苯并咪唑与去甲斑蝥素酰亚胺过渡金属配合物的合成、晶体结构及与DNA和BSA作用研究

发布时间：2018-07-05 02:59

本文选题：去甲基斑蝥酸根 + 苯并咪唑　；参考：《浙江师范大学》2014年硕士论文

【摘要】：癌症是严重危害人们安全的疾病。研发新型的治疗肿瘤的金属配合物类药物是生物化学家探究的热点。‘人们发现过渡金属类配合物越来越多地显示出广泛的生物活性。去甲斑蝥素是一种传统抗癌药物斑蝥素的衍生物。它不但具有很强的抗癌活性,并且对正常细胞的伤害较小。因此,我们以去甲斑蝥素为先导化合物,不仅设计合成了三种N-氮杂环去甲斑蝥素酰亚胺,而且合成了几种新型的过渡金属与去甲斑蝥素和苯并咪唑类化合物的配合物；研究了其与DNA和牛血清白蛋白(BSA)的作用,并测试了它们对人宫颈癌细胞(Hela)和人肝癌细胞(SMMC7721)的体外抗增殖活性。主要研究内容如下： 1、合成了三种N-芳(杂)环去甲斑蝥素酰亚胺化合物：N-苯去甲斑蝥素酰亚胺(L1)、N-2-吡啶去甲斑蝥素酰亚胺(L2)和N-2-甲基苯并咪唑去甲斑蝥素酰亚胺(L3)。化合物的组成通过元素分析、红外光谱、核磁共振等方法确定。它们的组成为：C14H13NO3(L1), C13H12N2O3(L2), C16H15N3O3(L3)。化合物与DNA的相互作用通过紫外光谱法、荧光光谱法、粘度法研究。研究结果表明三种化合物以中等强度与DNA发生部分插入作用。另外通过荧光光谱法探究了化合物和BSA的相互作用。化合物与BSA通过静态猝灭机制发生强烈的相互作用。同时测试了化合物对人宫颈癌细胞(Hela)的体外抗增殖活性,实验表明,化合物L2和L3抗癌细胞的增殖活性较化合物L1高。其中化合物L3具有最强的抗增殖活性。 2、采用溶液法合成了两种新颖的铜配合物：N-2-甲基苯并咪唑去甲斑蝥素酰亚胺合铜(Ⅱ)配合物(1)、苯并咪唑与去甲斑蝥酸根合铜(Ⅱ)混配配合物(2)。配合物的成和结构通过元素分析、红外光谱、X-射线单晶衍射等方法被确定下来。它们的组成为：[Cu(Ac)2(L3)2]·3H2O(1)(Ac=醋酸根,C2H3O2;L3=N-2-甲基苯并咪唑去甲斑蝥素酰亚胺,C16H15O3N3)、[Cu(bimz)2(DCA)](2)(bimz=苯并咪唑,C7H6N2; DCA=去甲斑蝥酸根,C8H805)。通过X-单晶衍射法确定了配合物1的配位中心空间结构是配位数为四的平面四方型；配合物2的配位中心空间结构是配位数为五的四方锥型。配合物与DNA的相互作用是通过紫外光谱法、荧光光谱法、粘度法和琼脂糖凝胶电泳法进行了研究。配合物和BSA的相互作用是运用荧光光谱法进行研究的。同时测试了配合物1和2对人肝癌细胞(SMMC-7221)的体外抗增殖活性。结果显示配合物和DNA以中等强度发生部分插入作用,配合物1和2均以氧化还原机制切割超螺旋质粒DNA。配合物与BSA通过静态猝灭机制发生强烈的相互作用。同时在测试浓度范围内,配合物1和2比化合物L3和Na2(DCA)有很强的体外抗人肝癌细胞(SMMC-7221)的效果。其中,配合物1的体外抗增殖活性最强。 3、合成了四种2-氨基苯并咪唑与去甲斑蝥酸根(DCA)合过渡金属(钴、镍、铜和锌)的混配配合物。采用元素分析、红外光谱和X-射线单晶衍射法确定了它们的组成和结构。组成为：(Habiz)2[M(DCA)2]-4H2O(M=Co (Ⅱ)(3), Ni(Ⅱ)(4),Cu(Ⅱ)(5),Zn(Ⅱ)(6); Habiz=质子化的2-氨基苯并咪唑)。确定了四种配合物的配位中心的空间结构均为配位数为六的八面体型,配位的基团呈现中心对称结构。通过紫外吸收光谱法、粘度法和琼脂糖凝胶电泳法研究了配合物和DNA的作用,结果显示配合物以较强的强度与DNA发生部分插入作用,配合物5的作用最强。通过荧光光谱法研究了配合物和BSA的作用,研究发现配合物均以静态猝灭模式猝灭BSA的荧光,发生强烈的相互作用。配合物6对人肝癌细胞SMMC-7221具有很强的体外抗增殖活性。
[Abstract]:Cancer is a disease that seriously endangers people's safety. Developing a new type of metal complex to treat tumors is a hot spot for biochemists. 'people find that the transition metal complexes are increasingly showing extensive biological activity. Norcantharidin is a derivative of cantharidin, a traditional anticancer drug. It is not only very good. Strong anticancer activity and less harm to normal cells. Therefore, we use norcantharidin as the precursor compound, not only designed and synthesized three kinds of N- nitrogen heterocyclic norcantharidin, but also synthesized several new transition metals with norcantharidin and benzimidazole compound, and studied it with DNA and bovine blood. The effect of albumin (BSA) and their antiproliferative activity to human cervical cancer cells (Hela) and human hepatoma cells (SMMC7721) in vitro were tested. The main contents are as follows:
1, three kinds of N- aromatic (heterozygous) norcantharidin imide compounds are synthesized: N- benzocancantharidimide (L1), N-2- pyridine norcantharidimide imide (L2) and N-2- methyl benzimidazole norcantharidimide (L3). The composition of the compounds is determined by elemental analysis, red spectrum, nuclear magnetic resonance and so on. Their composition is C14H13NO 3 (L1), C13H12N2O3 (L2), C16H15N3O3 (L3). The interaction between compounds and DNA is studied by ultraviolet spectroscopy, fluorescence spectroscopy, viscosity method. The results show that the three compounds are partially inserted with DNA in medium strength. In addition, the interaction between compounds and BSA is explored by fluorescence spectroscopy. Compounds and BSA are static by static quenching. The antiproliferative activity of compounds on human cervical cancer cells (Hela) in vitro was also tested. The experimental results showed that the proliferation activity of compound L2 and L3 cancer cells was higher than that of compound L1. Compound L3 had the strongest antiproliferative activity.
2, two novel copper complexes were synthesized by solution method: N-2- methyl benzimidazole norcantharidimidimide copper (II) complex (1), benzimidazole and norcantharidis copper (II) mixed ligand complexes (2). The formation and structure of the complexes were determined by elemental analysis, infrared spectra, and single crystal diffraction of X- ray. The composition is: [Cu (Ac) 2 (L3) 2]. 3H2O (1) (Ac= acetate root, C2H3O2; L3=N-2- methyl benzimidazole norcantharidimide, C16H15O3N3), [Cu (bimz) 2 (DCA)] (2). The coordination center space structure of complex 1 is determined by the single crystal diffraction method of the planar Quartet of the coordination number of four. The coordination center space structure of the complex 2 is a four square cone type with a coordination number of five. The interaction between the complexes and DNA is studied by UV spectroscopy, fluorescence spectroscopy, viscosity and agarose gel electrophoresis. The interaction of the complexes and BSA is studied by fluorescence spectrometry. The complexes are also tested by 1 and 2. The anti proliferative activity of human hepatoma cells (SMMC-7221) in vitro. The results showed that the complexes and DNA were partially inserted at medium intensity, and the complexes 1 and 2 both cut the super helix plasmid DNA. complex with BSA by the mechanism of static quenching. Compounds L3 and Na2 (DCA) have strong anti human hepatoma cells (SMMC-7221) in vitro. Among them, complex 1 has the strongest antiproliferative activity in vitro.
3, four mixed complexes of 2- amino benzimidazole and norcantharidis (DCA) transition metals (cobalt, nickel, copper and zinc) were synthesized. Their composition and structure were determined by elemental analysis, IR and X- ray diffraction. The composition is: (Habiz) 2[M (DCA) 2]-4H2O (M=Co (II) (3), Ni (II) (4), Cu (5), Zn (6) (6); Habiz=); 2- amino benzimidazole is a protonated amino benzimidazole. The coordination center of the four complexes is determined that the coordination center of the complex is six of the coordination number and the coordination group presents a central symmetric structure. The complexes and DNA are studied by UV absorption spectrometry, viscosity method and agarose gel electrophoresis. The results show that the complexes are strong strong. The role of degree and DNA was partially inserted, the role of complex 5 was the strongest. The effects of complexes and BSA were studied by fluorescence spectroscopy. It was found that the complexes all quenched the fluorescence of BSA by static quenching mode and had strong interaction. Complex 6 had strong in vitro antiproliferative activity to human hepatoma cells in vitro.
【学位授予单位】：浙江师范大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R914

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