药物晶体材料的合成与性质研究

发布时间：2018-11-08 18:17

【摘要】：药物晶体材料作为一类非常有研究价值的材料，在疾病研究与治疗领域起到了至关重要的作用，主要可包括药物多晶型、药物共晶、盐型、溶剂化物或水化物，药物金属配合物等多种分类。药物共晶在保证药物分子结构不变的前提下，改善药物活性成分的理化性质和药学性质，并且自身受到专利等知识产权的保护。而药物金属配合物作为一种合成手段成熟的药物材料，也具有较高的研究价值。因此，药物晶体材料作为多学科交叉的产物，受到了科学家们的广泛关注。本论文依据超分子化学原理和晶体工程学，以姜黄素药物活性分子为主要配体，通过对药物晶体材料的设计与合成，仔细研究和探讨了此类材料在生物和化学领域的潜在应用。主要内容如下： 1.我们以姜黄素为药物活性分子，选用4,4’-联吡啶-N,N’-二氧化物为共晶前驱体制备了两个药物共晶。两种药物共晶是采用同样的API和CCF在不同的溶剂体系中制备而成的。单晶结构显示JUC-C14结构中姜黄素分子以烯醇式存在；而JUC-C15结构中，甲醇分子的存在结构中姜黄素以二酮式存在，这在以往的报道中不常见到。两个共晶都是通过分子间O-H O氢键相连的。单晶X-射线衍射显示JUC-C14是1维链状结构，JUC-C15是2维网状结构，并且两个药物共晶在溶剂作用下可以发生单晶-单晶之间的转化。我们对合成的药物共晶做了体内吸收的药学性质测试和稳定性测试，用以评估药物共晶。 2.我们以药物活性分子姜黄素为配体，选用生物相容性的锌离子成功合成了具有高孔道的药物-金属有机骨架化合物，medi-MOF-1。它具有持久性的孔道和较高比表面积（Langmuir比表面积可达3002m2/g），在已发表的文献中，它是只用生物活性分子就可以构建的bio-MOFs中比表面积最高的。通过进行细胞毒性实验，显示出材料对人体胰腺癌细胞的生长具有抑制作用。我们进一步研究了medi-MOF-1的体外降解过程以及载药能力，分别用布洛芬和5-氟尿嘧啶作为模型药物分子，可以实现姜黄素与布洛芬或5-氟尿嘧啶两种药物分子的共同释放，从而达到药物协同作用的目标。 3.我们在不同条件下对药物-金属有机骨架化合物medi-MOF-1进行了多种气体吸附性质表征，，以考察其气体吸附与捕获性能。实验结果证实了medi-MOF-1材料对氢气具有较好的吸附性能，吸附量可达1.57wt%,且对二氧化碳气体具有一定的选择性吸附能力（相比氮气及甲烷等气体）。热稳定性实验证明材料在300°C时结构仍然保持完整，骨架没有坍塌。不同溶剂中的稳定性实验证实，medi-MOF-1在乙醇、二氯甲烷、正己烷等溶剂中浸泡3天结构不发生变化。此外，材料还表现出了较好的碘单质捕捉和释放能力，1克材料可以吸附0.5克的碘单质。medi-MOF-1的配体为药物活性分子，为这一材料在生物领域应用提供了可能。
[Abstract]:As a kind of material of great research value, drug crystal material plays an important role in the field of disease research and treatment, including drug polycrystalline, drug eutectic, salt, solvation or hydrate. Drug metal complexes and so on many kinds of classification. On the premise of keeping the molecular structure of drugs unchanged, the eutectic can improve the physical and chemical properties and pharmacological properties of the active components of drugs, and be protected by intellectual property rights such as patents and so on. As a kind of mature drug material, metal complexes also have high research value. Therefore, drug crystal materials, as a product of multi-disciplinary intersection, have been widely concerned by scientists. Based on the principle of supramolecular chemistry and crystal engineering, the potential applications of curcumin active molecules in biological and chemical fields were studied and discussed through the design and synthesis of drug crystal materials with curcumin active molecules as main ligands. The main contents are as follows: 1. Two drug eutectics were prepared by using curcumin as drug active molecule and using 4 ~ (4) O ~ (4) -bipyridine-N (N) -N ~ (2) -O _ (2) as eutectic precursor. Two kinds of drug eutectic were prepared by using the same API and CCF in different solvent systems. The single crystal structure shows that curcumin molecule exists in enol form in JUC-C14 structure, while in JUC-C15 structure, curcumin exists as diketone type in methanol molecule structure, which is rarely seen in previous reports. Both eutectics are connected by O-H O hydrogen bonds between molecules. Single crystal X-ray diffraction shows that JUC-C14 is one dimensional chain structure, JUC-C15 is 2 dimensional network structure, and two drug eutectic can be transformed between single crystal and single crystal under the action of solvent. The pharmacological properties and stability of the synthesized drug eutectic were measured in vivo to evaluate the drug eutectic. 2. Using curcumin as ligand and biocompatible zinc ion as ligand, we have successfully synthesized a high pore drug-metal organic skeleton compound, medi-MOF-1.. It has persistent pore and high specific surface area (Langmuir specific surface area up to 3002m2/g). In the published literature, it has the highest specific surface area of bio-MOFs which can be constructed only by bioactive molecules. The cytotoxicity test showed that the material could inhibit the growth of human pancreatic cancer cells. We further studied the degradation process and drug loading ability of medi-MOF-1 in vitro, using ibuprofen and 5-fluorouracil as model drug molecules, respectively. Curcumin and ibuprofen or 5-fluorouracil can be released together to achieve the goal of drug synergism. 3. In order to investigate the gas adsorption and trapping properties of the drug-metal organic skeleton compound medi-MOF-1 was characterized by various gas adsorption properties under different conditions. The experimental results show that medi-MOF-1 has a good adsorption capacity for hydrogen, with a adsorption capacity of 1.57 wtand a certain selective adsorption capacity for carbon dioxide (compared with nitrogen and methane). The thermal stability experiments show that the structure of the material remains intact at 300 掳C and the skeleton does not collapse. The stability experiments in different solvents confirmed that the structure of medi-MOF-1 in ethanol, dichloromethane, n-hexane and other solvents did not change for 3 days. In addition, the material also showed a good ability to capture and release iodine simple substance. 1 gram material can adsorb 0.5 g iodine simple substance. The ligand of medi-MOF-1 is a drug active molecule, which provides the possibility for the application of this material in the biological field.
【学位授予单位】：吉林大学
【学位级别】：博士
【学位授予年份】：2015
【分类号】：TB39

【共引文献】