氟硼吡咯衍生物及其纳米复合物的合成、表征和性能研究
发布时间：2018-09-19 17:03
【摘要】：近红外荧光成像以及近红外荧光探针技术在诊断学、生物医学、环境科学和材料化学等领域已经成为重要的技术手段。发展具有高效的近红外荧光探针在离子检测、生物分子检测、细胞成像和肿瘤治疗等方面具有重要的意义。氟硼吡咯(BODIPY)具有良好的光稳定性、热稳定性和生物相容性。此外,基于不同的功能特性可以对BODIPY的结构修饰,以改变其光学性能应用于近红外荧光探针、电化学传感以及生物成像等领域。本论文总结了氟硼吡咯的合成方法、氟硼吡咯类化合物在肿瘤治疗上的应用以及近红外氟硼吡咯作为生物体内荧光分子探针的运用。设计合成了三种不同氟硼吡咯八号位(meso)位取代的化合物及其十个相关的共轭化合物,并研究了这些化合物的光学特性;进一步制备了近红外氟硼吡咯-离子液体复合物以及氟硼吡咯锰复合物,通过核磁、质谱、元素分析、透射电镜(TEM)等方法表征了配合物的结构,研究了它们的细胞成像、光致毒性以及锰复合物在肿瘤光动力学治疗方面的运用。主要创新结果如下:(1)合成了三种不同八号位(meso)位取代的氟硼吡咯衍生物及其十个共轭化合物,比较了这些化合物紫外吸收、荧光量子产率、荧光寿命等光学特性与结构之间的关系,发现3,5-位侧链二甲胺基苯乙烯基取代的氟硼吡咯,其Stocks位移增大,同时荧光量子产率增高;meso位引入吗啉基团使该类化合物具有一定的亲水性和质子化能力,能运用于细胞成像中。细胞毒性实验显示,取代基对化合物的毒性有一定的影响。实验结果为构建近红外细胞成像剂提供了理论基础。(2)合成了氟硼吡咯锰纳米复合物PMnD,并研究其催化水氧化活性和光动力学治疗肿瘤方面的运用。发现PMnD具有催化剂和光敏剂于一体的特点,其与水作用释放出氧气,PMn D-水体系是较好的光驱动氧释放体。细胞实验结果表明PMnD具有线粒体靶向性、光激活的抗肿瘤活性和对HIF-ɑ的抑制性能,可望用于缺氧肿瘤的成像和光控制治疗。(3)比较了2d、DTM和DTP三种BODPY衍生物对pH的响应,发现具有吗啉基团的化合物其质子化效率高于异喹啉基团,化合物颜色随pH变化肉眼可见,同时turn-on的荧光变化特性使DTP有望作为pH的荧光探针。(4)合成了一种新型的吡咯甲酮取代咪唑盐,利用其带正电荷性质与DPD组装获得DPD-Ps复合物,DPD-Ps具有较好水溶性并被细胞吸收,DPD能作为核酸载体,DPD-Ps-核酸可作为肿瘤靶向成像剂。
[Abstract]:Near-infrared fluorescence imaging and near-infrared fluorescence probe technology have become important technical means in diagnostics, biomedicine, environmental science and material chemistry. The development of NIR fluorescent probes with high efficiency is of great significance in ion detection, biomolecular detection, cell imaging and tumor therapy. Fluoropyrrole (BODIPY) has good photostability, thermal stability and biocompatibility. In addition, the structure of BODIPY can be modified based on different functional characteristics to change its optical properties and be used in near infrared fluorescence probe, electrochemical sensing and biological imaging. In this paper, the synthesis method of fluoroboropyrrole, the application of fluorboropyrrole compounds in tumor therapy and the application of near infrared fluoropyrrole as fluorescence molecular probe in vivo were summarized. Three kinds of (meso) substituted compounds at the eighth position of fluorboron and their ten conjugated compounds were designed and synthesized. The optical properties of these compounds were studied. Near-infrared fluoropyrrole-ionic liquid complexes and fluorboropyrrolidene manganese complexes were further prepared. The complexes were characterized by NMR, mass spectrometry, elemental analysis and transmission electron microscopy (TEM), and their cellular imaging was studied. Phototoxicity and application of manganese complex in photodynamic therapy of tumor. The main innovative results are as follows: (1) three kinds of fluoroboropyrrole derivatives and their ten conjugated compounds were synthesized and their UV absorption and fluorescence quantum yields were compared. The relationship between the optical properties such as fluorescence lifetime and the structure shows that the Stocks shift increases with the substitution of fluoroboron pyrrole with dimethylamino styrene-group in the 3 ~ (5) -position side chain. At the same time, the introduction of morpholine group at meso site to increase the fluorescence quantum yield makes the compounds have certain hydrophilicity and protonation ability, and can be used in cell imaging. Cytotoxicity tests showed that the substituents had a certain effect on the toxicity of the compounds. The experimental results provide a theoretical basis for the construction of near infrared cell imaging agents. (2) the fluoroboropyrrole manganese nanocomposite PMnD, was synthesized and its catalytic water oxidation activity and photodynamic therapy were studied. It is found that PMnD has the characteristics of catalyst and Guang Min, and it is a good photo-driven oxygen releasing agent when it acts with water to release oxygen and PMN D- water system. The results of cell experiments showed that PMnD had mitochondrial targeting, photoactivated anti-tumor activity and inhibitory effect on HIF-. It is expected to be used in hypoxic tumor imaging and photocontrol therapy. (3) the responses of two BODPY derivatives of DTM and DTP to pH were compared. It was found that the protonation efficiency of the compounds with morpholine group was higher than that of isoquinoline group, and the color of the compounds varied with pH. At the same time, the fluorescence characteristics of turn-on make it possible to use DTP as a fluorescence probe for pH. (4) A novel pyrrolidone substituted imidazole salt was synthesized. The DPD-Ps complex DPD-Ps assembled with DPD with positive charge can be used as carrier of nucleic acid, DPD-Ps- nucleic acid can be used as tumor target imaging agent.
【学位授予单位】：江苏大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：O657.3;O626.13
本文编号：2250764
[Abstract]:Near-infrared fluorescence imaging and near-infrared fluorescence probe technology have become important technical means in diagnostics, biomedicine, environmental science and material chemistry. The development of NIR fluorescent probes with high efficiency is of great significance in ion detection, biomolecular detection, cell imaging and tumor therapy. Fluoropyrrole (BODIPY) has good photostability, thermal stability and biocompatibility. In addition, the structure of BODIPY can be modified based on different functional characteristics to change its optical properties and be used in near infrared fluorescence probe, electrochemical sensing and biological imaging. In this paper, the synthesis method of fluoroboropyrrole, the application of fluorboropyrrole compounds in tumor therapy and the application of near infrared fluoropyrrole as fluorescence molecular probe in vivo were summarized. Three kinds of (meso) substituted compounds at the eighth position of fluorboron and their ten conjugated compounds were designed and synthesized. The optical properties of these compounds were studied. Near-infrared fluoropyrrole-ionic liquid complexes and fluorboropyrrolidene manganese complexes were further prepared. The complexes were characterized by NMR, mass spectrometry, elemental analysis and transmission electron microscopy (TEM), and their cellular imaging was studied. Phototoxicity and application of manganese complex in photodynamic therapy of tumor. The main innovative results are as follows: (1) three kinds of fluoroboropyrrole derivatives and their ten conjugated compounds were synthesized and their UV absorption and fluorescence quantum yields were compared. The relationship between the optical properties such as fluorescence lifetime and the structure shows that the Stocks shift increases with the substitution of fluoroboron pyrrole with dimethylamino styrene-group in the 3 ~ (5) -position side chain. At the same time, the introduction of morpholine group at meso site to increase the fluorescence quantum yield makes the compounds have certain hydrophilicity and protonation ability, and can be used in cell imaging. Cytotoxicity tests showed that the substituents had a certain effect on the toxicity of the compounds. The experimental results provide a theoretical basis for the construction of near infrared cell imaging agents. (2) the fluoroboropyrrole manganese nanocomposite PMnD, was synthesized and its catalytic water oxidation activity and photodynamic therapy were studied. It is found that PMnD has the characteristics of catalyst and Guang Min, and it is a good photo-driven oxygen releasing agent when it acts with water to release oxygen and PMN D- water system. The results of cell experiments showed that PMnD had mitochondrial targeting, photoactivated anti-tumor activity and inhibitory effect on HIF-. It is expected to be used in hypoxic tumor imaging and photocontrol therapy. (3) the responses of two BODPY derivatives of DTM and DTP to pH were compared. It was found that the protonation efficiency of the compounds with morpholine group was higher than that of isoquinoline group, and the color of the compounds varied with pH. At the same time, the fluorescence characteristics of turn-on make it possible to use DTP as a fluorescence probe for pH. (4) A novel pyrrolidone substituted imidazole salt was synthesized. The DPD-Ps complex DPD-Ps assembled with DPD with positive charge can be used as carrier of nucleic acid, DPD-Ps- nucleic acid can be used as tumor target imaging agent.
【学位授予单位】：江苏大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：O657.3;O626.13
【参考文献】
相关期刊论文 前1条
1 LI Xiang;ZHAO KaiDi;GUO WenJie;LIU Xu;LIU Jia;GAO Jing;CHEN QiuYun;BAI YiDong;;A novel manganese complex LMnAc selectively kills cancer cells by induction of ROS-triggered and mitochondrial-mediated cell death[J];Science China(Life Sciences);2014年10期
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