基于核酸和蛋白质相互作用的铜（Ⅱ）配合物的设计合成、结构及其抗肿瘤活性研究

发布时间：2018-06-30 05:00

本文选题：N + N′-双取代草酰胺　；参考：《中国海洋大学》2014年硕士论文

【摘要】：目前，金属配合物与生物大分子之间相互作用的研究已经成为了无机药物化学领域的研究热点。DNA是生物体内重要的遗传物质，而蛋白质是生物功能的重要载体，二者都是生物体内重要的生物大分子，同时也是许多药物在体内作用的靶向目标。因此，合成能够与DNA和蛋白质键合的金属配合物，对其抗癌细胞活性的研究以及设计现代药物和分析药物的抗肿瘤机理具有深远的意义。基于这一背景，本文合成了一个单核铜配合物单晶，并合成N,N’-对称双取代草酰胺作为桥联配体，设计合成了多个多核铜配合物并培养得到了三个配合物单晶，对其晶体结构进行了解析，并用一系列方法研究了其与DNA和BSA的相互作用和体外抗肿瘤活性，具体如下： 1、金属配合物的合成与单晶结构解析：用Cu(pic)2·4H2O和bpy为原料合成了一个单核铜配合物单晶[Cu(bpy)2(pic)](pic)(1)；选取N,N’-双(N,N’-二乙基丙二胺)草酰胺为配体，选择不同的铜盐和端基配体，合成得到了三个配合物的单晶：一个一维铜聚合物单晶[Cu2(deap)(N3)2]n(2)以及两个双核配合物单晶[Cu2(deap)(bpy)2](ClO4)2(3)和Cu2(deap)(SCN)2(4)。 2、配合物与DNA和BSA相互作用的研究：从分子水平上运用紫外和荧光光谱学等方法研究了配合物与HS-DNA分子之间的相互作用，研究结果表明四个配合物均能与DNA发生插入作用，并研究了他们的结合能力大小；通过光谱法测定了配合物与BSA的相互作用，结果表明合成的配合物单晶其均能与BSA发生相互作用，并且作用强度与配合物浓度成正比。 3、配合物体外抗肿瘤细胞的研究：从细胞水平上用SRB方法研究了上述配合物对三种肿瘤细胞株：人肝癌细胞SMMC-7721、人肺腺癌细胞A549以及人肝癌细胞株Hep G2的体外细胞毒活性，发现配合物对肿瘤细胞均有不同程度的抑制作用，并且IC50值均在100μg/mL以下。 4、金属离子对卡马西平与BSA相互作用的影响：从分子水平上，运用荧光光谱法初步研究不同金属离子对卡马西平(CBZ)与牛血清白蛋白(BSA)的相互作用的影响。本论文设计合成的单核以及草酰胺多核金属配合物，进一步丰富了桥联多核配合物在生物无机化学领域中的作用，对配合物的结构对其与DNA和BSA相互作用的影响进行了探索，对研究配合物的构效关系具有一定的参考价值，，并为毒性较低的金属类药物的设计与合成提供了指导性信息。
[Abstract]:At present, the study of the interaction between metal complexes and biomolecules has become a hot topic in the field of inorganic pharmaceutical chemistry. DNA is an important genetic material in organisms, and protein is an important carrier of biological functions. Both are important biological macromolecules in organisms, and are also the target of many drugs in vivo. Therefore, it is of great significance to synthesize metal complexes that can bond with DNA and protein, to study their anticancer activity and to design modern drugs and analyze their antitumor mechanisms. Based on this background, a single crystal of a mononuclear copper complex was synthesized, and a series of mononuclear copper complexes were designed and synthesized, and three single crystals were obtained by the synthesis of NN-N-symmetric disubstituted oxalamide as bridged ligands. Its crystal structure was elucidated, and its interaction with DNA and BSA and its antitumor activity in vitro were studied by a series of methods. The main contents are as follows: 1. Synthesis and structure analysis of metal complexes: a mononuclear copper complex [Cu (bpy) 2 (pic)] (pic) (1 was synthesized from Cu (pic) 24H 2O and bpy. Different copper salts and terminal ligands were selected, Three complexes have been synthesized: one one-dimensional copper polymer single crystal [Cu _ 2 (deap) (N _ 3) _ 2] n (2) and two binuclear complexes [Cu _ 2 (deap) (bpy) _ 2] (CLO _ 4) _ 2 (3) and Cu _ 2 (deap) (SCN) _ 2 (4). Fluorescence spectroscopy and other methods were used to study the interaction between the complexes and HS-DNA molecules. The results showed that the four complexes could intercalate with DNA and their binding ability was studied, and the interaction between the complexes and BSA was determined by spectrophotometry. The results show that the synthesized complexes can interact with BSA. And the action intensity is proportional to the concentration of the complex. The antitumor effect of the complexes was studied by SRB method at the cell level: human hepatoma cell line SMMC-7721, human lung cancer cell line SMMC-7721. In vitro cytotoxic activity of human hepatoma cell line Hep G2 and A549 cell line. It was found that the complexes had different inhibitory effects on tumor cells, and the IC50 values were below 100 渭 g / mL. 4. The effect of metal ions on the interaction between carbamazepine and BSA: at the molecular level, The effect of different metal ions on the interaction between carbamazepine (CBZ) and bovine serum albumin (BSA) was studied by fluorescence spectrometry. In this thesis, mononuclear and oxalamide polynuclear metal complexes were designed and synthesized, which further enriched the role of bridged polynuclear complexes in the field of bioinorganic chemistry, and explored the effects of the structure of the complexes on their interactions with DNA and BSA. It has some reference value for studying the structure-activity relationship of the complexes and provides guidance information for the design and synthesis of metal drugs with low toxicity.
【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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