【作者】 汪宝堆；

【导师】 杨正银；

【作者基本信息】 兰州大学 ， 无机化学， 2008， 博士

【摘要】 恶性肿瘤是威胁人类健康的常见疾病。人类因恶性肿瘤而引发的死亡率在所有疾病死亡率中占据第二,仅次于心血管疾病。目前肿瘤的主要治疗手段仍然为化学治疗。但目前临床使用的化疗试剂仍然有无法克服的毒性高、水溶性差、在血液中循环时间短等缺陷。为了克服这些缺陷,人们一方面在进一步寻找合成新的高效低毒的抗癌药物;另一方面使用药物载体来克服目前使用抗癌药物毒性高、水溶性差、靶向性低等缺陷。为了进一步合成出更好应用前景的抗癌药物和多功能化的药物载体。在本研究中,我们对癌细胞有很好抗癌活性但对正常细胞无毒的天然产物黄酮及其对应的衍生物作为配体合成了其金属配合物。这样使合成的药物分子既具有很好的抗癌活性,又具有很低的毒性。由于目前临床使用的药物载体普遍具有水溶性差、功能化单一、且有些具有毒性等缺陷。在本研究中我们应用多功能化的磁性纳米粒子作为药物载体,使其合成的药物载体既具有靶向运输药物的能力,同时在体内又具有实时监控能力。为此本论文工作包括以下四个部分:1.对抗癌药物的研究现状及在本工作中作为药物载体的磁性纳米粒子的制备和应用做了概述。2.用四氧化三铁纳米粒子和哑铃状的金-四氧化三铁纳米粒子合成了两个磁性纳米粒子的药物载体,这两个载体可以通过pH、氯离子浓度和酶来调节相应黄酮药物和顺铂药物的释放。当药物载体载上色酮后,色酮在水中溶解度由2.5μg/mL增加到633μg/mL,从而使其细胞毒活性明显增强。3.把四氧化三铁纳米粒子引入到临床使用的小分子造影剂（Gd-DTPA）上。这样一方面增强了小分子造影剂的靶向性,另一方面使合成的造影剂纵向驰豫效率增加到44.36 mmol^-1·L·s^-1。由于四氧化三铁纳米粒子可以实现T₂成像,所以本工作合成的造影剂是一中多功能化的造影剂。在本部分内容中,我们同时用有生物靶向性和良好生物活性的色酮类物质对Gd-DTPA的结构进行了改造,得到了两个配体及两个对应的钆的配合物。驰豫效率的测定表明,这两个配合物明显高于临床使用的Gd-DTPA小分子造影剂。这样得到了既具有检测功能又具有治疗作用的双功能的造影剂。4.为了寻求高效低毒的抗癌药物,在本部分用具有很好抗癌活性的但低毒性的天然产物色酮为骨架合成了十一个相应的希夫碱配体和四十多个相应的配合物。同时对所合成的化合物与DNA的结合机理及抗癌活性进行了研究,结果表明所合成的化合物与DNA皆为插入作用。体外细胞毒性实验也证明这些化合物在测试浓度范围内对癌细胞均表现出一定的抑制作用。更多还原

【Abstract】 Malignant tumor is a common disease that threatens the human heath. At present, the mortality rate induced by malignant tumor is at the second places in all disease, followed the cardiovascular disease. The chemistry therapy is still the mostly means in all methods that cure tumour. However, many drugs used in clinic suffer from several drawbacks: high toxicity, low solubility, poor target character and short blood circulation. In order to solve these problems, on the one hand, people are struggling to synthesize the new drugs that have high cure effect to tumour cells and low toxicity to normal cells; on the other hand, drug delivery system are used to decrease the toxicity and enhance the targeted ability of the drugs. In this work, the chromone derivatives that have high anticancer activity and low toxicity to normal cells are used as ligand to synthesize the metal complexes. At the same time, we use the magnetic nanoparticles as drug carrier to delivery the anticancer drug.This paper is divided into four parts:1. It was given a brief review of the research progress about anticancer drug. At the same time, the preparation and application of magnetic nanoparticles used as drug carrier were summarized.2. Using iron oxide and gold-iron oxide nanoparticles, we synthesized two drug carriers. These two drug carriers can control release the chromone and Cisplatin, respectively.3. Iron oxide nanoparticles were successfully introduced into the framework of Gd（DTPA）^2-. The advantages of this work exhibit two aspects: （1） enhanced the targeted ability of Gd （DTPA）^2-, （2） increased the spin-lattice relaxation time of Gd （DTPA）^2-. Due to iron oxide nanoparticles can realize the T2 imagine, the MRI agent synthesized in this work is a multifunction agent. Another work is synthesis two novel MRI agents that use chromone to modify the Gd （DTPA）^2-. Because compounds containing chromone framework have good anticancer activity. Using these compounds to modify the Gd （DTPA）^2-, we can obtain bifunctional MRI agents that bear the survey and cure function. 4. In order to seek the new drugs that have high cure effect to tumour cells and low toxicity to normal cells, eleven chromones Schiff-base ligands and forty corresponding metal complexes have been synthesized and characterized on the basis of elemental analyses, molar conductivities, IR spectra, ¹H NMR spectra and crystal structure. We investigate the interaction mode of these compounds with CT-DNA. The experiment results suggest that these compounds can bind DNA by intercalation mode, but binding affinities of these compounds to DNA are much higher than ligand. Cytotoxic activities experiments in vivo suggest that these compounds exhibit good activities to tumour cells in our measure range.更多还原