【作者】 刘林；

【导师】 周翔； 翁小成；

【作者基本信息】 武汉大学 ， 有机化学， 2012， 博士

【摘要】 DNA是生命遗传的物质基础,它起着十分重要的作用,控制着生命体内的许多过程,对DNA的研究有助于人们从分子水平上进一步了解自身。DNA的错误复制和许多疾病的发生密切相关,例如癌症的产生即来源于基因突变,因此,加入药物破坏癌细胞内DNA的结构,使其不能正常的复制转录,进而引起癌症细胞的死亡,这成为众多的以DNA为靶点的抗癌药物的设计原理。此外,DNA除了作为药物设计的靶点外,它的独特的碱基互补配对方式和可控多变的结构使其作为一种工具分子而应用于医学、材料学等许多领域,尤其在生物分析领域有着十分广泛的应用,本论文以DNA的这两个特性为出发点,进行了靶向DNA小分子的设计合成和银离子探针的研究：(1)提高抗癌药物的选择性一直是现代抗癌药物设计面临的一个重大挑战,其中采取的一些手段包括前药分子的设计,以及增加药物的DNA序列识别能力。寡聚酰胺是一种具有优异的DNA识别能力的小分子,本文将寡聚酰胺与其它前药分子相连,例如DNA光诱导交联剂—联苯酚季铵盐分子,以及DNA光照损伤试剂—芘,合成一系列新型抗肿瘤化合物,并完成了相关的表征工作。(2)本文利用一段特殊DNA序列CatG4和银离子的相互作用后结构的变化,设计了两种银离子检测体系；首先基于石墨烯和CatG4序列形成的G-四链体对荧光分子吖啶橙的吸附能力不同,根据DNA二级结构—G四链体的形成与破坏来控制吖啶橙分子在石墨烯上的结合和分离,设计了一种银离子的荧光检测方法,检测结果显示该体系能实现对银离子进行灵敏、快速及选择性的检测；其次,由于Ag离子能与CatG4特异性的结合,我们对CatG4进行荧光标记,通过和银离子的反应使DNA的结构改变,从而改变它在石墨烯的表面吸附或脱附,由此产生荧光信号的改变,简化了Ag离子的检测。更多还原

【Abstract】 As the material base of life, DNA plays an important role in controlling a lot of biological processes. The researches of it will without a doubt help people to know about themselves in a deeper degree at molecular level. The mistake in the reproduction of DNA is closely related to the happenning of many diseases. For example, cancer is deemed to origin form gene mutation. To kill the cancer cells, we can destroy the DNA in them at the addition of drugs which will leads to the failure of DNA’s reproduction, and this is a base thinking in anti-cancer drug’s design. In addition, DNA is also widely used as a tool molecule in many fields such as medecine and materials science, especially in biological analysis due to its unique base-pairing mode and variety of secondary structures besides the use as a target in the design of anti-cancer drugs. Based on the two characters of DNA, works about the design and synthsis of drugs which target DNA as well as DNA used as a probe in the detection of silver ion were done in this thesis.(1) How to improve the selectivity of drugs is always being a big challenge in the modem anti-cancer drugs’design. To solve this problem, several strategies were developed, including the pre-drug strategy and the increase of the DNA sequence recognizing ability of drugs. Polyamide is such a molecule that has excellent DNA sequence recognizing ability. In this thesis it was designed to combine with some pre-drug molecules such as light induced DNA cross-linking agent—phenol quaternary ammonium sa Its and light induced DNA damage agent—pyrene to form some new kinds of anti-cancer drugs. Synthsis and characterization of the target molecules were done.(2) In this thesis two kinds of silver ion detection systems were designed which based on the conversion of the structure of a sequence special DNA—CatG4when reacting with sivler ion. Firstly, based on the different adsorption abilities to the fluorescent molecule—acridine orange between graphene and the G-quadruplex structure formed by CatG4, the combination and separation of acridine orange from the surface of graphene oxide could be controlled by the formation and ruin of G-quadruplex structure, A sensitively, rapidly and selectively silver ion detection system was designed and demonstrated. Secondly, as CatG4can specifically bind to silver ion which leads to the change of its structure, its combination and separation to graphene can be controlled. Fluorophores marked CatG4was used and thus to generate a change in fluorescence signal which can be used to detect silver ion. And the detection process was simplified.更多还原