基于MOF-磁性石墨烯功能材料富集和分离手性药物的研究

Chiral separation medium is the core and key of chiral drug separation. Metal-Organic Frameworks (MOF)-modified materials show the potential research and application values in the chiral drug separation. The design and synthesis of novel MOF-magnetic graphene functionalized composite materials are proposed in this project. The enrichment of chiral drugs such as metoprolol, ibuprofen, praziquantel and the directly fast separation and preparation from their enantiomers can be realized by taking advantage of the magnetic solid phase extraction (MSPE) technology. The simplification of enrichment steps and short enrichment time will remedy the shortcomings of expensive chiral column and high mobile phase cost in chromatography. The main contents are as follows. Firstly, the preparation of magnetic graphene nanomaterials will be studied. Then the magnetic graphene nanomaterials will be functionalized by binding chiral MOF reagents. Secondly, fast chiral analysis methodology will be set up through optimizing the conditions of chiral compounds recognition and evaluating their enrichment performance by combing LC and CE techniques. In additon, the effect of the introduction of graphene structure on the enrichment performance of composite materials should be investigated. Thirdly, the effect of thermodynamics and kinetics parameters in the extraction process will be discussed, the enrichment performance of the functionalized materials will be clarified based on the structures of composites and the drug enantiomers. Fourthly, quantum chemistry calculation method will be introduced to study the interaction between the MOF-graphene composites and chiral drug molecules. The specific recognition and enrichment models of MOF-graphene composites toward guest molecules will be constructed. All of this will provide the theoretical and experimental basis for the synthesis of new MOF-magnetic graphene functionalized materials. Fifthly, the enrichment and analytical methods of the new chiral drugs will be studied. The aim of this study is to develop the new materials and new technology for drug enantiomers separation and preparation. So it has important scientific and application values.

手性分离介质是手性药物分离的核心和关键，手性金属-有机骨架化合物(MOF)的改性材料在手性药物分离中显示出了潜在的研究与应用价值。本项目拟制备具有手性识别能力的MOF-磁性石墨烯功能材料，利用磁性固相萃取技术，实现对美托洛尔、布洛芬、吡喹酮等手性药物的富集及与其对映体的直接快速分离、制备，弥补色谱法中存在的手性柱价格昂贵、流动相成本高等不足。主要内容包括：1）研究制备磁性石墨烯纳米粒子，用MOF手性拆分试剂对其功能化，制备MOF-磁性石墨烯功能材料；2）通过对功能材料识别药物分子的条件进行优化，结合LC、CE等手段，对其选择富集性能进行评价，对比石墨烯结构的引入对复合材料富集性能的影响；3）探讨各种热、动力学参数对手性药物对映体的萃取效率的影响，阐明功能材料、对映体结构与富集效能之间的关系；4）采用量子化学计算方法研究MOF-石墨烯复合物与手性药物分子间的相互作用机制，构建其对客体分子特异性识别和富集模型，为发展新型MOF-磁性石墨烯功能材料提供理论和实验依据；5）开展实际新型手性药物的富集萃取分离研究。本项研究旨在发展药物对映体分离制备的新材料、新技术，具有重要的科学与应用价值。

手性化合物尤其是手性药物的分离在药物研究和医药工业发展方面具有重要意义。含有手性中心的药物，其立体异构体通常具有极为相近的理化性质，对映体在生物体内的药理活性、代谢过程、代谢速率及毒性等方面存在显著差异，服用外消旋药物具有极大的潜在危险性。然而发展更高效、快速且经济的手性分离介质和技术，却依然是药物研究和医药工业发展中亟待解决的难题。鉴于此，我们合成了11种手性MOF功能材料，基于多种分析技术，开展了此类功能材料的手性分析应用，特别是手性药物的分离分析研究。. 在该项目的资助下，我们首先合成了4种具有手性识别能力的功能化磁性MOF-石墨烯复合材料，对其进行结构表征，通过对功能材料识别手性药物分子的条件进行优化，利用磁性固相萃取技术，实现对手性甲基苯基亚砜、联萘酚、联糠醛、安息香等手性药物和药物中间体的富集分离，利用材料的可重复使用性能，分别对盐酸普萘洛尔对映异构体进行直接快速分离及制备；采用CCK-8法对拆分后的两种盐酸普萘洛尔光学对映体及盐酸普萘洛尔外消旋体进行肺腺癌细胞A549的毒性检测，根据细胞存活率比较对映异构体的活性差异；用不用的金属源，以客体分子为目标，设计合成了2种新型手性MOF配合物，实现了联糠醛、氨基酸等手性分子的选择性识别；在此基础上，借助固体核磁、XPS等仪器手段和对比实验，进一步通过实验确定了手性MOF材料对氨基酸手性识别机理；以二氧化硅为模板，采用不同的组装策略，合成了3种无机有机杂化材料，结合SPE和HPLC等手段，实现了苯基甲基亚砜、联萘酚、布洛芬、尼莫地平、尼群地平、苹果酸、柳胺苄心定及复杂杂环化合物的手性分离分析；通过原位生长法制备了两种以不同羟基铜盐为模板的巯基功能化的新型MOFs材料DMS-Cu和DMP-Cu，探讨各种热、动力学参数对Hg2+富集效率的影响，结合原子荧光光谱法，实现了水中Hg2+的吸附去除以及大米中痕量总汞的富集分离。上述结果不仅产生了重要的创新性基础研究成果，同时也发展了系列药物对映体分离制备的新材料、新技术，具有重要的科学与应用价值。