新型胺基和双膦酸酯轴向取代硅酞菁的合成及生物活性测试

发布时间：2018-03-26 12:31

本文选题：光动力治疗　切入点：化疗　出处：《山东大学》2017年硕士论文

【摘要】：由于硅酞菁中硅的六配位属性,使其具有可以在轴向上引入配体的特性。因此通过引入功能化的基团不仅可以改善硅酞菁性能,还可以增加空间位阻改善聚集。胺类化合物在细胞的增殖和分化中扮演着重要的角色;双膦酸酯通过抗侵入性、抗血管生成、免疫调节等活动直接抑制肿瘤生长是常用的化疗药物。将第二代光敏剂与化疗抗癌药物一起作用能够产生协同效应,显著增强抗癌功效,减小副作用,解决耐药性等问题。在本论文中,我们首先合成了两种不同长度胺基链轴向取代的硅酞菁,发现长链胺基硅酞菁具有较好的性质,以此为前置配体,接上双膦酸酯,成功合成了双膦酸酯取代硅酞菁,测试了合成物的光物理化学及生物性质。论文的主要内容如下:1 以二氯硅酞菁为原料,2-(2-胺基乙氧基)乙醇和乙醇胺作为配体分别轴向取代硅酞菁。通过核磁氢谱、碳谱,质谱,元素分析,红外等方法对合成的两种硅酞菁进行表征,确保与设计的分子结构一致。2 紫外可见光谱显示除了在常规有机溶剂中,两种胺基硅酞菁在水溶液中也表现出了良好的溶解性。荧光光谱显示两种胺基硅酞菁的荧光强度均随着pH值的降低而有所增强。3 用Hela细胞进行细胞吸收、体外细胞毒性和荧光成像实验。长链胺基硅酞菁的吸收和荧光强度均高于短链胺基硅酞菁,对细胞荧光成像的进一步研究中发现两种硅酞菁均在线粒体中显示较大的聚集。长链和短链硅酞菁均具有较高的光毒性和低暗毒性,符合理想光敏剂特点。4 以合成的长链胺基硅酞菁作为配体,与设计合成的带有羧基的双膦酸酯室温反应,利用核磁氢谱、碳谱、磷谱,质谱,元素分析,红外等方法对合成的硅酞菁进行表征,确保与设计的分子结构一致。5 光物理化学测试结果显示,与长链胺基硅酞菁相比,双膦酸酯的引入对酞菁本身的性质影响较小,其紫外可见光谱和荧光光谱未发生明显变化,单线态氧产率也很相近,但荧光量子产率有所提高。6 用A549肺癌细胞和HELF正常肺细胞进行细胞吸收、体外细胞毒性和荧光成像实验。双膦酸酯硅酞菁在A549细胞中的吸收和荧光强度均高于HELF细胞。对细胞荧光成像的进一步研究中发现双膦酸酯硅酞菁在线粒体和溶酶体中均有聚集。在光照条件下,双膦酸酯硅酞菁在A549细胞中的光毒性高于HELF细胞,而且双膦酸酯硅酞菁比胺基硅酞菁表现出了更好的光毒性。在避光时,低浓度条件下胺基硅酞菁几乎没有表现出暗毒性,但是双膦酸酯硅酞菁仍有一定的暗毒性。这些结果表明双膦酸酯硅酞菁是潜在的具有光动力治疗和化疗协同作用的光敏剂。
[Abstract]:Because of the six-coordination property of silicon phthalocyanine, the ligand can be introduced in the axial direction, so the functional group can not only improve the performance of silicon phthalocyanine. Amines play an important role in cell proliferation and differentiation. Bisphosphonates resist angiogenesis by resisting invasiveness. Immunoregulation and other activities directly inhibit tumor growth are commonly used chemotherapeutic drugs. When combined with chemotherapy and anticancer drugs, the second generation Guang Min can produce synergistic effects, significantly enhance the anticancer effect and reduce side effects. In this thesis, we first synthesized two kinds of silyphthalocyanines with different lengths, which were substituted in the axial direction. We found that the long chain silyl phthalocyanines had good properties and were used as preligants to attach diphosphonates. Diphosphonate substituted silicon phthalocyanine was synthesized successfully. The photophysicochemical and biological properties of the synthesized were tested. The main contents of the thesis are as follows: 1. The main contents of the thesis are as follows: 1. The main contents of this thesis are as follows: 1. The ethanolamine and ethanol alcohol were used as ligands to replace silica phthalocyanines in the axial direction respectively. The main contents of this thesis are as follows: hydrogen NMR, carbon spectrum, mass spectrometry, Elemental analysis, IR and other methods were used to characterize the two kinds of silicone phthalocyanines. The results showed that they were in good agreement with the designed molecular structure, except in conventional organic solvents. The fluorescence spectra showed that the fluorescence intensity of the two kinds of aminosilyphthalocyanines increased with the decrease of pH value, and that the absorption of Hela cells was enhanced with the decrease of pH value. In vitro cytotoxicity and fluorescence imaging experiments. The absorption and fluorescence intensity of long chain silyl phthalocyanine was higher than that of short chain aminosilyl phthalocyanine. In the further study of cell fluorescence imaging, it was found that both of the two kinds of silicophthalocyanines showed large aggregation in mitochondria. Both long-chain and short-chain silicon phthalocyanines had high phototoxicity and low dark toxicity. In accordance with the ideal Guang Min characteristic, the synthesized long chain amino-silyphthalocyanine was used as ligands to react with the designed bisphosphonate with carboxyl groups at room temperature. Nuclear magnetic resonance spectroscopy (NMR), carbon spectrum, phosphorus spectrum, mass spectrometry and elemental analysis were used. The synthesized silicone phthalocyanines were characterized by IR, and the results showed that compared with the long chain amino-silicone phthalocyanines, the introduction of bisphosphonate had less influence on the properties of phthalocyanines. The UV-Vis spectra and fluorescence spectra did not change obviously, and the singlet oxygen yields were similar, but the fluorescence quantum yields increased. 6. The absorption of A549 lung cancer cells and HELF normal lung cells was increased. In vitro cytotoxicity and fluorescence imaging experiments. The absorption and fluorescence intensity of bisphosphonate silicon phthalocyanine in A549 cells were higher than those in HELF cells. There is aggregation in the body of the body. The phototoxicity of bisphosphonate silicon phthalocyanine in A549 cells was higher than that in HELF cells, and the phototoxicity of bisphosphonate silicon phthalocyanines was better than that of aminosilyl phthalocyanines. However, siphthalocyanines of bisphosphonates still have some dark toxicity. These results indicate that siphthalocyanines of bisphosphonates are potential Guang Min agents with synergistic effects of photodynamic therapy and chemotherapy.
【学位授予单位】：山东大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：O641.4;TQ460.1

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