衍生化环糊精修饰的纳米金粒子用于开管毛细管电色谱手性药物分离研究

The search for efficient and effective methods for enantioseparation of chiral drugs has always been the focus of chemists. Capillary electrochromatography (CEC), which combines the high efficiency of CE and the high selectivity of HPLC, exhibits great performance in chiral separation and has been extensively used. Open-tubular capillary electrochromatography (OTCEC), an important branch in CEC, provides advantages of ease of preparation, absence of bubble formation, and simple instrumental handling. But in OTCEC, superficial area of the inner face wall is small, and the amount of coating stationary phase is limited, resulting in relatively poor phase ratio and sample separation efficiency. Gold nanoparticles (GNPs) have their special characteristics of large specific surface area, easy formation of active complexes, and controllable particle size with narrow size distribution. They could compensate the lack mentioned above for OTCEC, and widen the application of OTCEC. In this research, GNPs will be modified by cyclodextrin derivatives (CDs), and these functionalized CD-GNPs are subsequently immobilized on capillaries as stationary phase for chiral separation. Enantioseparation systems of various kinds of chiral drugs will be established utilizing these prepared open-tubular capillaries. Then the host-guest interaction mode and inclusion binding site between CDs and chiral drug will be studied by means of spectrum methods and molecular modeling. The possible enantioseparation mechanism at the molecular level will also be discussed. The project will provide theoretical and practical support for establishing new enantioseparation platform of chiral drugs and promote the development of CEC technology.

手性药物分离一直是分析化学家们面临的一个挑战。毛细管电色谱法（CEC）兼具毛细管电泳法（CE）的高分离效能和HPLC的高选择性，是功能强大的手性药物对映体分离技术。开管毛细管电色谱法(OTCEC)是CEC的重要分支，被认为是填充柱的理想替代模式，是当前CEC研究的热点。由于毛细管内表面积小，开管柱可涂布的固定相量少、相比低，致使样品分离效率低，制约了开管柱分离技术的应用和发展。本项目拟利用纳米金比表面积大，容易功能化的特点，采用新设计合成的衍生化环糊精（CDs）为手性选择剂，制备以CDs修饰的纳米金为涂层的开管毛细管电色谱柱。在此基础上，建立多种类型手性药物的对映体分离系统，结合光谱分析法和分子模拟技术判断主客体分子间的作用类型和结合位点，从分子水平上阐明其分离机理。本项目的实施，将推动毛细管电色谱分离技术的发展，提高手性药物对映体分离能力和水平，具有较高的学术意义和应用价值。

毛细管电色谱法（CEC）是毛细管电泳法（CE）的发展方向。而毛细管色谱柱的制备是CEC发展的瓶颈。环糊精及其衍生物(CDs)是CE和HPLC中使用的优良手性选择剂。为解决开管毛细管电色谱柱比表面积小、相比低的缺点，项目利用纳米金（GNPs）比表面积大，容易功能化的特点，制备了8种CDs/ GNPs修饰的开管毛细管电色谱柱：（1）采用化学键合法制备了β-CD/ GNPs修饰的开管柱；（2）采用自组装技术制备了β-CD/ GNPs修饰的开管柱；（3）采用层层组装技术制备了β-CD/ GNPs修饰的开管柱；（4）采用化学键合法制备了β-CD/ GNPs/聚多巴胺修饰的开管柱；（5）采用化学键合法制备了磺酸化-β-CD/ GNPs/聚多巴胺修饰的开管柱；（6）采用化学键合法制备羧甲基-β-CD/GNPs修饰的开管柱。（7）采用静电吸附法制备了β-CD/ GNPs修饰的开管柱；（8）采用溶胶-凝胶法制备了β-CD/GNPs修饰的开管柱。通过考察纳米金的涂布层数、CDs浓度和涂布时间等因素对开管柱制备的影响，优化了制备工艺。利用扫描电镜、红外光谱、核磁共振氢谱等手段对制备的开管柱进行了表征。电渗流的改变也证明了CDs/ GNPs被成功修饰到毛细管内壁。分离结果表明，CDs功能化的开管柱对选择的消旋药物（化合物）具有很好的对映体选择性。证明将GNPs与CDs结合用于开管毛细管电色谱柱的制备，对于增大毛细管的内表面和相比，提高其对映体分离能力，具有重要作用。重复性和稳定性研究结果表明，与静电吸附法和溶胶-凝胶法比较，化学键合法制备的开管柱有更好的重复性和稳定性。因此，化学键合法是目前制备开管柱的首选方法。另外，同样作为β-CD / GNPs修饰的开管柱，制备方法不同，色谱柱的对映体选择性明显不同。鉴于目前还没有商品化的毛细管电色谱柱上市，本项目的研究，对于推动毛细管电色谱分离技术的发展，提高手性药物对映体分离能力和水平，具有较高的学术意义和应用价值。