新型分子表面印迹法对手性药物对映体的高效识别与拆分机理研究

In the highly asymmetric environment of biomass, different enantiomers of chiral drugs inevitably exhibit different biological activity, metabolism, pesticide effect and side effects. Thus the preparation of pure optically chiral drugs through efficient resolution technology has become an urgently solved scientific and technological challenges of medical science and the pharmaceutical industry. Molecularly imprinted polymers are materials with a high degree host-guest recognition capabilities. Levamisole and mandelic acid was chosen as two model chiral drugs in the project. The functional macromolecules of model chiral drugs which have strong intermolecular forces were grafted on the surface of micron-sized silica particles through sophisticated molecules design technology. A single enantiomer molecular surface imprinted materials was obtained by new molecular surface imprinting technique. The chiral cavity was build to achieve the identification and separation of chiral drugs to enantiomers at the molecular configuration level. The identify selective and binding affinity of the single enantiomer molecules surface imprinted materials was investigated. The subject and object recognition mechanism of the surface imprinted materials was explored. The resolution ability of enantiomer molecules surface imprinted materials to the chiral drugs racemic was studied. The relationship between recognition properties and structure of chiral hole was established. The new creation technology of chiral drugs (Molecular Surface Imprinted Solid Phase Extraction Method) was originated in the project.

在生命体内高度不对称的环境中，手性药物的不同对映体必然表现出不同的生物活性、代谢作用、药效及毒副作用，设法通过高效拆分技术获得光学纯的手性药物，已成为医药科学与制药工业迫切需要解决的重大科技难题。分子印迹聚合物是具有高度主客体识别能力的材料。本项目旨在以四咪唑与扁桃酸为两种模型手性药物，通过精细的分子设计，设法将对模型手性药物具有强分子间作用力的功能大分子，接枝于微米级硅胶微粒表面，采用新型分子表面印迹技术，制备单一对映体分子表面印迹材料，构建手性空穴，以期实现在分子构型水平上对手性药物对映体的识别与分离；深入研究单一对映体分子表面印迹材料的识别选择性与结合亲和性；深入探索该表面印迹材料的主客体识别机理；充分考察其对手性药物外消旋体的拆分能力；建立手性空穴结构与识别性能之间关系的理论，最终创立手性药物拆分新技术—分子表面印迹固相萃取法。

本课题主要研究在硅胶表面进行接枝改性制备表面分子印迹聚合物材料。分别以四咪唑L-TM、S-扁桃酸分子、R-扁桃酸分子、S-布洛芬分子为模板分子制备了相应的印迹聚合物，并考察了相关性能，主要工作有以下几部分组成：.一、采用新型分子表面印迹技术，以左旋四咪唑(L-TM)为模板手性药物分子，制得了L-TM分子表面印迹材料，并考查了该印迹材料对外消旋体（D,L-TM）的拆分性能，本研究结果对于提升手性药物的拆分技术水平具有重要的科学意义与价值。.实验结果表明，印迹材料MIP-PMAA/SiO2对L-TM分子具有特异的分子识别选择性与优良的结合亲和性，相对于右旋对映体D-TM，识别选择性系数为4.03， MIP-PMAA/SiO2对外消旋体D,L-TM中的两种对映体表现出优良的拆分性能。 .二、分别在非水介质中和水相介质中成功制得了高性能的S-扁桃酸印迹材料MIP-PMAA/SiO2和MIP-PDMAEMA/SiO2，并考察了两种印迹材料对外消旋扁桃酸的手性识别与拆分性能，研究结果具有一定的应用价值。.研究结果表明，在DMF中，S-扁桃酸表面印迹材料MIP-PMAA/SiO2具有良好的识别选择性和对映体拆分性能：相对于R-扁桃酸，印迹材料MIP-PMAA/SiO2对S-扁桃酸的选择性系数k为4.9；吸附后的上清液中主要含R-扁桃酸，其对映体过量为40%；洗脱液中主要为S-扁桃酸，其光学纯度高达81%。.在水相介质中，S-扁桃酸表面印迹材料MIP-PDMAEMA/SiO2对S-扁桃酸具有特异的识别选择性和对映体拆分性能：相对于R-扁桃酸，印迹材料MIP-PDMAEMA/SiO2对S-扁桃酸的选择性系数为3.9；吸附后所得上清液中主要含R-扁桃酸，其对映体量为44%；洗脱液中主要含S-扁桃酸，其光学纯度为79%。.三、在非水介质中，成功制得了高性能的R-扁桃酸和S-布洛芬分子表面印迹材料，深入考察研究了印迹材料的手性识别与拆分性能，本研究结果在医药学领域具有重要的科学意义和应用价值。.研究结果表明，S-布洛芬表面印迹材料MIP-PHEMA/SiO2对异构体S-布洛芬具有特异的识别与拆分性能：相对于R-布洛芬，印迹材料MIP-PHEMA/SiO2对S-布洛芬的选择性系数为4.99；吸附后的上清液中主要含R-布洛芬，其光学纯度为44%；洗脱液中主要含S-布洛芬，其光学