法。2.制备了壳聚糖负载铜催化剂,并用XRD、TEM、IR、TG和ICP-AES等进行了表征。然后应用该催化剂开发了一种以卤代芳烃和亚磺酸钠为底物,简单、高效、绿色的砜类物质合成方法。我们用壳聚糖负载醋酸铜作催化剂,以醋酸钾为碱,在含水溶剂中以较高的收率合成了各种砜类化合物。另外,这种容易分离回收的催化剂在循环使用了5次之后依旧保持着较好的催化活性。最后,我们用这种简单高效的方法合成了抗溃疡药佐利米定。3.开展了埃罗替尼糖基化的研究,应用铜催化糖基叠氮与埃罗替尼进行的click反应合成了一系列糖基埃罗替尼衍生物。用MTS法测试了这些新化合物对MDA-MB-231、HepG-2、A549和MCF-7四种肿瘤细胞增殖的抑制活性。结果表明糖基三氮唑修饰后的埃罗替尼衍生物对MDA-MB-231和HepG-2这两种肿瘤细胞的抑制活性有明显的提高。分子对接的研究结果显示,部分糖基化合物可以较好的与表皮生长因子受体EGFR和HER2结合。这些研究为进一步开发氨基喹啉类抗肿瘤药物打下了基础。
[Abstract]:In the process of drug research and development, the construction of compound library plays an important role in drug screening and structure-activity relationship research. The development of new chemical techniques and methods provides a guarantee for the rapid construction of compound library. Catalytic reaction technology is one of the important techniques to achieve this goal. The application of catalytic reaction can easily complete the structural modification of drug molecules, transformation and efficient synthesis of target molecules. Copper as catalyst is cheap and easy to obtain. In this paper, two kinds of copper catalysts supported on natural polysaccharides were prepared. According to the application of the two kinds of supported copper catalysts in drug research, the following work was carried out: 1.Cellulose supported copper catalysts were prepared and characterized by XPSN TEMICP-AES. Then the supported catalyst was applied to the cycloaddition reaction of glycosyl azide and terminal acetylene. Cellulose supported copper could catalyze the synthesis of glycosyltriazole compounds in water without any other ligands or bases. Five quinolones with zidovudine structure were synthesized by this method. Cellulose supported copper catalytic reaction provided an effective method for constructing glycosyltriazole compound library. 2. Chitosan supported copper catalyst was prepared. The catalyst was used to develop a simple, efficient and green synthesis method of sulfone based on halogenated aromatics and sodium sulfonate. We used chitosan supported copper acetate as catalyst. Using potassium acetate as base, various sulfone compounds were synthesized in aqueous solvent in high yield. In addition, the catalyst, which is easy to be separated and recovered, still has good catalytic activity after five cycles. We used this simple and efficient method to synthesize the anti-ulcer drug Zolimidine. 3. The study of glycosylation of erotinib was carried out. A series of glycosylerotinib derivatives were synthesized by click reaction of glycosylazide with erotinib catalyzed by copper. The inhibitory activities of these new compounds on the proliferation of MDA-MB-231 HepG-2A549 and MCF-7 tumor cells were tested by MTS method. The inhibitory activity of glycosyltriazole-modified Erotini derivatives on MDA-MB-231 and HepG-2 tumor cells was significantly increased. Some of the glycosylated compounds can bind well to epidermal growth factor receptor EGFR and HER2. These studies have laid a foundation for the further development of aminoquinoline antitumor drugs.
【学位授予单位】：浙江工业大学
【学位级别】：博士
【学位授予年份】：2016
【分类号】：R914.5

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