具有DNA和BSA键合功能的N,N’-双取代草酰胺多核铜配合物的合成、结构及抗肿瘤活性研究

发布时间：2018-03-24 16:25

本文选题：不对称　切入点：N　出处：《中国海洋大学》2014年硕士论文

【摘要】：有机小分子特别是过渡金属配合物与生物大分子相互作用的研究是配位化学和药物化学领域的研究热点。而DNA和BSA不仅是重要的生物大分子，也是许多药物体内的作用靶点。因此，为进一步探索和认识DNA和BSA的结构和功能，了解药物的抗癌机理，设计和合成具有DNA和BSA键和功能的金属配合物具有重要意义。本论文选择两种N,N'-双取代草酰胺作为桥联配体，以设计合成广谱、高效、低毒的结构新颖的抗癌金属配合物为主线，合成了一系列具有不同端基配体的多核铜配合物，并使用X-射线单晶衍射进行了结构的解析，并采用了紫外荧光等多种手段研究了配体及其配合物与DNA、BSA的相互作用模式及强度，对体外细胞毒活性进行了测定。本论文具体研究内容主要包括以下三部分： 1、配体及其桥联的多核铜配合物的合成及结构解析：N-[2-(2-羟乙基氨基)乙基]-N′-(2-羧基苯基)草酰胺(H3bhyox)和N-(3-二乙氨基丙基)-N′-(2-羧基苯基)草酰胺(H3bdpox)作为桥联配体，改变端基配体进行多核铜配合物的合成，并得到了一个四核铜配合物[Cu4(bhyox)2(phen)2(H2O)2](pic)2(1)单晶，一个配体H3bdpox(2)单晶，一个一维铜聚合物{[Cu2(bdpox)(dabt)]NO3·H2O}n(3)单晶，以及两个四核铜配合物单晶[Cu4(bdpox)2(phen)2](NO3)2·2H2O (4)、[Cu4(bdpox)2(Me2bpy)2]-(ClO4)2·2C2H5OH (5)，采用元素分析、红外光谱进行了结构的表征，并使用单晶X射线衍射对单晶结构进行了解析。在结构部分讨论了氢键、π-π堆积等分子间作用力在晶体超分子结构方面的影响。 2、配体及配合物与生物大分子DNA、BSA的键合活性研究：采用光谱法(紫外光谱法、荧光光谱法)、粘度法等研究了配体及四个配合物与鲱鱼精DNA(HS-DNA)的相互作用；采用紫外光谱法和荧光猝灭光谱法研究了上述五个化合物与牛血清蛋白(BSA)的相互作用。与DNA的研究结果表明除配体与DNA发生沟槽结合，四个配合物均与DNA发生插入作用，且由于端基配体的影响，插入作用强度为(4)(5)(3)(2)。与BSA的研究结果表明，，五个化合物均能与BSA发生相互作用，引起其蛋白质构象的改变。 3、配体及配合物抗肿瘤活性研究：采用SRB法对上述配体及配合物对两种肿瘤细胞株—人肝癌细胞(SMMC-7721)和人肺腺癌细胞(A549)进行了体外细胞毒活性研究，研究结果表明：上述化合物对两种肿瘤细胞株均具有不同程度的抑制作用，且配合物的抗肿瘤活性优于自由配体的。本论文在前期实验室研究工作的基础上丰富了草酰胺类配合物的研究内容，为研究配合物的构效关系对DNA和BSA键合强度与活性的影响，设计与合成高效、低毒、广谱的配合物提供了指导性信息。
[Abstract]:The interaction of organic small molecules, especially transition metal complexes, with biomolecules is a hot topic in the field of coordination chemistry and pharmaceutical chemistry. DNA and BSA are not only important biomolecules. Therefore, it is of great significance to design and synthesize metal complexes with DNA and BSA bonds and functions in order to further explore and understand the structure and function of DNA and BSA, and to understand the anticancer mechanism of drugs. In this paper, two kinds of NN-N-disubstituted oxalamide were selected as bridged ligands. A series of polynuclear copper complexes with different terminal ligands were synthesized by designing and synthesizing broad spectrum, high efficiency and low toxicity anticancer metal complexes. The structure was elucidated by X-ray single crystal diffraction, and the interaction mode and intensity of ligand and its complexes with DNA-BSA were studied by means of ultraviolet fluorescence and other methods. The cytotoxic activity in vitro was determined. The main contents of this thesis include the following three parts:. Synthesis and structural Analysis of Ligand and its bridged Polynuclear Copper complexes. The polynuclear copper complexes were synthesized by changing the terminal ligands. A tetranuclear copper complex (Cu4(bhyox)2(phen)2(H2O)2), a ligand H3bdpoxt2) single crystal, a one-dimensional copper polymer {[Cu2bdpoxnabt] NO3 H2O} N3], and two tetrachronuclear copper complexes [Cu4(bdpox)2(phen)2] no _ 3O _ 2 2H2O _ 4, [Cu4(bdpox)2(Me2bpy)2] -CIO _ 4O _ 4 2C2H5OH _ 5N _ 5 were obtained by elemental analysis. The structure of single crystal was characterized by infrared spectroscopy and analyzed by single crystal X-ray diffraction. In the structure part, the influence of intermolecular forces such as hydrogen bond, 蟺-蟺 stacking and other intermolecular forces on the crystal supramolecular structure was discussed. (2) study on the binding activity of ligand and its complexes with biomolecules DNABSA: the interaction of ligand and its four complexes with herring sperm DNA HS-DNA was studied by means of spectroscopic method (UV), fluorescence spectroscopy and viscosity method. The interaction of the above five compounds with bovine serum protein (BSA) was studied by ultraviolet spectroscopy and fluorescence quenching spectroscopy. The results of the study with DNA showed that the ligand was trenched with DNA and the four complexes were intercalated with DNA. Because of the effect of the terminal ligand, the insertion intensity was 4x4, 5, 5, 3, 2. The results of the study with BSA showed that the five compounds could interact with BSA, resulting in the conformation change of their proteins. 3, the antitumor activity of ligands and their complexes: the cytotoxic activities of these ligands and complexes against two kinds of tumor cell lines, human hepatoma cell line SMMC-7721) and human lung adenocarcinoma cell line A549, were studied by SRB assay in vitro. The results showed that these compounds had different inhibitory effects on both tumor cell lines and the antitumor activity of the complexes was superior to that of free ligands. In this paper, the research contents of oxalamide complexes were enriched on the basis of previous laboratory work. In order to study the effect of structure-activity relationship of complexes on the bond strength and activity of DNA and BSA, the design and synthesis of oxalamide complexes were highly efficient and low toxic. Broad spectrum complexes provide guidance information.
【学位授予单位】：中国海洋大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R914.5;R96

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