摘要
无机化学领域中金属配合物的结构和它们的生物活性是一个比较热门的研究领域。DNA结合的研究对新发展的治疗试剂寻找DNA探针的有非常重要的作用。此外，血清白蛋白(SA)是血浆中最丰富的蛋白，并具有非常重要的生理功能，如运输，缓冲，营养等。这引起了科学家研究金属配合物生物化学特性的兴趣，包括配合物与主要目标分子DNA和血清白蛋白的相互作用。
论文共分为四部分：
第一章：介绍了DNA、蛋白的结构、功能和性质，综述了金属配合物与DNA、蛋白的作用机制与应用研究进展。
第二章：合成了四种含硫氨基葡萄糖金属配合物(M-GLUS，M=Co，Cu，Ni，Zn)，利用元素分析，摩尔电导，核磁共振氢谱进行了结构表征，结果表明含硫配体与这四种二价金属离子均形成了2：1型非电解质配合物。在pH=7．08 Tris缓冲液中，采用紫外吸收光谱和荧光光谱研究了金属配合物与小牛胸腺DNA的作用机制，发现随着金属配合物量的逐渐增加，DNA电子吸收光谱的最大吸收峰呈增色效应，对配合物DNA-EB体系也能产生荧光猝灭作用，说明四种金属配合物均可与DNA发生相互作用，结合方式为部分插入；进而在近似生理酸度条件下，利用荧光光谱，对金属配合物与HSA/BSA的结合特性进行了初步分析，发现配合物均能猝灭HSA/BSA的荧光强度，利用Scatchard方程计算了四种金属配合物与HSA/BSA的结合常数和结合位点数，结果表明金属配合物与血清白蛋白有较强的结合且只有1类键合位，其中Co-GLUS与蛋白的结合力最强。
第三章：合成了N，N’-联苄基-1,2-二胺(L)及四种过渡金属配合物，ML_2(OAc)_2·2H_2O(M=Cu，Ni，Zn，Co，并利用元素分析，质谱，摩尔电导，NMR及IR进行结构表征。另外，利用单晶X射线衍射仪测定Cu(Ⅱ)和Ni(Ⅱ)金属配合物的晶体结构，表明配合物有相似的分子结构。Ni(Ⅱ)配合物为一个规则的正八面体配位环境，但受典型Jahn Teller效应影响，Cu(Ⅱ)处于一个拉长的八面体环境。利用UV和荧光光谱法分析配合物与小牛胸腺DNA的作用机制，结果表明，配合物与DNA之间的结合方式为插入。在近似生理酸度条件下，研究Cu(OAc)_2L_2·2H_2O和Ni(OAc)_2L_2·2H_2O与蛋白相互作用的情况。应用荧光分析法对其与HSA的结合特征以及热力学作用进行分析。结果表明，主要作用力为疏水作用。根据Scatchard's方程计算，Cu(OAc)_2L_2·2H_2O、Ni(OAc)_2L_2·2H_2O的焓变和熵变分别为-11．533 kJ·mol~(-1)和46．339 J·mol~(-1)·K~(-1),-11．026 kJ·mol~(-1)和46．396J·mol~(-1)·K~(-1)。
第四章：苯甲醛与二乙烯三胺浓缩反应得到的Schiff碱，经KBH_4还原得到一个新配体，N-苯甲基-N'-[2-(苄氨基)乙基]乙烷-1，2-二胺，其与过渡金属氯酸盐合成金属配合物，通式为M_2L_2Cl_3(M=Cu，Ni，Zn，Co)。利用摩尔电导，元素分析，IR光谱对其进行表征，通过X射线单晶衍射仪确定Ni(Ⅱ)配合物的晶体结构，氯原子为桥联原子。应用紫外和荧光光谱法，研究小牛胸腺DNA与配合物的相互作用，表明配合物与DNA的结合模式为静电作用，结合力为Cu(Ⅱ)配合物>Zn(Ⅱ)配合物>Ni(Ⅱ)配合物>Co(Ⅱ)配合物。通过Scatchard方程分析金属配合物与人血白蛋白的结合常数与结合位点，结果表明配合物与HSA有很强的相互作用。热力学作用分析，主要作用力为疏水作用。
Many studies on the molecular structure of metal complexes and their biological activity caused much interest in the field of inorganic chemistry. DNA binding studies are very important for the development of new therapeutic reagents and DNA probes. Furthermore, human serum albumin (HSA) is the most abundant protein in the blood plasma, and has very important physiological functions, such as transportation, buffering, nutrition, etc. These inspire considerable interest in the study of the biochemical behavior of these complexes including their interactions with DNA and serum proteins, which are primary target molecules, when metal compound is administered intravenously.
This dissertation consists of four chapters:
Chapter 1: The structure, function and properties of DNA and protein were introduced, the methods for the analysis of the interaction of drugs with DNA, protein and research progress in preparation, bioactivities and application of complexes were summarized.
Chapter 2: Four sulfur-containing D(+)-glucosamine metal complexes have been synthesized (M-GLUS, M = Co, Cu, Ni, Zn) and characterized by elementary analysis, molar conductance, and proton nuclear magnetic resonance. The yields of all these complexes were about 70%, they dissolved easily in water. The ligand coordinate metal ions mainly between sulphur and metalions, the coordination molar ratio of the ligand to metalion was 2:1, the molar conductivity indicated that all the complexes are nonelectrolyte. The mechanism of the interaction between metal complexes and calf thymus (ct) DNA has also been studied by ultraviolet absorption and fluorescence spectroscopy in Tris buffer (pH=7.08). The results from varied experiments show that the intensity of the maximal absorption peaks increased with gradual addition of metal complexes, but the metal ions can decrease the maximal absorption and the ligand has no effect on it. Meanwhile, metal complexes could remarkably quench the emission intensity of the DNA-EB system, the metal complexes could be bound to ct DNA. The quenching mechanism was discussed by Stern-Volmer's equation, the figure showed that it is influenced by static quenching and dynamic quenching, so the partial interaction of the complexes and ct DNA was the major mode. Under physiological pH condition, this study was designed to examine the effect of complexes on human serum albumin and bovine serum albumin by fluorescence, the complexes can decrease the intensity. The binding constants and sites of the interaction with serum albumin were analyzed by the Scatchard's equation, the results indicated that there was a strong interaction between the four metal complexes and serum albumin, the binding force was Co-GLUS > Zn-GLUS > Cu-GLUS＞Cu-GLUS, and the binding site is only one.
Chapter 3: A new ligand, V,V'-dibenzylethane-l,2-diamine (L) and its four transition metal(Ⅱ) complexes, ML_2(OAc)_2·2H_2O (M = Cu, Ni, Zn, Co), have been synthesized and characterized by elemental analysis, mass spectra, molar conductivity, NMR and IR. Moreover, the crystals structure of Cu(Ⅱ) and Ni(Ⅱ) complexes characterized by single crystal X-ray diffraction showed that the complexes have a similar molecular structure. Ni(Ⅱ) has an regular octahedral coordination environment complexes, but typical Jahn Teller effect influenced Cu(Ⅱ) in an elongated octahedral environment. The interaction between complexes and calf thymus DNA were studied by UV and fluorescence spectra measure, which showed that the binding mode of complexes with DNA is intercalation. Under physiological pH condition, the effects of Cu(OAc)_2L_2·2H_2O and Ni(OAc)_2L_2·2H_2O on human serum albumin were examined by fluorescence. The results of spectroscopic measurements suggested that the hydrophobic interaction is the predominant intermolecular force. The enthalpy change△H~0 and the entropy change△S~0 of Cu(OAc)_2L_2·2H_2O and Ni(OAc)_2L_2·2H_2O were calculated to be -11.533 kJ·mol~(-1) and 46.339 J·mol~(-1)·K~(-1), -11.026 kJ·mol~(-1) and 46.396 J·mol~(-1)·K~(-1) respectively, according to the Scatchard's equation. The quenching mechanism and the number of binding site (n≈l) were also obtained from fluorescence titration data.
Chapter 4: A new ligand, N-benzyl-N'-[2-(benzylamino)ethyl]ethane-l,2-diamine, is a KBH_4 reduction product of the Schiff base derived from the condensation reaction of A-(2-aminoethyl)ethane-l,2-diamine with 2 equiv of benzaldehyde. Its complexes with transition metal chlorides were synthesized. These complexes with the general formula of M_2L_2Cl_3 (M=Cu, Ni, Zn, Co) were characterized by molar conductivity, elemental analysis, IR spectra. And the crystal structure of Ni (II) complex determined by single crystal X-ray diffraction show that there was a chlorine atom as bridge. The interaction of complexes with calf thymus DNA was investigated by ultraviolet spectroscope and fluorescent spectroscopy, which showed that the mode of complexes binding to DNA was electrostatic binding, and the binding affinity with DNA was Cu(Ⅱ) complex＞Zn(Ⅱ) complex＞Ni(Ⅱ) complex＞Co(Ⅱ) complex. The binding constants and sites of the interaction with human serum albumin were analyzed by the Scatchard' equation, the results indicated that there was a strong interaction between the metal complexes and HSA. As indication by thermodynamic analyses, the binding was mainly based on hydrophobic interaction.
引文
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